Cardiovascular Research

Cardiovascular Research 2004 62(1):9-33; doi:10.1016/j.cardiores.2003.12.026
© 2004 by European Society of Cardiology

This Article Abstract FREE Full Text (PDF) E-letters: Submit a response Alert me when this article is cited Alert me when E-letters are posted Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to My Personal Archive Download to citation manager Request Permissions Disclaimer Google Scholar Articles by Tamargo, J. Articles by Delpón, E. Search for Related Content PubMed PubMed Citation Articles by Tamargo, J. Articles by Delpón, E. Social Bookmarking          What's this?

Copyright © 2004, European Society of Cardiology

Pharmacology of cardiac potassium channels

Juan Tamargo^*, Ricardo Caballero, Ricardo Gómez, Carmen Valenzuela and Eva Delpón

Department of Pharmacology, School of Medicine, Universidad Complutense, 28040 Madrid, Spain

^* Corresponding author. Tel.: +34-91-3941472; fax: +34-91-3941470. Email address: jtamargo{at}med.ucm.es

Received 7 August 2003; revised 11 December 2003; accepted 29 December 2003

	Abstract

Top Abstract 1. Introduction 2. K+ channel diversity... 3. Cardiac voltage-gated... 4. Inward rectifying K+... 5. Two pore or... 6. Conclusions and perspectives References

 
Cardiac K⁺ channels are membrane-spanning proteins that allow the passive movement of K⁺ ions across the cell membrane along its electrochemical gradient. They regulate the resting membrane potential, the frequency of pacemaker cells and the shape and duration of the cardiac action potential. Additionally, they have been recognized as potential targets for the actions of neurotransmitters and hormones and class III antiarrhythmic drugs that prolong the action potential duration (APD) and refractoriness and have been found effective to prevent/suppress cardiac arrhythmias. In the human heart, K⁺ channels include voltage-gated channels, such as the rapidly activating and inactivating transient outward current (I_to1), the ultrarapid (I_Kur), rapid (I_Kr) and slow (I_Ks) components of the delayed rectifier current and the inward rectifier current (I_K1), the ligand-gated channels, including the adenosine triphosphate-sensitive (I_KATP) and the acetylcholine-activated (I_KAch) currents and the leak channels. Changes in the expression of K⁺ channels explain the regional variations in the morphology and duration of the cardiac action potential among different cardiac regions and are influenced by heart rate, intracellular signalling pathways, drugs and cardiovascular disorders. A progressive number of cardiac and noncardiac drugs block cardiac K⁺ channels and can cause a marked prolongation of the action potential duration (i.e. an acquired long QT syndrome, LQTS) and a distinct polymorphic ventricular tachycardia termed torsades de pointes. In addition, mutations in the genes encoding I_Kr (KCNH2/KCNE2) and I_Ks (KCNQ1/KCNE1) channels have been identified in some types of the congenital long QT syndrome. This review concentrates on the function, molecular determinants, regulation and, particularly, on the mechanism of action of drugs modulating the K⁺ channels present in the sarcolemma of human cardiac myocytes that contribute to the different phases of the cardiac action potential under physiological and pathological conditions.

KEYWORDS K⁺ channels; Cardiomyocytes; Pharmacology; Cardiac arrhythmias; Antiarrhythmic agents; Torsades de pointes

	1. Introduction

Top Abstract 1. Introduction 2. K+ channel diversity... 3. Cardiac voltage-gated... 4. Inward rectifying K+... 5. Two pore or... 6. Conclusions and perspectives References

 
Cardiac K⁺ channels determine the resting membrane potential, the heart rate, the shape and duration of the action potential and are important targets for the actions of neurotransmitters, hormones, drugs and toxins known to modulate cardiac function [1–3]. Blockers of certain or most K⁺ channels prolong the cardiac action potential duration (APD) and refractoriness without slowing impulse conduction, i.e. they exhibit Class III antiarrhythmic actions, being effective in preventing/suppressing re-entrant arrhythmias. Unfortunately, drugs that delay the repolarization prolong the QT interval of the electrocardiogram and represent a major cause of acquired long QT syndrome (LQTS) [4–6].

Cardiac K⁺ currents can be distinguished on the basis of differences in their functional and pharmacological properties. In mammalian cardiac cells, K⁺ channels can be categorized as voltage-gated (Kv) and ligand-gated channels [1–4]. The first category includes the rapidly activating and inactivating transient outward current (I_to1), the ultrarapid (I_Kur), rapid (I_Kr) and slow (I_Ks) components of the delayed rectifier and the inward rectifier (I_K1), whereas the ligand-gated channels include those activated by a decrease in the intracellular concentration of adenosine triphosphate (K_ATP) or activated by acetylcholine (K_Ach) [1–4]. The configuration and duration of the cardiac action potentials vary considerably among species and different cardiac regions (atria vs. ventricle) and specific areas within those regions (epicardium vs. endocardium). This heterogeneity mainly reflects differences in the type and/or expression patterns of the K⁺ channels that participate in the genesis of the cardiac action potential. Moreover, the expression and properties of K⁺ channels are not static but are influenced by heart rate, neurohumoral state, pharmacological agents, cardiovascular diseases (cardiac hypertrophy and failure, myocardial infarction) and arrhythmias (atrial fibrillation-AF) [1,7–10].

The cardiac action potential reflects a balance between inward and outward currents. Fig. 1 shows the relationship between a cardiac action potential and the time course of individual ionic currents that participate in its genesis. The initial upstroke of the atrial and ventricular cells (phase 0) is due to the activation of the fast inward Na⁺ current (I_Na). Initial rapid repolarization (phase 1) is a consequence of the rapid voltage-dependent inactivation of I_Na and the activation of I_to1 and the I_Kur. During phase 2 inward depolarizing currents through Na⁺ (slowly inactivated) and L-type Ca²⁺ channels (I_CaL) are balanced by the different components of the delayed rectifier K⁺ current (I_Kur, I_Kr and I_Ks). The terminal phase 3 of repolarization is due to the increasing conductance of the I_Kr, I_Ks and I_K1. I_K1 is also responsible for the maintenance of the resting potential.

View larger version (11K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 1 Cardiac action potential (A) and the schematic representation of the major ionic currents (B) contributing to its waveform. The amplitudes of the depolarizing (downward) and repolarizing (upward) currents are not on the same scales. Abbreviations: see text. Modified from Ref. [1].

 
In this review we shall attempt to address (1) the function and molecular basis of cardiac K⁺ channels, (2) the pharmacological modulation and its cellular consequences, and (3) the signaling pathways involved in the regulation of channel function and expression under pathophysiological conditions. This information should provide fundamental understanding of the role of K⁺ channels in modulating cardiac function, in the genesis and maintenance of cardiac arrhythmias and as potential targets of potentially useful therapeutic agents. For more detailed review of structure–function relationship, distribution and pharmacological modulation of K⁺ channels, the reader is referred to recent reviews [11–16].

	2. K+ channel diversity and classification

Top Abstract 1. Introduction 2. K+ channel diversity... 3. Cardiac voltage-gated... 4. Inward rectifying K+... 5. Two pore or... 6. Conclusions and perspectives References

 
K⁺ channels are formed by coassembly of pore-forming -subunits which surround a water-filled pore and accessory β-subunits. Over 80 human K⁺ channel-related genes have been cloned and characterized [1–4,11]. The genes encoding the - and β-subunits of cardiac K⁺ channels are shown in Table 1. Key features of -subunits are: (a) a pore region through which K⁺ ions flow across the plasma membrane, (b) a selectivity filter that allows K⁺ but not other ions to cross the pore, and (c) a gating mechanism that controls switching between open-conducting and closed-nonconducting states and determines whether permeation occurs in response to either changes in membrane potential or a ligand. The recent identification of the atomic structures of several K⁺ channels (KcsA, KvAP and MthK) provides the basis for understanding, at a molecular level, the mechanisms that control ion selectivity and conduction [15]. K⁺ channels have been classified into three major families on the basis of the primary amino acid sequence of the -subunit [1–4,11]:

View this table: [in this window] [in a new window]   Table 1 Genes encoding the and β subunits of cardiac potassium channelsa

 
(1) Channels containing six transmembrane segments and one pore-forming region (Fig. 2A). This architecture is typical of Kv channels, whose members include Shaker-related channels (Kv1–4), ether-a-go-go-related channels (ERG) and KCNQ channels. Immediately after depolarization Kv channels move from the closed to the open state (activation) and then many channels enter into a nonconducting state (inactivation), leading to a decline in activated macroscopic current. When the membrane is repolarized channels recover from the inactivated state and are once again capable of opening in response to membrane depolarization. There are two major types of inactivation [16]. N-type inactivation results from the occlusion of the intracellular mouth of the pore by a "ball and chain" mechanism when the channel opens. C-type inactivation appears to involve a rearrangement of residues in the external mouth of the channel that becomes occluded.

View larger version (37K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 2 Side view of the topology of three classes of K+ channels subunits. (A) Schematic representation of a voltage-gated K channel subunit composed of six membrane-spanning helices (S1 to S6) and one pore. The C-terminal cytoplasmic domain is drawn off to the side of the T1 domain, but its precise relative location is until yet unknown. The schematic representation of single transmembrane spanning proteins, such as minK and minK-related proteins (MiRPs) is also shown. NBD: nucleotid binding domain (B) Schematic representation of the subunit of an inward rectifier K+ channel (Kirs) formed only by two transmembrane domains (M1 and M2) connected by a pore. The topology of the sulfonylurea receptor (SUR) that interacts with Kir6.x subunits is also shown. SUR has been proposed to have three transmembrane domains (TMDO, TMD1A and TMD2), each of which consists of five, five and six membrane spanning regions. (C) Schematic representation of the subunit of "background" channels formed by four transmembrane segments and two pores. SID: self-interacting domain. Abbreviations: see text.

 
Kv channel subunits have six transmembrane-spanning segments (S1–S6) with cytoplasmic N- and C-terminal domains and a pore loop between S5 and S6 bearing the K⁺ selectivity filter signature TxGYG [1,4,11]. The pore region, formed by S5 and S6 segments and the S5–S6 linker, is responsible for K⁺ ion conduction and selectivity. The S4 segment contains positively charged residues (R/K) at approximately every third position and serves as the voltage sensor. Most Kv channels contain a Pro-X-Pro sequence (PXP) that induces a sharp bend in the S6 helices near the activation gate and reduces the inner vestibule of the pore [16]. Kv channels can be formed from four identical -subunits (homomultimers) or from combinations of different -subunits from the same subfamily (heteromultimers). In the Kv1 subfamily, tetramerization appears to be controlled to some extent by the N-terminal intracellular T1 domain (T1) that immediately precedes S1. However, in HERG and KCNQ1 channel subfamilies, C-terminal domains appear to be important for heterotetramerization [13,16].

(2) Inward rectifier K⁺ channels (Kirs) contain two transmembrane domains (M1 and M2) connected by a pore containing the G(Y/F)G sequence and intracellular N- and C-termini (Fig. 2B). This architecture is typical of K₁, K_ATP and K_Ach channels [1–3,17–19]. They conduct K⁺ currents more in the inward direction than the outward and play an important role in setting the resting potential close to the equilibrium potential for K⁺ (E_K, approximately –90 mV for [K⁺]_o=5 mM) and in repolarization [1,11,17–19]. Kir channels form either homo- or heterotetramers.

(3) Four transmembrane segments and two pore channels (K_2P) have intracellular N- and C-termini and exist as homodimers or heterodimers (Fig. 2C) [20–22]. The conventional G(Y/F)G of K⁺-selective motif is preserved in the first pore loop, but it is replaced by G(F/L)G in the second. K_2P currents display little time- or voltage-dependence and I/V curves can be described by the Goldman–Hodgkin–Katz (GHK) equation, thus regulating resting membrane potential and excitability. There are four classes of cardiac K_2P: TASK, TWIK, TREK and THIK.

The diversity of K⁺ currents in native tissues exceeds the number of K⁺ channel genes identified. The explanations for this diversity include alternative splicing of gene products, post-translational modification, heterologous assembly of -subunits within the same family and assembly with accessory β-subunits that modulate channel properties (see below) [1–4,11,23].

2.1. Auxiliary subunits
Recapitulation of the physiological features of the native K⁺ current frequently requires accessory β-subunits. Most Kvβ subunits assemble with -subunits giving rise to an 4β4 complex. K⁺ channel β-subunits represent a diverse molecular group, which includes cytoplasmic proteins (Kvβ1-3, KChIP and KChAP) that interact with the intracellular domains of Kv channels, single transmembrane spanning proteins, such as minK and minK-related proteins (MiRPs) encoded by the KCNE gene family, and large ATP-binding cassette (ABC) transport-related proteins, such as the sulfonylurea receptors (SUR) for the inward rectifiers Kir6.1–6.2 (Fig. 2) [2–4,23–25]. Coexpression of β subunits with -subunits regulates cell surface expression, gating kinetics and drug-sensitivity of K⁺ channels [25,26]. Kvβ1.1–1.3 and Kvβ3.1 have an inactivation domain at the N-terminus similar to the N-terminal inactivation ball of the -subunit and when coassembled can produce a N-type inactivation [26]. Kvβ2.1 and Kvβ4.1 behave as chaperone proteins, promoting proper protein folding and/or subunit coassembly, channel trafficking and cell surface expression of coexpressed subunits [26]. KChIPs are cytosolic Ca²⁺-binding subunits that interact with the N-terminus of the Kv4.3 -subunits and enhance their expression in the cell membrane [24,26]. Coexpression of KChAP with Kv channels also enhances total current density, suggesting a true chaperone function [23].

	3. Cardiac voltage-gated channels

Top Abstract 1. Introduction 2. K+ channel diversity... 3. Cardiac voltage-gated... 4. Inward rectifying K+... 5. Two pore or... 6. Conclusions and perspectives References

 
3.1 The transient outward current, I_to1
I_to is rapidly activated and inactivated in response to depolarization [3,27]. I_to is the sum of a voltage-dependent, 4-aminopyridine (4-AP)-sensitive, calcium-independent K⁺ current (I_to1) and a 4-AP-insensitive, Ca²⁺-activated Cl^– or K⁺ current (I_to2). In human atrial and ventricular myocytes the presence of I_to2 has not been clearly demonstrated, so it will be not discussed further. I_to1 is responsible for early rapid repolarization (phase 1) and determines the height of the early plateau, thus influencing activation of other currents that control repolarization, mainly I_CaL and the delayed rectifier K⁺ currents (I_K). Furthermore, variations in cardiac repolarization associated with I_to1 differences strongly influence intracellular Ca²⁺ transient by modulating Ca²⁺ entry via I_CaL and Na⁺–Ca²⁺ exchange, potentially exacerbating impaired Ca²⁺ cycling in heart disease [28].

I_to1 density is 4- to 6-fold higher in atrial tissue, Purkinje fibers, epicardial and midmyocardial (M) cells than in the endocardial cells [29,30]. In human subendocardial cells I_to1 is lower and recovers more slowly than in epicardial or M cells [29]. In canine right atria, I_to1 density is lower in the appendage than in the crista terminalis, pectinate muscle and AV ring area cells [31]. I_to1 density is higher in the right than in the left canine ventricular M cells [32] and differences in I_to1 density across the ventricular wall are causally linked to the J wave of the ECG [30]. The prominent epicardial I_to1 contributes to the selective electrical depression of the epicardium during ischemia and to the development of a marked dispersion of repolarization between normal and ischemic epicardium and between epicardium and endocardium, thereby providing the substrate for reentrant arrhythmias [33]. Furthermore, flecainide-induced abolition of the action potential dome in epicardial but not in endocardial cells leads to a marked dispersion of repolarization across the ventricular wall that, when accompanied by prominent conduction delays related to Na⁺ channel blockade, results in extrasystolic activity through a phase 2 reentrant mechanisms [34].

3.1.1 Molecular basis of I_to1
Kv4.3 channels are the leading candidate for encoding human I_to1 [35,36]. Kv4.3 mRNA decreases in failing hearts and this reduction correlates with the reduction in I_to1 density, indicating that part of the downregulation of this current may be transcriptionally regulated [3,9,35]. However, Kv1.4 channels possibly represent the I_to1 in the human endocardium [3,29]. Heterologous expression of hKv4.3, Kv1.4 or both does not reproduce the properties of the native I_to1 [3,27,29]. KChIP2, when coexpressed with hKv4.3, increases surface channel density and current amplitude, slows the inactivation, accelerates the recovery from inactivation and shifts the half-maximal inactivation to more positive potentials [23,24]. Thus, features of Kv4.2/KChIP2 currents closely resemble those of I_to1. In human ventricle KChIP2 mRNA is 25-fold more abundant in the epicardium than in the endocardium, and this gradient parallels the gradient in I_to1 expression, while Kv4.3 mRNA is expressed at equal levels across the ventricular wall. Thus, transcriptional regulation of the KChIP2 gene is the primary determinant of I_to1 expression in the ventricular wall [37].

3.1.2 Pharmacology of I_to1
I_to1 is blocked by 4-AP in the mM range in a fashion suggesting a preferential interaction with the closed state [38]. Table 2 shows the blocking potencies, expressed as IC₅₀ values (i.e, concentrations producing 50% inhibition of the current), of several drugs on native I_to1 [38–59]. 4-AP, quinidine and propafenone produce an open channel blockade and accelerate I_to1 inactivation [38]. Quinidine, but not flecainide, propafenone or tedisamil, produces a frequency-dependent block of I_to1 that results from a slow rate of drug dissociation from the channel [38,60]. Ambasilide reduces I_to1 by changing conductance rather than by influencing the gating mechanism [40].

View this table: [in this window] [in a new window]   Table 2 Pharmacological blockade of voltage-gated potassium channels

 
It has been proposed that I_to1 blockers prolong the APD in human atrial myocytes [61] and in ischemic ventricular muscles [62]. However, since the net effects of I_to1 blockade on repolarization may depend on secondary changes in other currents, the reduction of I_to1 density can result in a shortening of the ventricular action potential [27,62,63]. Moreover, heterogeneous ventricular distribution of I_to1 may increase the disparity in the APD and facilitate the initiation or perpetuation of reentrant arrhythmias [64]. Thus, the role of I_to1 in the control of human cardiac repolarization still is unclear.

3.1.3. Pathological role
Heart failure, cardiac hypertrophy and myocardial ischemia and infarction are associated with prolongation of the APD, an effect that has been attributed, in part, to a downregulation of I_to1 [8,9,27]. The decrease in I_to1 in heart failure may be adaptive in the short-term because increased depolarization during the cardiac cycle means that more time is available for excitation–contraction coupling, which mitigates the decrease in cardiac output, but it becomes maladaptive in the long-term, since a prolongation of the APD may contribute to arrhythmogenesis, either by causing inhomogeneous repolarization or by increasing the likelihood of early afterdepolarizations [27]. However, there is also evidence of an up-regulation of I_to1 in hypertrophied cardiac myocytes [9,65] and in cardiac myocytes after induced myocardial infarction [8,66]. It can be speculated that up-regulation of I_to1 may represent a protection mechanism counteracting the excessive prolongation of the APD and Ca²⁺ influx, in order to minimize the incidence of ventricular proarrhythmia. Chronic AF reduces I_to1 density and Kv4.3 mRNA levels [10]. Hypothyroidism reduces the expression of KCND2 (Kv4.2) genes [67].

3.1.4 Regulation of I_to1
The phosphorylation, mediated by protein kinase A (PKA) and C (PKC), alters channel properties by modifying the kinetics and/or the expression of active channels present on the cell surface. Phorbol 12-myristate 13-acetate (PMA), an unspecific activator of serine/threonine and tyrosine protein kinases, suppresses both Kv4.2 and Kv4.3 currents and native I_to1 but not after preincubation with PKC inhibitors (chelerythrine) and staurosporine, a nonspecific inhibitor of serine/threonine protein kinases [68]. PKC increases the inactivation time constants and slows the time course of recovery from inactivation of I_to1. -adrenergic agonists (phenyleprine and methoxamine) reduce I_to1 in rat ventricular myocytes [63], whereas β-adrenergic agonists have no effects on I_to1. Furthermore, phenylephrine and carbachol inhibit Kv4.3 currents only when coexpressed, respectively, with 1-adrenoceptors or M1 receptors and this effect is also prevented by chelerythrine, suggesting that it may be mediated by activation of PKC [68]. In hKv4.1 channels, PMA causes an initial increase followed by a reduction in current amplitude and these effects are prevented by staurosporine or chelerythrine [69]. Angiotensin II inhibits I_to1 in rat ventricular myocytes, an effect prevented by PD123391, a selective antagonist of AT2 receptors. This inhibition is abolished by okadaic acid, an inhibitor of protein phosphatases 1 and 2A, suggesting that the stimulation of AT2 receptors activates the serine–threonine protein phosphatases to reduce I_to1 density [70].

3.2 The delayed rectifier K⁺ currents
In the human heart, I_K can be separated into at least three different components, the ultrarapid (I_Kur), rapid (I_Kr) and slow (I_Ks) components. These currents exhibit different kinetics and pharmacological properties, are regulated by different intracellular signaling pathways and encoded by separate genes [1–4,71–75].

3.2.1 The ultrarapid component of the delayed rectifier K⁺ current, I_Kur
Atrial cells possess a K⁺ current that activates rapidly in the plateau range (<10 ms), displays outward rectification and inactivates very slowly during the time course of the action potential [72,76,77]. I_Kur has been recorded in human atria but not in human ventricular tissue, so that it is the predominant delayed rectifier current responsible for human atrial repolarization [72,77]. I_Kur density is similar in cells isolated from different regions of the canine right atrium [31]. Kv1.5 protein is located at the intercalated disks, a pattern that is disrupted after ischemic damage.

3.2.1.1 Molecular basis of I_Kur
Kv1.5 (613 amino acids) encodes the -subunit of the I_Kur channel (10–14 pS). Heterologous expression of Kv1.5 results in a delayed rectifier current with the biophysical and pharmacological characteristics of I_Kur and exposure to Kv1.5 antisense oligodeoxynucleotides-AsODN specifically inhibits I_Kur density in human atrial myocytes [72,77]. Kv1.5 subunits coassemble with Kvβ1.2 subunits to form the I_Kur in human atrium [26].

3.2.1.2 Pharmacology of I_Kur
I_Kur is relatively insensitive to TEA [76,78], Ba²⁺ and class III antiarrhythmics of the methanesulfonanilide group [39,78], but is highly sensitive to 4-AP [38,76–78]. Selective inhibition of I_Kur by 4-AP prolongs the human atrial APD [77] and the atrial but not the ventricular refractoriness in the dog [84]. The potency of various drugs to block I_Kur and heterologously expressed Kv1.5 channels is summarized in Table 2 [47,58,76–95].

3.2.1.3 State specific block of I_Kur
Antiarrhythmic drugs and local anesthetics are weak bases that predominate in their cationic form at physiological pH. The cationic form enters into the permeation pathway only after channel opening and blocks the current by binding at a site in the internal mouth of the ionic pore. The binding of these drugs is determined by an electrostatic component reflecting the electrical binding distance (about 20% of the transmembrane electrical field) and a hydrophobic component that largely determines the intrinsic stability of the drug–receptor complex, and thus, the affinity (Fig. 3A and B). It has been proposed that most of the critical residues for hydrophobic binding of quinidine in the hKv1.5 channel are aligned on one side of the putative S6, so that it is hypothesized that this region is the pore-lining region and is important in determining drug affinity and specificity [96]. Stereoselective bupivacaine block of hKv1.5 channels is determined by a polar interaction with T507 and two hydrophobic interactions at positions L510 and V514 [97]. The length of the alkyl substituent at position 1 of bupivacaine-related local anesthetics determine their potency and stereoselectivity, possibly because this alkyl chain interacts with a hydrophobic residue (L510) in the S6 of the channel [98]. In contrast, at low concentrations uncharged-neutral (benzocaine [82,99], nifedipine [100], loratadine [89]) and negatively charged drugs (angiotensin II type 1 receptor antagonists [84,86,88]) affect the gating properties of hKv1.5 channels without obvious block (Fig. 3C–E), and, frequently, they increase the current amplitude at voltages at which activation of channels reaches saturation (Fig. 3C) [82,86]. Moreover, these drugs produce a voltage-dependent block, but their voltage-dependence is exactly a mirror image of that observed in the presence of cationic drugs (Fig. 3D) [84,93]. Furthermore, the residues in the S6 segment that determine the binding of quinidine and bupivacaine also determine the binding of neutral and acid drugs (benzocaine [99]) suggesting the existence of a common receptor site at the channel level. Very recently ala-scanning mutagenesis within the pore helix and the S6 segment identifies the residues (T479, T480, V505, I508 and V512) that determine the binding of S0100176, a new selective open I_Kur blocker [101]. The implicated residues face towards the central cavity and overlap with putative binding sites for other blockers and Kv channels, like HERG and KCNQ1, indicating a conservation of drug binding sites among different K⁺ channel families.

View larger version (21K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 3 Effects produced by weak bases (bupivacaine and IQB-9302) and weak acids (losartan) on hKv1.5 channels. (A) Current traces of hKv1.5 currents obtained by applying 250 ms depolarizing pulses from –80 to +60 mV in 10 mV steps in control conditions and in the presence of bupivacaine (20 µM). Tail currents were elicited upon repolarization to –40 mV. (B) Relative hKv1.5 current obtained in the presence and in the absence of bupivacaine and IQB-9302 (20 µM), plotted together with the activation curve (dotted line). At membrane potentials positive to 0 mV, a shallower increase in block was observed. This voltage-dependence was fitted (continuous line) following a Woodhull equation (f=[D]/{[D]+KD*exp(–zFE/RT)}) and yielded -values of 0.20 and 0.17 for bupivacaine and IQB-9302, respectively. Modified from Ref. [83]. (C) Effects of losartan (1 µM) 4 min after beginning the infusion (left) and after steady-state was reached (right). hKv1.5 currents traces were elicited by 500 ms pulses to +60 mV and tail currents upon return to –40 mV. (D) Relative hKv1.5 current obtained in the presence and in the absence of losartan, plotted together with the mean activation curve (dotted line). At membrane potentials positive to 0 mV, a shallower decrease in block was observed. This voltage-dependence was fitted (continuous line) following a Woodhull equation and yielded z-values of –0.27. (E) Effects of losartan on the voltage-dependence of hKv1.5 channels activation. Activation curve in control conditions was fitted with a single Boltzmann component (y=A/{1+exp[(Vh–Vm)/k]}) (continuous line). Dashed line shows that this approach was not optimal for data in the presence of losartan, whereas best fit was obtained with a sum of two Boltzmann components. Modified from Ref. [86].

 
The external mouth of the channel pore formed by the P loop and adjacent S5–S6 segments is the binding site for some drugs [3,12]. Long-chain polyunsaturated fatty acids (arachidonic and docosahexaenoic acids) bind to an external site and block Kv1.5 channels [102] and R(+)-N-methyl-bupivacaine, a membrane-impermeant permanently charged drug, produces different effects on Kv1.5 channels when applied from the intra or the extracellular side of the membrane, thus confirming the existence of an external binding site for bupivacaine-like local anesthetics [103].

3.2.1.4 Clinical consequences of I_Kur block
I_Kur is a promising target for the development of new safer antiarrhythmic drugs to prevent atrial fibrillation and/or flutter without a risk of ventricular proarrhythmia [104]. However, in patients with chronic AF, I_CaL is inhibited which limits the increase in the plateau height produced by I_Kur blockade resulting in a significative lengthening of the atrial APD. However, I_Kur density and Kv1.5 expression are reduced in these patients [10], so that the degree of APD prolongation produced by selective I_Kur blockers under these conditions is unknown. In a rat model, rapid atrial pacing immediately and transiently increases Kv1.5 mRNA levels (Kv4.3 mRNA levels decreased, while mRNA levels of Kv2.1, erg, KCNQ1 and KCNE1 remained unaltered), which might contribute, at least in part, to the rapid shortening of the atrial refractoriness at the onset of AF [105]. If so, selective I_Kur blockers might antagonize the shortening of the atrial APD produced at rapid atrial rates and prevent episodes of paroxysmal AF. Selective I_Kur blockers (NIP-142, S9947, AVE0118, S0100176 and S20951 [GenBank] ) have no effect on the QT interval and markedly prolong left vs. right atrial refractoriness, decrease left atrial vulnerability and reverse AF to sinus rhythm [90,104,106]. Unfortunately, there are few clinical data on the efficacy and safety of these drugs.

3.2.1.5 Regulation of I_Kur
Membrane depolarization and elevated [K⁺]_o, reduce Kv1.5 expression, while dexamethasone increases ventricular Kv1.5 mRNA [72]. Cyclic adenosine 3',5'-monophosphate (cAMP), mechanical stretch and hyperthyroidism increase, whereas extracellular acidosis, phenylephrine, and hypothyroidism decrease Kv1.5 expression [67,72,107]. Kv1.5 mRNA levels decrease in hypertensive hypertrophied rat ventricle [108] and in the epicardial border zone of the infarcted canine ventricle [8].

hKv1.5 has one consensus site for phosphorylation by PKC located on the extracellular S4–S5 linker and 4 consensus sites for PKA located in the N- and C-terminal domains. Isoproterenol increases I_Kur in human atrial myocytes and this effect is mimicked by direct stimulation of adenylate cyclase and suppressed by a PKA inhibitor peptide [109]. In the presence of propranolol, phenylephrine inhibits I_Kur, an effect that is prevented by the PKC inhibitor bisindolylmaleimide. These results indicate that β-adrenergic stimulation enhances, whereas -adrenergic stimulation inhibits I_Kur and suggest that these actions are mediated by PKA and PKC, respectively.

Coexpression of Kv1.5 channels and human thrombin or rat 5-HT1c receptors, two receptors that increase phospholipase C (PLC) activity, inhibits Kv1.5 current amplitude without altering the kinetics or voltage sensitivity of activation [110]. Simultaneous injection of inositol 1,4,5-trisphosphate and superfusion of PMA reproduces the modulation of the Kv1.5 current suggesting that these receptors can modulate Kv1.5 channels by increasing PLC activity [110]. The hKv1.5 channel can associate via its N-terminus-located proline-rich sequences with the SH3 domain of the Src tyrosine kinase [111] and coexpression of Kv1.5 with v-Src leads to tyrosine phosphorylation of the channel and inhibition of the current.

Coexpression of Kvβ1.3 with Kv1.5 induces a fast inactivation and a hyperpolarizing shift in the activation curve, i.e. Kvβ1.3 subunit converts Kv1.5 from a delayed rectifier with a modest degree of slow inactivation to a channel with both fast and slow components of inactivation [26]. These effects do not occur when Kv1.5 is coexpressed with either Kvβ1.2 or Kvβ1.3 lacking the N-terminus, after removal of a consensus PKA phosphorylation site on the Kvβ1.3 N-terminus (S24) or following preincubation with calphostin C, a PKC inhibitor [26]. Moreover, okadaic acid blunts the effects of calphostin as predicted if protein dephosphorylation be required to remove the β-induced inactivation. These data suggest that Kvβ1.2 and Kvβ1.3 subunit modification of Kv1.5 currents require phosphorylation by PKC or a related kinase. PMA has minimal effect on Kv1.5 channels, but markedly reduces Kv1.5/Kvβ1.2 currents and this effect is inhibited by chelerythrine, indicating that Kvβ1.2 enhances the response of Kv1.5 to PKC activation [112]. Kv1.5/Kvβ1.3 channels are less sensitive to quinidine- and bupivacaine-induced block than homomeric Kv1.5 channels [113]. These results suggest that the Kvβ1.3 subunit markedly reduce the affinity of these drugs for their internal receptor site in hKv1.5 channels.

3.2.2 The rapidly activating component of the delayed rectifier K⁺ current, I_Kr
I_Kr is characterized by rapid activation at –30 mV, rapid inactivation and strong inward rectification at positive potentials which is due to rapid voltage-dependent C-type inactivation [16,71,73]. Inward rectification results from the fact that channel inactivation develops faster than channel activation at positive potentials and limits the amount of time that channels spend in the open state [73,114]. On repolarization the rate of recovery from inactivation through the open state is much more rapid than deactivation, which at voltages negative to 0 mV results in a large outward current and promotes phase 3 of repolarization. Thus, I_Kr plays an important role in governing the cardiac APD and refractoriness.

I_Kr has been identified in human atrial and ventricular myocytes, rabbit sinoatrial (SA) and atrioventricular (AV) nodal cells and Purkinje cells [3,14]. In rabbit SA myocytes HERG channels play an important role in the pacemaker activity and I_Kr blockers decrease the maximum rate of diastolic depolarization [115]. In rats I_Kr density is higher in atria than in ventricles, while in humans HERG expression is higher in the ventricles [116]. In canine atria I_Kr density is larger in the AV ring region and the left atrial wall than in crista terminalis, pectinate muscles, appendage cells and right atrial wall, which may account for the shorter APD of the left atria [14,31]. However, in the canine ventricle I_Kr is distributed homogeneously [117], while in guinea pig left ventricle, I_Kr is smaller in subendocardial than in midmyocardial or epicardial myocytes [118]. In rabbit left ventricle, I_Kr is greater in the apex than in the basal regions and I_Kr blockers cause more significant APD prolongation in the apex than in the base, increasing the regional dispersion of APD [119].

3.2.2.1. Channel gating
The S4–S5 linker and the C-terminal half of the S6 are crucial components of the activation gate and point mutations at these regions have marked effects on the voltage-dependence and kinetics of channel activation and deactivation [73,74]. The N-termini of HERG is involved in the slow deactivation process and some mutations in this region linked with type 2 (LQT2) of the Romano–Ward variant of the congenital long QT syndrome (cLQTS) reduce outward currents through the HERG channel by accelerating channel deactivation [74]. Deletion of amino acids 2 to 354 or 2 to 373 markedly increase HERG deactivation rates [73]. HERG channels also contain a PAS (Per–Arnt–Sim) domain on their cytoplasmic N-terminus that may interact with other regions of HERG such as the S4–S5 linker to affect channel deactivation [73,74,114]. C-type inactivation of HERG channels is slowed by extracellular TEA and elevated [K⁺]_o and can be removed by mutations in the outer mouth of the pore or the N-terminal half of S6 [73,74]. It involves a rearrangement of the outer pore region of the channel that either constricts the pore and prevents ion fluxes, or alters the ion selectivity in such a way that the channel cannot conduct K⁺ currents.

3.2.2.2 Molecular basis of I_Kr
HERG -subunits (1159 amino acids) encoded by the KCNH2 gene coassemble to form heterotetrameric channels [120]. However, native I_Kr and HERG channels expressed in heterologous systems differ in terms of gating, regulation by external K⁺ and single channel conductance [73,74]. These findings suggest the presence of a modulating subunit that co-assembles with HERG in order to reconstitute native I_Kr currents. A likely candidate is MiRP1 (123 amino acids) encoded by the KCNE2 gene. When coexpressed with HERG, KCNE2 shifts the HERG activation curve in the positive direction, accelerates the rate of deactivation, decreases single channel conductance (from 13 to 8 pS) and mediates the direct stimulatory effect of cAMP on HERG/KCNE2 channels [120,121]. KCNE2 reduces channel sensitivity to [K⁺]_o and enhances sensitivity to clarithromycin [120] but not to dofetilide, E-4031 or quinidine [122]. KCNE2 can also modulate KCNQ1, Kv4.2 and even the distinctly related hyperpolarization-activated cation (HCN) pacemaker channels [74]. HERG can coassemble with other β-subunits like minK encoded by KCNE1 gene (Table 1). Treating AT-1 cells with AsODNs against KCNE1 reduces I_Kr amplitude [123] and when HERG and KCNE1 are coexpressed in HEK293 cells, the HERG current amplitude increases.

KCNH2 and KCNE2 have been identified as the loci of mutations associated with LQT2 and LQT6 of the Romano–Ward variant of cLQTS, respectively [4,124,125]. The cLQTS is a complex disease characterized by marked QT-interval prolongation and polymorphic ventricular tachycardias called torsades de pointes (TdP), causing syncope, seizures and sudden death [4,6,124,125]. More than 100 mutations in the KCNH2 gene have been described, including frameshifts, insertions, deletions and missense and nonsense mutations [124–127]. Mutant channels cause a net reduction in outward K⁺ current during repolarization that can result from different mechanisms, including generation of nonfunctional channels, altered channel gating and abnormal protein trafficking.

3.2.2.3 Pharmacology of I_Kr
I_Kr is the target of class III antiarrhythmic drugs of the methanesulfonanilide group (almokalant, dofetilide, D-sotalol, E-4031, ibutilide, and MK-499) (Table 2). These drugs produce a voltage- and use-dependent block, shorten open times in a manner consistent with open-channel block and exhibit low affinity for closed and inactivated states [73,74,128,129]. Drugs that block both native I_Kr and heterologously expressed HERG channels are shown in Table 2 [6,12,71,122,123,129–158] and in Fig. 4A and B. I_Kr blockers prolong atrial and ventricular APD (QT prolongation) and refractoriness in the absence of significant changes in conduction velocity (AH, HV and PR intervals) [159]. In animal models, I_Kr blockers suppress ventricular tachycardia induced by programmed electrical stimulation or a new ischemic insult in dogs with prior infarct [159,160]. However, these drugs are probably not effective against triggered activity or increased automaticity [159].

View larger version (23K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 4 Effects produced by propafenone (a weak base) and by candesartan (weak acid) on HERG channels. (A) HERG current traces obtained by applying 5 s pulses from –80 to +60 mV in 10 mV steps in control conditions and with 2 µM propafenone. Tail currents were elicited upon return to –60 mV (B) Relative current as a function of the membrane potential. Block increases in the range of membrane potentials that coincides with the activation of HERG channels. At membrane potentials positive to 0 mV, a shallower increase in block was observed. This voltage-dependence was fitted following a Woodhull equation and yielded -values of 0.09. Modified from Ref. [153]. (C) HERG current traces obtained with the voltage protocol illustrated at top for control conditions and with candesartan. (D) Current–voltage relationships (5 s isochronal) of HERG channels recorded in the absence and in the presence of candesartan (0.1 µM). (E) Effects of candesartan on the voltage-dependence of HERG channels activation. Activation curves in the absence and in the presence of drug were fitted with a single Boltzmann component. Squares represent the fractional block (f=IDRUG/ICON) from data obtained in the presence and in the absence of candesartan. In panels D and E, *P<0.05 vs. control. Modified from Ref. [84].

 
Some LQT2-causing HERG mutations give rise to defects in channel trafficking resulting from improper protein folding and/or incorrect molecular assembly in the sarcoplasmic reticulum and/or Golgi apparatus, resulting in their retention and degradation by quality control machinery. Trafficking of some mutant channels (N470D, G601S) into the sarcolemma can be restored by HERG channel blockers (i.e. cisapride, terfenadine, astemizole, E-4031) [73,126,127], even when fexofenadine rescues mutant HERG channels at concentrations that do not cause channel block [127]. However, since I_Kr blockers failed to rescue other trafficking-defective mutants, it is evident that multiple mechanisms may exist for pharmacological rescue of LQT2 mutations [127]. Moreover, some drugs (almokalant [12], norpropoxyphene [161], azimilide [162], candesartan (Fig. 4C–E) [84] and E3174, the active metabolite of losartan [86]) can exhibit an "agonist" I_Kr action at low concentrations. Flufenamic acid and niflumic acid also increase HERG currents by accelerating channel opening [163]. These results open the possibility of developing new I_Kr openers for the treatment of patients with congenital (LQT2) or drug-induced LQTS. Lysophosphatidylcholine increases HERG currents, an effect that may contribute to K⁺ loss in the ischemic heart [164].

An increasing number of drugs with diverse chemical structures block I_Kr, delay ventricular repolarization, prolong the QT interval (acquired LQTS) and induce TdP (for review see Refs. [5,6,165,166]). Thus, it is important to understand the molecular determinants of drug binding to HERG channels as well as the consequences of drug action to develop safer and more effective drugs.

3.2.2.4 Structural basis of I_Kr/HERG blockade
Most I_Kr blockers gain access to a binding site from the intracellular side of the membrane and require channel opening before they can gain access to a high affinity binding site located inside the channel vestibule [73,74]. Once inside the pore, I_Kr blockers bind within the central cavity of the channel between the selectivity filter and the activation gate and can be trapped in the inner vestibule by closure of the activation gate when the channel deactivates during repolarization [167]. If a drug is charged and appropriately sized, then block is nearly irreversible as long as channels are not reopened even at negative potentials. However, the drug-trapping hypothesis predicts that unbinding and exit from the channel vestibule of a positively charged drug should be favored by membrane hyperpolarization if not impeded by the closed gate. Indeed, using a mutant HERG channel (D540K) that opens in response to hyperpolarization, it was found that channel reopening allows recovery from block by MK-499 [177].

The finding that drugs with such different chemical structures and sizes block I_Kr can be interpreted through two unique structural features of the HERG channel: (a) the lack of the PXP motif in the S6 segment (Fig. 2A) that makes larger volume of the inner vestibule of the channel pore thus increasing easy drug entry. Kv1–4 channels contain the PXP sequence that is believed to induce a sharp bend in the inner S6 helices of Kv channels [16] reducing the inner vestibule and precluding the trapping of large molecules like MK-499. (b) The presence of two aromatic residues (Y652, F656) located in the S6 domain facing the channel vestibule, that establishes specific interactions with aromatic moieties of several drugs by electron stacking [129]. Alanine mutagenesis of both residues drastically reduces the potency of channel block by MK-499, dofetilide, quinidine, cisapride, terfenadine or chloroquine [129,136,168]. Mutations that result in loss of inactivation (S631A, G628C/S631C) reduce the affinity of methanesulfonanilides, while mutations that increase inactivation (T432S, A443S, A453S) enhance the blocking potency of dofetilide [74,169]. It has been hypothesized that the reduced affinity of noninactivating HERG mutant channels is not due to inactivation per se but to inactivation gating-associated reorientation of residues Y652 and F656 in the S6 domain that comprise a high-affinity binding site [168].

Very recently, the selective serotonin reuptake inhibitor fluvoxamine has been shown to exhibit HERG channel blocking properties that are different from those previously described. In fact, the S6 mutations, Y652A and F656A, and the pore helix mutant S631A only partially attenuate the fluvoxamine-induced blockade at concentrations causing profound inhibition of wild-type HERG channels [144]. Moreover, this blockade resembles that produced by canrenoic acid (CA), the main metabolite of spironolactone, on HERG channels expressed in CHO cells [135]. Fluvoxamine- and CA-induced HERG block is far more rapid (occurring within 10 msec) than that produced by the more potent methanesulfonanilides, suggesting that they exhibit either a closed-state block or extremely rapidly developing open channel blockade. Furthermore, channel inactivation was not a prerequisite for fluvoxamine- and CA-induced block.

3.2.2.5 Clinical consequences of I_Kr block
I_Kr blockers prolong atrial and ventricular APD and the QT interval and may cause TdP that can degenerate into ventricular fibrillation and sudden cardiac death. Proarrhythmia induced by I_Kr blockers is related to [4,5,165,166]: (a) excessive prolongation of APD near plateau voltages which favor the development of early after-depolarizations and (b) a more marked prolongation of the APD in M-cells than in subepicardial or subendocardial ventricular muscle possibly because of the relative scarcity of I_Ks in M cells [117]. Thus, triggered focal activity and ventricular reentry associated to an increased inhomogeneity of repolarization across the ventricular wall would lead to the development of TdP. The incidence of TdP increases in the presence of hypokalemia, slow heart rates (recent conversion from AF), QT prolonging drugs, pre-existing cardiac diseases (hypertrophy, myocardial infarction), female gender or baseline QTc interval >0.46 s [4–6].

Unlike most other K⁺ currents, I_Kr amplitude increases upon elevation of [K⁺]_o and decreases after removal of extracellular K⁺ [73,74]. Elevation of [K⁺]_o reduces C-type inactivation and increases the single channel conductance of HERG channels [154]. This explains why the APD are shorter at higher [K⁺]_o and longer at low [K⁺]_o and the association between hypokalemia, APD prolongation and induction of TdP in patients treated with I_Kr blockers. On the contrary, modest elevations of [K⁺]_o using K⁺ supplements and spironolactone in patients given I_Kr blockers or with LQT2 significantly shortens the QT interval and may prevent TdP [170]. Moreover, the antiarrhythmic actions of I_Kr blockers can be reversed during ischemia, which is frequently accompanied by elevations of the [K⁺]_o in the narrow intercellular spaces and by catecholamine surges that occur with exercise or other activities associated with fast heart rates [159,160].

Unfortunately, the prolongation of the APD produced by I_Kr blockers is more marked at normal resting potentials and slow heart rates, while at depolarized potentials or during tachycardia this prolongation is much less marked or even absent [5,159,160]. This reverse use-dependence limits antiarrhythmic efficacy, while maximizing the risk of TdP associated with bradycardia-dependent early afterdepolarizations. In guinea pigs, reverse use-dependence is attributed to a progressive I_Ks accumulation as the heart rate increased (due to the incomplete deactivation of this current), which shortens the APD and offsets the APD prolongation produced by the I_Kr blocker [73]. Another explanation is that I_Kr block itself is reverse use-dependent, this property being promoted by KCNE2 coexpression [120].

All these disadvantages, together with the finding that inherited mutations of KCNH2 and KCNE2 genes are linked to LQT2 and LQT6 forms of the Romano–Ward syndrome, have decreased the initial interest for developing selective I_Kr blockers.

3.2.2.6 Regulation of I_Kr
HERG channels presents four cAMP-dependent PKA phosphorylation sites and a cyclic nucleotide binding domain (CNBD) in the C-terminal and can be modulated via the cAMP-PKA phosphorylation pathway [121,171]. Activation of β-adrenergic receptors and elevation of intracellular cAMP levels regulate HERG channels both through PKA-mediated effects and by direct interaction with the protein [121]. PKA activation reduces HERG current amplitude and induces a depolarizing shift in the voltage-dependent activation curve [121,171]. This shift is inhibited by specific PKA inhibitors (H89, KT5720) and in channels missing all PKA phosphorylation sites (S283A, S890A, T895A, S1137A), while coexpression of HERG with KCNE1 or KCNE2 accentuates the cAMP-induced voltage shift [121]. The net result of these effects is a reduction in HERG current. However, isoproterenol increases I_Kr in guinea pig ventricular myocytes, an effect that was inhibited by bisindolylmaleimide [171]. In rabbit SA cells isoproterenol increases I_Kr and this effect is inhibited by H89, but not by bisindolylmaleimide [172]. These results suggest that regulation of I_Kr may be species- and tissue-specific and may also depend strongly on the experimental conditions.

HERG channels are modulated by PKC independently of direct phosphorylation of the channel [173]. PMA causes a positive shift of activation and reduces I_Kr and its effects can still be observed when the PKC-dependent phosphorylation sites are deleted by mutagenesis. Changes in phosphatidyl 4,5-biphosphate (PIP₂) levels result from activation of several adrenergic and muscarinic receptors. PIP₂ increases HERG current and shifts the voltage-dependence of activation in a hyperpolarizing direction [174]. Moreover, in cells coexpressing the _1A-receptor and HERG, phenylephrine reduces HERG currents and this effect is prevented by PIP₂ but not by PKC inhibition, suggesting that the mechanism is due to G-protein-coupled receptor stimulation of PLC resulting in the consumption of endogenous PIP₂. Since there are several polycationic segments in the cytoplasmic C-terminus of HERG, it is possible that an electrostatic interaction between the negatively charged phosphate groups of PIP₂ and positively charged amino acids in the channel protein can maintain the channel in an open state [174]. In human ventricular myocytes, endothelin-1 inhibits I_Kr, but fails to modify I_to1 and I_K1 [175].

3.2.2.7. Pathological role
I_Kr and HERG currents are unchanged in patients with chronic AF [10] and homogeneously distributed in failing canine hearts [176]. ATP, derived from either glycolysis or oxidative phosphorylation, is critical for HERG function. Both hyper- and hypoglycemia inhibit HERG currents and can cause QT prolongation and ventricular arrhythmias [177]. I_Kr density and HERG mRNA levels are reduced in myocytes from infarcted canine ventricle [178]. However, I_Kr density increases in subendocardial Purkinje cells from the 48 h infarcted heart [8], an effect that may increase the proarrhythmic effects of I_Kr blockers in patients with myocardial infarction.

3.2.3 The slowly activating component of the delayed rectifier K⁺ current, I_Ks
I_Ks is slowly activated at potentials positive to –30 mV with a linear current–voltage relationship, reaching half-maximum activation at +20 mV [71,74,179]. Thus, I_Ks contributes to human atrial and ventricular repolarization, particularly during action potentials of long duration and is a dominant determinant of the physiological heart rate-dependent shortening of APD. As heart rate increases, I_Ks channels have less time to deactivate, leading to an accumulation of open channels and a faster rate of repolarization [152,180]. In guinea pigs, the slow deactivation of I_Ks results in a reduction of outward current that contributes to the slow diastolic depolarization of SA node cells [179].

In guinea pigs, I_Ks density is greater in atrial than in ventricular myocytes and in subepicardial and M cells than in subendocardial cells [118], but is smaller in apical than in basal myocytes of the rabbit left ventricle [119]. There are no differences in I_Ks density among cells from different regions of the canine right atria [31], while in the canine ventricle, I_Ks density is higher in epicardial and endocardial cells than in the M cells [117] and in right than in left ventricular M cells [32]. The smaller I_Ks density in M cells may explain their steeper APD-rate relations and their greater tendency to display pronounced action potential prolongation and to develop early afterdepolarization at slow heart rates or in response to QT prolonging drugs [117]. I_Ks density is downregulated in all layers of the left ventricle of failing canine hearts [176] and a decrease in I_Ks and KCNQ1/KCNE1 mRNA levels is found in myocytes from infarcted canine ventricle [178].

3.2.3.1 Molecular basis of I_Ks
I_Ks is generated by the coassembly of four pore-forming KCNQ1 (676 amino acids) and two accessory KCNE1 β-subunits [181]. KCNE1 (129 amino acids) exhibits a single transmembrane spanning domain; the N-terminus is extracellular and the C-terminus intracellular. Heterologous expression of KCNQ1 produces rapidly activating, slowly deactivating currents, while KCNE1, by itself, does not form functional channels. Coexpression of KCNQ1/KCNE1 slows activation and deactivation kinetics, shifts the voltage dependence of channel activation to more positive potentials and increases the macroscopic current amplitude, thus reproducing the biophysical properties of the native cardiac I_Ks [182]. Additionally, KCNE1 confers regulation of I_Ks by PKC and alters the pharmacology of KCNQ1 [74,183].

KCNE1 is abundant in the SA node, but less abundant although homogeneously distributed throughout the ventricular wall and in the mouse heart expression is largely restricted to the conducting system. An alternatively spliced variant of KCNQ1 with a N-terminal deletion that produces a negative suppression of KCNQ1 is preferentially expressed in the M cells, which is consistent with the lower I_Ks density in this region [184]. Transgenic mice overexpressing this spliced variant present abnormalities of SA and AV function, which suggests a role of KCNQ1 in normal automaticity [185]. KCNQ1 and KCNE1 expression and I_Ks density increases in ventricular myocytes from hypothyroid rats, but decreases in hyperthyroidism [67] and in myocytes from infarcted canine ventricle [178]. Mutations in KCNQ1 and KCNE1 are associated with types 1 (LQT1) and 5 (LQT5) of the Romano–Ward variant of the cLQTS, respectively, and the Jervell–Lange–Nielsen syndrome associated with deafness arises in children who inherited abnormal KCNQ1 or KCNE1 alleles from both parents [124,186].

3.2.3.2 Pharmacology of I_Ks and cellular consequences of I_Ks channel blockade
I_Ks is resistant to methanesulfonanilides, but selectively blocked by chromanols (293B, HMR-1556) [46,49,187], indapamide [188], thiopentone, propofol [189] and benzodiazepines (L-768,673, L-735,821 or L-7) [190,191]. The open channel block produced by chromanols is enantioselective, (–)3R,4S-293B and (–)3R,4S-HMR 1556 being potent I_Ks blockers [192,193]. Table 2 summarizes the potency of various drugs to block I_Ks and heterologously expressed KCNQ1/KCNE1 channels [44,130,133,139,190–195].

Initially, I_Ks was considered an attractive target for class III antiarrhythmic drugs [159]. Because I_Ks accumulates at fast driving rates due to its slow deactivation, I_Ks blockers may be expected to be more effective in prolonging APD at fast rates [180]. Indeed, in human ventricular myocytes, 293B prolongs APD and refractoriness in a frequency-independent manner, so that it is proposed that I_Ks blockade might have less proarrhythmic potency as compared to I_Kr blockers [46]. Furthermore, because I_Ks activation occurs at around 0 mV and this voltage is more positive than the Purkinje fiber action potential plateau voltage, I_Ks block should not be expected to prolong the APD at this level. Conversely, in ventricular muscle, the plateau voltage is more positive (+20 mV) allowing I_Ks to be substantially more activated, so that I_Ks block would be expected to increase APD markedly. The net result of both effects might be less drug-induced dispersion in repolarization and reduced risk of arrhythmogenesis [196].

I_Ks blockers prolong the cardiac APD and QT interval and suppress electrically induced ventricular tachyarrhythmias in animals with acute coronary ischemia and exercise superimposed on a healed myocardial infarction [49,159,187]. This QT prolongation can be accentuated by β-adrenergic stimulation. In arterially perfused canine left ventricle, 293B prolongs the ventricular APD and the QT interval, but does not induce TdP. However, in the presence of 293B, isoproterenol abbreviates the APD of epicardial and endocardial, but not in the M cells, accentuates transmural dispersion of repolarization and induces TdP [197]. These results explain the therapeutic actions of β-adrenergic blockers in patients with LQT1 and LQT5 and the increased risk of fatal cardiac arrhythmias under physical activity or stressful situations that increase sympathetic activity in these patients [124,125,198].

Furthermore, under normal conditions 293B and L-7 minimally prolong the APD regardless of pacing frequency in dog ventricular muscles and Purkinje fibers, probably because other K⁺ currents may provide sufficient repolarizing reserve [190]. However, when the repolarizing reserve is decreased by QT prolonging drugs (I_Kr or I_K1 blockers), remodeling (heart failure, cardiac hypertrophy) or inherited disorders, I_Ks blockade can produce a marked prolongation of the ventricular APD, an enhanced dispersion of repolarization and TdP arrhythmias [196,199]. Moreover, I_Ks or I_K1 inhibition results in an increased reverse use-dependence in the presence of an I_Kr blocker [199]. These findings suggest that drugs that block several K⁺ channels are probably more hazardous than specific channel blockers. Thus, as occurred with I_Kr blockers, the characteristics of the I_Ks blockade together with the finding of an association between mutations in KCNQ1 and KCNE1 genes and LQT1 and LQT5 [124,125] lowers the initial interest for the I_Ks blockers as class III antiarrhytmic drugs.

3.2.3.3 KCNE1 modifies the pharmacology of I_Ks
KCNE1 modulates the effects of I_Ks blockers and agonists. In fact, KCNQ1/KCNE1 channels have 6–100 fold higher affinity for I_Ks blockers (293B, HMR-1556, XE991) than KCNQ1 channels [200,201] and the racemate and the enantiomers of 293B and HMR 1556 have different effects on I_Ks and KCNQ1 channels expressed in Xenopus oocytes [49,193,200]. Mutations in two residues located in the pore loop and the S5 segment of the KCNQ1 channel (G272, V307) strongly decrease 293B sensitivity, which suggests that KCNE1 does not directly take part in chromanol binding but acts allosterically to facilitate drug binding to KCNQ1 subunit. Moreover, the I_Ks activators mefenamic acid and DIDS have little effect on KCNQ1 channels, although they dramatically enhance KCNQ1/KCNE1 currents [200] and KCNE1 subunits are also responsible for the increase in I_Ks produced by docosahexaenoic, oleic and lauric acids [202].

L-364373 (L3) increases I_Ks and KCNQ1 currents and shortens the APD in guinea pig ventricular myocytes [203]. This effect is stereospecific, as S-L3 blocks I_Ks. Moreover, R-L3 attenuates the prolongation of the APD and suppresses the early afterdepolarizations in dofetilide-treated and in hypertrophied rabbit ventricular myocytes [204]. However, R-L3 does not affect KCNQ1/KCNE1 channels, which indicates that KCNE1 interferes with the binding of R-L3 or prevents its action once bound to KCNQ1 subunits [203]. Thus, specific I_Ks agonists may represent a new strategy to suppress arrhythmias resulting from excessive AP prolongation in patients with certain forms of LQTS or cardiac hypertrophy and failure.

3.2.3.4 Structural basis of I_Ks blockade
In chimeric constructs of KCNQ1 and KCNQ2 (insensitive to I_Ks blockers) expressed in Xenopus oocytes, the molecular determinants of channel block induced by 293B and L-7 are located in the pore loop (T312) and the S6 domain (I337, F339, F340 and A344) [191]. Mefenamic acid and DIDS bind to an extracellular N-terminal segment on KCNE1 [200] and restore I_Ks channel gating in otherwise inactive KCNE1 C-terminal mutants, including the LQT5 mutant D76N [205]. It has been proposed that KCNE1 acts as an allosteric regulator of channel gating and permeation, so that in KCNE1 C-terminal mutants the conformational equilibrium is shifted towards an inactivable closed state (i.e. a dominant negative phenotype) and DIDS and mefenamic acid bind to N-terminal residues and shift the equilibrium towards an activable closed state, leading to the functional recovery of wild-type I_Ks phenotype [163]. These results provide interesting clues for the design of new antiarrhythmic therapies for restoring functional defects responsible for the LQT5.

3.2.3.5 Regulation of I_Ks
Lowering [K⁺]_o and [Ca²⁺] _o increase I_Ks [74,179]. Stimulation of PKA by cAMP, phosphodiesterase inhibitors and β-adrenergic agonists increases I_Ks density and produces a rate-dependent shortening of the APD [206,207]. The KCNQ1/KCNE1 channel forms a macromolecular signaling complex that is coordinated by the binding of the targeting protein yotiao to a leucine zipper motif in the C-terminus of KCNQ1. Yotiao is a scaffold protein which binds and recruits PKA and protein phosphatase 1 to the channel microdomain and regulates it via a phosphorylation of a residue (S27) located in the N-terminal [207]. Disruption of the leucine zipper domain of KCNQ1 and the mutation S27A prevent cAMP-dependent up-regulation of I_Ks, whereas in the absence of yotiao, KCNQ1/KCNE1 currents are not increased by intracellular cAMP. Phosphorylation of the KCNQ1 subunit by PKA blunts quinidine- and 293B-induced block, probably by inducing a change in the KCNQ1 conformation that modifies the drug access to the blocking site [208]. Thus, β-adrenergic stimulation, itself a potent proarrhythmic stimulus, may also decrease the antiarrhythmic effects of I_Ks blockers. PKC modulation of I_Ks current is complex, suggesting that there are two functionally distinct PKC sites on KCNQ1–KCNE1 channels [206]. Moreover, premodulation by PKC prevents I_Ks modulation by PKA, and PKC has no effect on I_Ks current after potentiation by PKA. These data indicate that I_Ks is modulated by PKC and PKA in a mutually exclusive manner and suggest that multiple interacting phosphorylation sites are involved. Endothelin-1 inhibits the I_Ks enhanced by isoproterenol and forskolin and prolongs APD duration via the ET_A receptor pertussis toxin (PTX)-sensitive G protein/PKA pathway [209].

	4. Inward rectifying K+ channels

Top Abstract 1. Introduction 2. K+ channel diversity... 3. Cardiac voltage-gated... 4. Inward rectifying K+... 5. Two pore or... 6. Conclusions and perspectives References

 
4.1 The inward rectifier K⁺ current, I_K1
I_K1 is a strong rectifier that passes K⁺ currents over a limited range of membrane potentials [17]. At negative membrane potentials I_K1 conductance is much larger than that of any other current, and so it clamps the resting membrane potential close to the E_K. Upon depolarization, I_K1 channels close almost immediately, remain closed throughout the plateau and open again at potentials negative to –20 mV. Thus, I_K1 contributes to terminal phase 3 of repolarization. I_K1 density is higher in ventricular than in atrial myocytes, but is similar in epicardial, M and endocardial cells in canine and guinea pig hearts [14]. I_K1 is downregulated in endocardial, epicardial and M cells of heart failure canine hearts [176]. I_K1 density is very low in SA and AV pacemaker cells and, therefore, the maximum diastolic potential is more depolarized than in atrial and ventricular muscle cells [14].

4.1.1 Molecular basis of I_K1
Kir2.1 subunits (427 amino acids) encoded by the KCNJ2 gene, coassemble to form tetrameric channels [17]. Several I_K1 channels with conductances of 9, 21, 35 and 41 pS are recorded in human atrial myocytes [210]. Likewise, different gene families (Kir2.1–2.3) have been found in human heart encoding I_K1 [17]. Kir2.1 overexpression increases I_K1 density, shortens the APD and hyperpolarizes the resting membrane potential in guinea pig myocytes, while genetic suppression of I_K1 results in opposite changes and in a pacemaker phenotype accelerated by isoproterenol [211]. The proximal C-terminus and the M2 domain control the ability of Kir2.1 to interact with other Kir subunits [17].

4.1.2 Intrinsic gating of I_K1
The rectification of I_K1 channels results from a voltage-dependent blockade of the inner channel pore by cytosolic Mg²⁺, Ca²⁺ and polyamines (spermine, spermidine, putrescine) [17]. Mg²⁺ blocks single I_K1 channels with a low K_D (10.5 µM at +30 mV), so that at physiological concentrations of cytoplasmic Mg²⁺ (0.5–2 mM), the blocking rate is so fast that inward rectification appears as an instantaneous process. Polyamine-induced inward rectification depends on two negatively charged residues, D172 and E224, located in the M2 domain and in the C-terminal region, respectively [212].

4.1.3 Pharmacology of I_K1
Ba²⁺ is a potent I_K1 blocker (IC₅₀=20 µM) [210]. Other I_K1 blockers are summarized in Table 3 [42,45,47,49,52,54,56,57,59,151,213]. I_K1 blockers prolong atrial, AV node and ventricular APD and are effective against various types of experimental reentrant ventricular tachycardias [159]. Moreover, I_K1 blockers produce membrane depolarization (an effect that slows conduction velocity due to a voltage-dependent inactivation of Na⁺ channels) and prolongs the QT interval, both actions being proarrhythmic. Fast heart rates increase the [K⁺] in the narrow intercellular space to several mM and the I_K1 density, which results in a shortening of the APD that might offset the ability of I_Kr blockers to prolong the APD under these conditions.

View this table: [in this window] [in a new window]   Table 3 Pharmacological blockade of inward rectifier potassium channels

 
4.1.4 Regulation of I_K1
Isoproterenol and forskolin inhibit I_K1 in human ventricular myocytes [17,213], suggesting that I_K1 can be suppressed by a PKA-mediated phosphorylation of the channel. Moreover, the effects of isoproterenol are inhibited by propranolol and acetylcholine [214]. PMA inhibits I_K1 in human atrial myocytes and in Kir2.1b channels but this effect is inhibited by chelerytrine [215] and mutations of PKC phosphorylation sites (S64A, T353A). In human atrial myocytes, methoxamine inhibits I_K1 and this effect is prevented by H-9, a specific PKC inhibitor, suggesting that 1-adrenergic stimulation reduces I_K1 via PKC-dependent pathways [216]. Kir2.1 channels are negatively controlled by a tyrosine kinase-dependent phosphorylation process [217]. Acidosis modulates I_K1 but its effect is species-dependent [17]. PIP₂ directly activates I_K1, perhaps by an electrostatic interaction of the negatively charged head groups of PIP₂ with charged residues in the C-terminal region of the Kir channel [17].

4.1.5. Pathology
I_K1 is downregulated in spontaneously hypertensive rats, in models of cardiac hypertrophy and in patients with severe heart failure and cardiomyopathies [7,9,35]. The reduction in ventricular I_K1 density is transmurally homogeneous in failing canine hearts [176]. Reduced I_K1 density is observed in canine Purkinje cells after myocardial infarction [8] and in a 3-day-old infarcted rat heart, but this reduction is greater in epicardial than in endocardial myocytes [66]. The ventricular myocytes from patients with idiopathic dilated cardiomyopathy exhibits decreased channel activity, longer APD and lower resting membrane potentials than those from patients with ischemic cardiomyopathy [218]. The downregulation of I_K1 produces membrane depolarization, prolongation of the APD and both early and delayed afterdepolarizations [7,9]. However, I_K1 density increases in patients with chronic AF [219]. Mutations of KCNJ2 encoding Kir2.1 result in dominant negative effects on the current and have been associated with Andersen's syndrome, an inherited disease characterized by periodic paralysis, dysmorphic features, QT prolongation and ventricular arrhythmias [220].

4.2 The acetylcholine-activated K⁺ current, I_KAch
Acetylcholine activates K⁺ channels (K_Ach) in pacemaker SA and atrial cells, thus regulating heart rate [19]. I_KAch density is 6 times greater in the atrium than in the ventricle [14] and results from a tetrameric complex of two Kir3.1 (501 amino acids) and two Kir3.4 (419 amino acids) subunits [221]. Following the binding of acetylcholine to muscarinic M2 receptors, the Gβ subunits of the PTX-sensitive G protein (G_o/G_i family) activate the K_Ach channel by interacting directly to its cytoplasmatic N- and C-termini. Activation of I_KAch hyperpolarizes the membrane potential, slows the spontaneous firing rate of the pacemaker cells of the SA and AV nodes and delays AV conduction [1,12]. These effects explain why vagal maneuvers or intravenous adenosine can terminate atrioventricular reentrant tachyarrhythmias. I_KAch activity can be stimulated by intracellular ATP, PIP₂ and ET_A endothelin, µ opioid, ₂-adrenergic and A1 adenosine receptor agonists [11,12,222] and inhibited by intracellular acidification and several antiarrhythmic drugs (Table 3) [223–225]. Disopyramide, procainamide and pilsicainide mainly block the muscarinic receptors, while flecainide and propafenone act as open channel blockers [224]. Atrial K_Ach channels are inhibited by membrane stretch, possibly serving as a mechanoelectrical feedback pathway, a property conferred by the Kir3.4 subunit [226]. Vagal stimulation produces a nonuniform shortening of the atrial APD and refractoriness mediated by activation of I_KACh, an effect that may contribute to the perpetuation of AF [227]. Chronic AF reduces I_KAch density possibly to counteract the AF-induced nonuniform shortening of the atrial refractoriness [219].

4.3 ATP-sensitive K⁺ channels, K_ATP
Cardiac K_ATP (70–90 pS) are inhibited by physiological intracellular ATP levels (ATP_i), coupling cell metabolism to membrane potential [18,228]. The mechanism of inward rectification involves an open channel blockade by intracellular Mg²⁺ and Na⁺ ions [229].

4.3.1 Molecular basis of I_KATP
Cardiac K_ATP results from the coassembly of four inwardly rectifying channel -subunits (Kir6.2) and four regulatory SUR2A subunits (Fig. 2B) [18,228]. Kir6.2 subunits confer inhibition by ATP [230]. The SUR2A subunit has three transmembrane domains (TMD0, TMD1, and TMD2), each of which consists of five, five, and six membrane spanning regions and two nucleotide binding folds (NBF-1 and NBF-2) located in the loop between TMD1 and TMD2 and in the C-terminus, respectively [18,231]. The SUR2A subunit confers sensitivity to MgADP, sulfonylureas and K⁺ channel openers (KCOs) and ATP hydrolysis at each NBF gates the K⁺ permeation through the Kir6.2 -subunit [18,228]. There is an endoplasmic reticulum retention motif (RKR) in the C-terminal region in Kir6.2 and in an intracellular loop between TMD1 and NBF-1 in SUR2A that prevents their surface expression in the absence of the other subunit [232].

4.3.2 Role of K_ATP channels
Opening of K_ATP during myocardial ischemia shortens the APD and decreases Ca²⁺ influx through L-type channels. Both effects prevent cardiac Ca²⁺ overload, preserve ATP levels and increase cell survival [233,234]. Activation of K_ATP plays an important role in ischemic preconditioning (IPC), wherein single or multiple brief periods of myocardial ischemia confer protection against a subsequent prolonged ischemia, reducing myocardial infarct size, severity of stunning and incidence of cardiac arrhythmias. However, activation of K_ATP also resulted in shortening of the APD, accumulation of extracellular K⁺, membrane depolarization and slow conduction velocity, effects that render the ischemic heart vulnerable to reentrant arrhythmias [159]. Kir6.2–/– mice lack K_ATP and present an aberrant regulation of cardiac excitability, inadequate Ca²⁺ handling, ventricular arrhythmias and sudden death following sympathetic stimulation [235]. These results suggest that Kir6.2 is required for adaptation to stress.

4.3.3 Pharmacology of I_KATP
K_ATP are inhibited by ATP_i and activated by MgADP, so that the channel activity is regulated by the ATP/ADP ratio [16]. Several factors desensitize K_ATP to inhibition by ATP_i, including nucleotide diphosphates, lactate, oxygen-derived free radicals and adenosine A1 receptor stimulation [18,228].

KCOs (pinacidil, cromakalim, rimakalim and nicorandil) bind at two distinct regions of TMD2, the intracellular loop joining TM13 and TM14 and TM16 and TM17 (residues K1249 and T1253) [18,228,236]. They exert cardioprotective effects in experimental models of myocardial ischemia/reperfusion and in patients with acute myocardial infarction [159,233]. However, KCOs also activate vascular K_ATP (Kir6.1/SUR2B) and produce hypotensive effects that limit their use in the treatment of myocardial ischemia. Moreover, since I_KATP density is larger in the epicardium, KCOs produce a more marked shortening of APD in epicardial cells, leading to a marked dispersion of repolarization and to the development of extrasystolic activity via a mechanism of phase 2 reentry [237]. However, KCOs shorten the APD (QT interval), reduce transmural dispersion of repolarization and suppress early and late afterdepolarizations induced in patients with LQT1 [238]. Thus, KCOs may prevent spontaneous TdP when congenital or acquired LQTS is secondary to reduced I_Kr or I_Ks.

K_ATP are blocked by sulfonylureas (i.e. glibenclamide, glicazide, glipizide, glimepiride, tolbutamide), glinides (repaglinide, nateglinide) and various antiarrhythmic drugs (Table 3) [12,239–243]. The sulfonylurea binding sites include the region between TM15 and TM16 in TMD2 and S1237, located in the loop between TM15 and TM16 [18,244]. Cardiac I_KATP blockers prevent the shortening of the APD and the incidence of ventricular fibrillation during the myocardial ischemia, even when in models of ischemia–reperfusion they are mainly arrhythmogenic [159,233,234]. The clinical effects of glibenclamide are also contradictory in type 2 diabetic patients with coronary artery disease [245]. Moreover, since K_ATP are present in pancreatic β-cells and smooth muscle [18], I_KATP blockers can produce hypoglycemia and coronary vasoconstriction, effects that may preclude their interest as antiarrhythmic agents. Cardioselective I_KATP blockers (clamikalant, HMR 1098) inhibit hypoxia-induced APD shortening and prevent ventricular fibrillation induced by coronary artery occlusion in post-infarcted conscious dogs at doses that have no effect on insulin release, blood pressure or coronary blood flow [233,234]. Thus, they may represent a new therapeutic approach to the treatment of ventricular arrhythmias in patients with coronary heart disease.

Recently, it has been postulated that mitochondrial K_ATP (mitoK_ATP) rather than sarcolemmal K_ATP (sarcK_ATP) are responsible for IPC [233]. In fact, diazoxide, a selective mitoK_ATP agonist mimicks IPC, whereas 5-hydroxydecanoate (5-HD), a selective mitoK_ATP blocker, suppresses the cardioprotection induced by IPC and diazoxide. Since cardiac mitoK_ATP appear to be pharmacologically distinct from sarcK_ATP, it seems possible to develop selective mitoK_ATP openers devoid of hemodynamic and cardiac electrophysiological side effects of first generation K_ATP openers. The selective mitoK_ATP opener BMS-191095 exerts cardioprotective effects without shortening APD, which may explain the reduced propensity for reentrant arrhythmias [246]. However, recent evidence has demonstrated that diazoxide also activates sarcK_ATP channels [247], an effect that is inhibited by HMR1098 but not by 5-HD and that it does not improve contractile function in Kir6.2–/– mice [248]. These data suggest that activation of sarcK_ATP rather than of mitoK_ATP is responsible for its cardioprotective effects. Therefore, further research is needed to determine the molecular basis of mitoK_ATP and the cardioprotection induced by specific mitoK_ATP openers [233].

4.3.4 Regulation of K_ATP
Both PKC and adenosine A1 receptor activation enhance K_ATP and induce IPC and these effects are suppressed by chelerythrine or bisindolylmaleimide [249]. The effects of PKC on K_ATP activity are associated with phosphorylation at T180 in the Kir6.2 subunit. K_ATP activated by glucose-free anoxia close immediately upon reoxygenation, but activation of both novel and conventional PKC isoforms contributes to the persistent opening of the channels under these circumstances [250]. K_ATP can be activated indirectly by PKA-coupled and other protein kinase-coupled receptors via phosphorylation of channel proteins or by depleting cellular ATP levels [244]. The PKA site responsible for channel stimulation includes the residues S372 and T224.

PIP₂ directly interacts with positively charged residues (R176, R177) at the C-terminus of Kir6.2 subunit stabilizing the open state of the channel and antagonizes ATP inhibition of K_ATP [17,251], whereas breakdown of PIP₂ by PLC enhances the ATP-sensitivity of K_ATP channels [252]. Moreover, PIP₂ mimics ATP in preventing current rundown and in rescuing activity after rundown [251]. Protein tyrosine kinases (PTKs) are also mediators of ischemic preconditioning. In guinea pig ventricular myocytes the PTK inhibitor genistein elicited I_KATP. Stimulation of receptor PTKs with epidermal growth factor, nerve growth factor or insulin attenuates, while the protein tyrosine phosphatase inhibitor orthovanadate prevents the effects of genistein on I_KATP [253]. These results suggest that the PTK-protein tyrosine phosphatase signaling pathway may be one of the regulators of cardiac sarcK_ATP.

The release of nitric oxide (NO) and bradykinin during ischemia can also play a role in IPC. K_ATP are activated via the NO-cGMP-PKG signaling pathway, which phosphorylates some serine–threonine residues and this activation is reversed by protein phosphatase 2A [254]. PKC- and PKC- are activated by NO donors in rabbit hearts [255] and their infarct-size limiting effects are abolished by chelerythrine. Interferon- inhibits I_KATP in rabbit ventricular cells and this effect is blocked by genistein, but is not affected by H-7, an inhibitor of PKC and PKA [256]. These findings suggest that tyrosine kinase-mediated inhibition of I_KATP by cytokines may aggravate cell damage during myocardial ischemia.

	5. Two pore or background K+ channels, K2P

Top Abstract 1. Introduction 2. K+ channel diversity... 3. Cardiac voltage-gated... 4. Inward rectifying K+... 5. Two pore or... 6. Conclusions and perspectives References

 
Cardiac cells have K_2P currents with little time- or voltage-dependency, termed background currents, that regulate resting membrane potential and cell excitability (Fig. 2C) [20–22]. K_2P are insensitive to conventional K⁺ channel blockers (4-AP, TEA, Ba²⁺, Cs⁺, glibenclamide), but show differential sensitivity to membrane stretch, changes in pH, fatty acids and inhalation (e.g. halothane, isoflurane, chloroform) and local (e.g. lidocaine, bupivacaine) anesthetic agents and are regulated by second messenger phosphorylation (Table 4) [22]. Cardiac expression of TWIK-1 may underlie the background K⁺ current active during the plateau of the action potential (I_Kp) [20].

View this table: [in this window] [in a new window]   Table 4 Pharmacological characteristics of leak channels

 
TASK currents are highly sensitive to variations in the extracellular pH in the physiological range. Mutations of the residue H98 (H98D) which lies immediately distal to the first pore domain reduces pH sensitivity [22]. TASK currents are insensitive to arachidonic acid, stretch and PKC activators, but are inhibited by local anesthetics and submicromolar concentrations of the endocannabinoid anandamide and increased by volatile anesthetics [22]. TREK and TRAAK channels are activated by membrane stretch, cell swelling, negative pressure and lysophosphatidylcholine. TREK and THIK-1 are stimulated by arachidonic acid and polyunsaturated fatty acids and THIK-1 channels are inhibited by intracellular acidification. TWIK currents are increased by arachydonic acid and PKC activation and inhibited by intracellular acidosis, but are insensitive to PKA activation. In contrast, TREK channels are modulated by G_q-, G_i- and G_s-coupled receptors, inhibited by activators of PKA and PKC and increased by intracellular acidosis. Thus, far from being passive leaks, as initially thought, K_2P channels are sensitive to changes in pH, membrane stretch and phosphorylation state, possibly acting as cellular sensors and tranducers, translating these stimuli into a change in the membrane potential and excitability [22]. If so, some K_2P channels will represent important therapeutic targets in the near future.

	6. Conclusions and perspectives

Top Abstract 1. Introduction 2. K+ channel diversity... 3. Cardiac voltage-gated... 4. Inward rectifying K+... 5. Two pore or... 6. Conclusions and perspectives References

 
Cardiac K⁺ channels have been recognized as potential therapeutic targets. However, the rational design of safer and more effective K⁺ channel blockers/openers and the attempts to prevent the proarrhythmic effects linked to the blockade of cardiac K⁺ channels should be based on a better understanding of the molecular basis of the target channel, its cardiac distribution and function and the type of drug–channel interaction. The past decade over 80 human genes enclosing various K⁺ channels have been cloned and their structural biophysical properties, subunit stoichiometry, channel assembly and modulation by intracellular second messengers and ligands have been characterized. Moreover, the recent identification of the structures of several K⁺ channels (KcsA, MthK and KvAP) provides the basis to understand the molecular mechanisms that control ion selectivity and conduction in K⁺ channels.

Despite of these considerable advances, much remains to be resolved before the full potential of K⁺ channel modulators can be realized. The function and expression of K⁺ channels differ widely in the different regions of the heart and are influenced by heart rate, neurohumoral state, cardiovascular diseases (cardiac hypertrophy, heart failure, myocardial infarction and atrial fibrillation) and inherited disorders (Romano–Ward and Jervell–Lange–Nielsen long QT syndromes). Moreover, given the diversity of - and β-subunits and splice variants that underlie the various K⁺ channels and the potential for heteromeric channel assemble, the precise role that each K⁺ channel gene product plays in the regional heterogeneity of native currents or in the cellular pathophysiology in the human heart is uncertain. Similarly, very little is known on the possible transcriptional, translational and post-translational mechanisms regulating the function and expression of K⁺ channel and β subunits as well as on the gene products required to maintain its normal function. All this information is the basis to understand the pathophysiology and arrhythmogenesis of the diseased hearts and to identify new targets for the development of K⁺ channel modulators safer and more effective than those actually prescribed.

Ion channel blockers tested in clinical trials have shown no decrease mortality outcome, but an increase in proarrhytmia. Thus, and despite the success of electrical devices and the promising alternative of somatic gene transfer, it is clear that we need safer and more effective antiarrhythmic drugs. In this review we indicated new promising targets, including atrioselective I_Kur blockers, I_Ks agonists and the possibility of drug-induced restoring trafficking deffects of HERG channels. However, there are several strategies for the development of new K⁺ channel modulators. Because of the multiple mechanisms of rhythm disturbances drugs with multiple modes of action (i.e. amiodarone-like drugs) are needed, even when we do not know how to optimize chemical structures for the rational targeting of multiple ion channels. Another possibility is to combine I_Kr/I_Ks with β-adrenergic blockade or I_Kr and I_CaL blockade in order to reduce the risk of proarrhytmia. An unexplored perspective is to develop drugs that affect Kv channel gating by interacting at regions away from the ion conducting pore to produce the desired changes in cardiac refractoriness. Other possible targets include accessory β-subunits and intracellular signalling molecules (PKA, PKC, cyclic nucleotides). Finally, to optimize drug–channel interaction thousands of chemical entities must be screened to identify a few candidate drugs. The new technological developments (planar-array chip-based approaches) address the high throughput restrictions of classical patch clamp electrophysiology and allow recordings from hundreds of cells per day and provide new perspectives for drug discovery. All this information is the basis to understand the pathophysiology and arrhythmogenesis of the diseased hearts and to identify new targets for the development of K⁺ channel modulators safer and more effective than those actually prescribed.

	Acknowledgements

 
This work was supported by Comisión Interministerial de Ciencia y Tecnología (SAF2002-02304), Comunidad Autónoma de Madrid (08.4/0038.1/2001) and Pfizer Foundation Grants.

	Notes

 
Time for primary review 26 days

	References

Top Abstract 1. Introduction 2. K+ channel diversity... 3. Cardiac voltage-gated... 4. Inward rectifying K+... 5. Two pore or... 6. Conclusions and perspectives References

 

1. Snyders D.J. Structure and function of cardiac potassium channels. Cardiovasc. Res. (1999) 42:377–390.[Abstract/Free Full Text]
2. Coetzee W., Amarillo Y., Chiu J., et al. Molecular diversity of K⁺ channels. Ann. N. Y. Acad. Sci. (1999) 868:233–285.[CrossRef][Web of Science][Medline]
3. Nerbonne J.M. Molecular basis of functional voltage-gated K⁺ channel diversity in the mamalian myocardium. J. Physiol. (2000) 525:285–298.[Abstract/Free Full Text]
4. Roden D.M., Balser J.R., George A.L. Jr., et al. Cardiac ion channels. Annu. Rev. Physiol. (2002) 64:431–475.[CrossRef][Web of Science][Medline]
5. Tamargo J. Drug-induced torsade de pointes: from molecular biology to bedside. Jpn. J. Pharmacol. (2000) 83:1–19.[CrossRef][Medline]
6. Clancy C.E., Kurokawa J., Tateyama M., et al. K⁺ channel structure–activity relationships and mechanisms of drug-induced QT prolongation. Annu. Rev. Pharmacol. Toxicol. (2003) 43:441–461.[CrossRef][Web of Science][Medline]
7. Näbauer M., Kääb S. Potassium channel downregulation in heart failure. Cardiovasc. Res. (1998) 37:324–334.[Abstract/Free Full Text]
8. Pinto J.M., Boyden P.A. Electrical remodeling in ischemia and infarction. Cardiovasc. Res. (1999) 42:284–297.[Abstract/Free Full Text]
9. Tomaselli G.F., Marbán E. Electrophysiological remodeling in hypertrophy and heart failure. Cardiovasc. Res. (1999) 42:270–283.[Free Full Text]
10. Nattel S. New ideas about atrial fibrillation 50 years on. Nature (2002) 415:219–226.[CrossRef][Medline]
11. Shieh C.-C., Coghlan M., Sullivan J.P., et al. Potassium channels: molecular defects, diseases, and therapeutic opportunities. Pharmacol. Rev. (2000) 52:557–594.[Abstract/Free Full Text]
12. Carmeliet E., Mubagwa K. Antiarrhythmic drugs and cardiac ion channels: mechanisms of action. Prog. Biophys. Mol. Biol. (1998) 70:1–72.[CrossRef][Web of Science][Medline]
13. Wickenden A.D. K⁺ channels as therapeutic drug targets. Pharmacol. Ther. (2002) 94:157–182.[CrossRef][Web of Science][Medline]
14. Schram G., Pourrier M., Nattel S. Differential distribution of cardiac ion channel expression as a basis for regional specialization in electrical function. Circ. Res. (2002) 90:939–950.[Abstract/Free Full Text]
15. MacKinnon R. Potassium channels. FEBS Lett. (2003) 555:62–65.[CrossRef][Web of Science][Medline]
16. Yellen G. The voltage-gated potassium channels and their relatives. Nature (2002) 419:35–42.[CrossRef][Medline]
17. Lopatin A.N., Nichols C.G. Inward rectifiers in the heart: an update on I_K1. J. Mol. Cell. Cardiol. (2001) 33:625–638.[CrossRef][Web of Science][Medline]
18. Seino S., Miki T. Physiological and pathophysiological roles of ATP-sensitive K⁺ channels. Prog. Biophys. Mol. Biol. (2003) 81:133–176.[CrossRef][Web of Science][Medline]
19. Mark M.D., Herlitze S. G-protein mediated gating of inward-rectifier K⁺ channels. Eur. J. Biochem. (2000) 267:5830–5836.[Web of Science][Medline]
20. Lesage F., Lazdunski M. Molecular and functional properties of two-pore-domain potassium channels. Am. J. Physiol. (2000) 279:F793–F801.[Web of Science]
21. Patel A.J., Honoré E. Properties and modulation of mammalian 2P domain K⁺ channels. Trends Neurosci. (2001) 24:339–346.[CrossRef][Web of Science][Medline]
22. O'Connell A.D., Morton M.J., Hunter M. Two-pore domain K⁺ channels-molecular sensors. Biochim. Biophys. Acta (2002) 1566:152–161.[Medline]
23. Pourrier M., Schram G., Nattel S. Properties, expression and potential roles of cardiac K⁺ channel accesory subunits: MinK, MiRPs, KChIP and KChAP. J. Membr. Biol. (2003) 194:141–152.[CrossRef][Web of Science][Medline]
24. An W.F., Bowlby M.R., Betty M., et al. Modulation of A-type potassium channels by a family of calcium sensors. Nature (2000) 403:553–556.[CrossRef][Medline]
25. Hanlon M.R., Wallace B.A. Structure and function of voltage-dependent ion channel regulatory β subunits. Biochemistry (2002) 41:2886–2894.[CrossRef][Web of Science][Medline]
26. Martens J.R., Kwak Y.-G., Tamkun M.M. Modulation of Kv channel /β subunit interactions. Trends Cardiovasc. Med. (1999) 9:253–258.[CrossRef][Medline]
27. Oudit G.Y., Kassiri Z., Sah R., et al. The molecular physiology of the cardiac transient outward potassium current I_to in normal and diseased myocardium. J. Mol. Cell. Cardiol. (2001) 33:851–872.[CrossRef][Web of Science][Medline]
28. Sah R., Ramirez R.J., Oudit G.Y., et al. Regulation of cardiac excitation–contraction coupling by action potential repolarization: role of the transient outward potassium current (I_to). J. Physiol. (2003) 546:5–18.[Abstract/Free Full Text]
29. Näbauer M., Beuckelmann D.J., Übverfuhr P., et al. Regional differences in current density and rate-dependent properties of the transient outward current in subepicardial and subendocardial myocytes of human left ventricle. Circulation (1996) 93:168–177.[Abstract/Free Full Text]
30. Yan G.X., Antzelevitch C. Cellular basis for the electrocardiographic J wave. Circulation (1996) 93:372–379.[Abstract/Free Full Text]
31. Feng J., Yue L., Wang Z., Nattel S. Ionic mechanisms of regional action potential heterogeneity in the canine right atrium. Circ. Res. (1998) 83:541–551.[Abstract/Free Full Text]
32. Volders P.G., Sipido K.R., Carmeliet E., et al. Repolarizing K⁺ currents I_to1 and I_Ks are larger in right than left canine ventricular midmyocardium. Circulation (1999) 99:206–210.[Abstract/Free Full Text]
33. Lukas A., Antzelevitch C. Differences in the electrophysiological response of canine ventricular epicardium and endocardium to ischemia. Role of the transient outward current. Circulation (1993) 88:2903–2915.[Abstract/Free Full Text]
34. Krishnan S.C., Antzelevitch C. Flecainide-induced arrhythmia in canine ventricular epicardium: phase 2 reentry? Circulation (1993) 87:562–572.[Abstract/Free Full Text]
35. Kääb S., Dixon J., Duc J., et al. Molecular basis of transient outward potassium current downregulation in human heart failure: a decrease in Kv4.3 mRNA correlates with a reduction in current density. Circulation (1998) 98:1383–1393.[Abstract/Free Full Text]
36. Wang Z., Feng J., Shi H., Pond A., et al. Potential molecular basis of different physiological properties of the transient outward K⁺ current in rabbit and human atrial myocytes. Circ. Res. (1999) 19:551–561.
37. Rosati B., Pan Z., Lypen S., et al. Regulation of KChIP2 potassium channel beta subunit gene expression underlies the gradient of transient outward current in canine and human ventricle. J. Physiol. (2001) 533:119–125.[Abstract/Free Full Text]
38. Wang Z., Fermini B., Nattel S. Effects of flecainide, quinidine, and 4-aminopyridine on transient outward and ultrarapid delayed rectifier currents in human atrial myocytes. J. Pharmacol. Exp. Ther. (1995) 272:184–196.[Abstract/Free Full Text]
39. Feng J., Wang Z., Li G., Nattel S. Effects of class III antiarrhythmic drugs on transient outward and ultra-rapid delayed rectifier currents in human atrial myocytes. J. Pharmacol. Exp. Ther. (1997) 281:384–392.[Abstract/Free Full Text]
40. Koidl B., Flaschberger P., Schaffer P., et al. Effects of the class III antiarrhythmic drug ambasilide on outward currents in human atrial myocytes. Naunyn-Schmiedeberg's Arch. Pharmacol. (1996) 353:226–232.[Web of Science][Medline]
41. Guo W., Kamiya K., Toyama J. Evidences of antagonism between amiodarone and triiodothyronine on the K⁺ channel activities of cultured rat cardiomyocytes. J. Mol. Cell. Cardiol. (1997) 29:617–627.[CrossRef][Web of Science][Medline]
42. Chen F., Esmailian F., Sun W., et al. Azimilide inhibits multiple cardiac potassium currents in human atrial myocytes. J. Cardiovasc. Pharmacol. Ther. (2002) 7:255–264.[Abstract/Free Full Text]
43. Castle N.A. Bupivacaine inhibits the transient outward K⁺ current but not the inward rectifier in rat ventricular myocytes. J. Pharmacol. Exp. Ther. (1990) 255:1038–1046.[Abstract/Free Full Text]
44. Delpon E., Valenzuela C., Tamargo J. Blockade of cardiac potassium and other channels by antihistamines. Drug Saf. (1999) 21(Suppl. 1):11–18.[CrossRef][Web of Science][Medline]
45. Sánchez-Chapula J.A., Salinas-Stefanon E., Torres-Jacome J., et al. Blockade of currents by the antimalarial drug chloroquine in feline ventricular myocytes. J. Pharmacol. Exp. Ther. (2001) 297:437–445.[Abstract/Free Full Text]
46. Bosch R.F., Gaspo R., Busch A.E., et al. Effects of the chromanol 293B, a selective blocker of the slow, component of the delayed rectifier K⁺ current, on repolarization in human and guinea pig ventricular myocytes. Cardiovasc. Res. (1998) 38:441–450.[Abstract/Free Full Text]
47. Castle N.A. Selective inhibition of potassium currents in rat ventricular by clofilium and its tertiary homolog. J. Pharmacol. Exp. Ther. (1991) 257:342–350.[Abstract/Free Full Text]
48. Sánchez-Chapula J.A. Mechanism of transient outward K⁺ channel block by disopyramide. J. Pharmacol. Exp. Ther. (1999) 290:515–523.[Abstract/Free Full Text]
49. Gögelein H., Bruggemann A., Gerlach U., et al. Inhibition of I_Ks channels by HMR 1556. Naunyn Schmiedeberg's Arch. Pharmacol. (2000) 362:480–488.[CrossRef][Web of Science][Medline]
50. Delpon E., Tamargo J., Sanchez-Chapula J. Effects of imipramine on the transient outward current in rabbit atrial single cells. Br. J. Pharmacol. (1992) 106:464–469.[Web of Science][Medline]
51. Lu Y., Yue L., Wang Z., et al. Effects of the diuretic agent indapamide on Na⁺, transient outward, and delayed rectifier currents in canine atrial myocytes. Circ. Res. (1998) 83:158–166.[Abstract/Free Full Text]
52. Wang H., Shi H., Wang Z. Nicotine depresses the functions of multiple cardiac potassium channels. Life Sci. (1999) 65:143–149.
53. Jahnel U., Klemm P., Nawrath H. Different mechanisms of the inhibition of the transient outward current in rat ventricular myocytes. Naunyn Schmiedeberg's Arch. Pharmacol. (1994) 349:87–94.[Web of Science][Medline]
54. Duan D., Fermini B., Nattel S. Potassium channel blocking properties of propafenone in rabbit atrial myocytes. J. Pharmacol. Exp. Ther. (1993) 264:1113–1123.[Abstract/Free Full Text]
55. Gross G.J., Castle N.A. Propafenone inhibition of human atrial myocyte repolarizing currents. J. Mol. Cell. Cardiol. (1998) 30:783–793.[CrossRef][Web of Science][Medline]
56. Gluais P., Bastide M., Caron J., et al. Risperidone prolongs cardiac action potential through reduction of K⁺ currents in rabbit myocytes. Eur. J. Pharmacol. (2002) 444:123–132.[CrossRef][Web of Science][Medline]
57. Yang B.F., Li G.R., Xu C.Q., et al. Effects of RP58866 on transmembrane K⁺ current in mammalian ventricular myocytes. Zhongguo Yao Li Xue Bao (1999) 20:961–969.[Medline]
58. Dukes I., Cleeman L., Morad M. Tedisamil blocks the transient and delayed rectifier K⁺ currents in mammalian cardiac and glial cells. J. Pharmacol. Exp. Ther. (1990) 254:560–569.[Abstract/Free Full Text]
59. McLarnon J.G., Xu R. Actions of the benzopyran compound terikalant on macroscopic currents in rat ventricular myocytes. J. Pharmacol. Exp. Ther. (1995) 275:389–396.[Abstract/Free Full Text]
60. Slawsky M.T., Castle N.A. K⁺ channel blocking actions of flecainide compared with those of propafenone and quinidine in adult rat ventricular myocytes. J. Pharmacol. Exp. Ther. (1994) 269:66–74.[Abstract/Free Full Text]
61. Shibata E.F., Drury T., Refsun H., et al. Contributions of a transient outward current to repolarization in human atrium. Am. J. Physiol. (1989) 257:H1773–H1781.[Web of Science][Medline]
62. Mubagwa R., Flameng W., Carmeliet E. Resting and action potentials of non ischemic and chronically ischemic human ventricular muscle. J. Cardiovasc. Electrophysiol. (1994) 5:659–671.[Web of Science][Medline]
63. Apkon M., Nerbonne J.M. ₁-Adrenergic agonists selectively suppress voltage-dependent K⁺ currents in rat ventricular myocytes. Proc. Natl. Acad. Sci. U. S. A. (1988) 85:8756–8760.[Abstract/Free Full Text]
64. Antzelevitch C., Sicouri S., Litovsky S.H., et al. Heterogeneity within the ventricular wall. Electrophysiological and pharmacological epicardial, endocardial, and M cells. Circ. Res. (1991) 69:1427–1449.[Free Full Text]
65. Bodi I., Muth J.N., Hahn H.S., et al. Electrical remodeling in hearts from a calcium-dependent mouse model of hypertrophy and failure. Complex Nature of K⁺ current changes and action potential duration. J. Am. Coll. Cardiol. (2003) 41:1611–1622.[Abstract/Free Full Text]
66. Yao J.A., Jiang M., Fan J.S., et al. Heterogeneous changes in K currents in rat ventricles three days after myocardial infarction. Cardiovasc. Res. (1999) 44:132–145.[Abstract/Free Full Text]
67. Le Bouter S., Demolombe S., Chambellan A., et al. Microarray analysis reveals complex remodeling of cardiac ion channel expression with altered tyroid status. Relation to cellular and integrated electrophysiology. Circ. Res. (2003) 92:234–242.[Abstract/Free Full Text]
68. Nakamura T., Coetzee W.A., Vega-Sáenz de Miera E., et al. Modulation of Kv4 channels, key components of rat ventricular transient outward K⁺ current, by PKC. Am. J. Physiol. (1997) 273:H1775–H1786.[Web of Science][Medline]
69. Murray K.T., Fahrig S.A., Deal K.K., et al. Modulation of an inactivating human cardiac K⁺ channel by protein kinase C. Circ. Res. (1994) 75:999–1005.[Abstract/Free Full Text]
70. Caballero R., Gómez R., Moreno I., et al. Interaction of angiotensin II with the angiotensin type 2 receptor inhibits the cardiac transient outward potassium current. Cardiovasc. Res. (2004) (in press).
71. Sanguinetti M., Jurkiewicz N. Two components of cardiac delayed rectifier K⁺ current. Differential sensitivity to block by class III antiarrhythmic agents. J. Gen. Physiol. (1990) 96:195–215.[Abstract/Free Full Text]
72. Nattel S., Yue L., Wang Z. Cardiac ultrarapid delayed rectifiers. A novel potassium current family of functional similarity and molecular diversity. Cell Physiol. Biochem. (1999) 9:217–226.[CrossRef][Web of Science][Medline]
73. Tseng G.-N. I_Kr: the hERG channel. J. Mol. Cell. Cardiol. (2001) 33:835–849.[CrossRef][Web of Science][Medline]
74. Tristani-Firouzi M., Sanguinetti M.C. Structural determinants and biophysical properties of HERG and KCNQ1 channel gating. J. Mol. Cell. Cardiol. (2003) 35:27–35.[CrossRef][Web of Science][Medline]
75. Li G.R., Feng J., Yue L., et al. Evidence for two components of delayed rectifier K⁺ current in human ventricular myocytes. Circ. Res. (1996) 78:689–696.[Abstract/Free Full Text]
76. Snyders D.J., Tamkun M.M., Bennett P.B. A rapidly activating and slowly inactivating potassium channel cloned from human heart. Functional analysis after stable mammalian cell culture expression. J. Gen. Physiol. (1993) 101:513–543.[Abstract/Free Full Text]
77. Wang Z., Fermini B., Nattel S. Sustained depolarization-induced outward current in human atrial myocytes. Evidence for a novel delayed rectifier K⁺ current similar to Kv1.5 cloned channel currents. Circ. Res. (1993) 73:1061–1076.[Abstract/Free Full Text]
78. Grissmer S., Nguyen A.N., Aiyar J., et al. Pharmacological characterization of five cloned voltage-gated K⁺ channels, types Kv1.1, 1.2, 1.3, 1.5, and 3.1, stably expressed in mammalian cell lines. Mol. Pharmacol. (1994) 45:1227–1234.[Abstract]
79. Nattel S., Matthews C., De Blasio E., et al. Dose-dependence of 4-aminopyridine plasma concentrations and electrophysiological effects in dogs: potential relevance to ionic mechanisms in vivo. Circulation (2000) 101:1179–1184.[Abstract/Free Full Text]
80. Yue L., Feng J.L., Wang Z., et al. Effects of ambasilide, quinidine, flecainide and verapamil on ultra-rapid delayed rectifier potassium currents in canine atrial myocytes. Cardiovasc. Res. (2000) 46:151–161.[Abstract/Free Full Text]
81. Kobayashi S., Reien Y., Ogura T., et al. Inhibitory effect of bepridil on hKv1.5 channel current: comparison with amiodarone and E-4031. Eur. J. Pharmacol. (2001) 430:149–157.[CrossRef][Web of Science][Medline]
82. Delpon E., Caballero R., Valenzuela C., et al. Benzocaine enhances and inhibits the K⁺ current through a human cardiac cloned channel (Kv1.5). Cardiovasc. Res. (1999) 42:510–520.[Abstract/Free Full Text]
83. González T., Longobardo M., Caballero R., et al. Effects of bupivacaine and a novel local anesthetic, IQB-9302, on human cardiac K⁺ channels. J. Pharmacol. Exp. Ther. (2001) 296:573–583.[Abstract/Free Full Text]
84. Caballero R., Delpón E., Valenzuela C., et al. Direct effects of candesartan and eprosartan on human cloned potassium channels involved in cardiac repolarization. Mol. Pharmacol. (2001) 59:825–836.[Abstract/Free Full Text]
85. Rampe D., Roy M.L., Dennis A., et al. A mechanism for the proarrhythmic effects of cisapride (Propulsid): high affinity blockade of the human cardiac potassium channel HERG. FEBS Lett. (1997) 417:28–32.[CrossRef][Web of Science][Medline]
86. Caballero R., Delpón E., Valenzuela C., et al. Losartan and its metabolite E3174 modify cardiac delayed rectifier K⁺ currents. Circulation (2000) 101:1199–1205.[Abstract/Free Full Text]
87. Valenzuela C., Delpón E., Franqueza L., et al. Comparative effects of nonsedating histamine H1 receptor antagonists, ebastine and terfenadine, on human Kv1.5 channels. Eur. J. Pharmacol. (1997) 326:257–263.[CrossRef][Web of Science][Medline]
88. Moreno I., Caballero R., González T., et al. Effects of irbesartan on cloned potassium channels involved in human cardiac repolarization. J. Pharmacol. Exp. Ther. (2003) 304:862–873.[Abstract/Free Full Text]
89. Delpon E., Valenzuela C., Gay P., et al. Block of human cardiac Kv1.5 channels by loratadine: voltage-, time- and use-dependent block at concentrations above therapeutic levels. Cardiovasc. Res. (1997) 35:341–350.[Abstract/Free Full Text]
90. Matsuda T., Masumiya H., Tanaka N., et al. Inhibition by a novel anti-arrhythmic agent, NIP-142, of cloned human cardiac K⁺ channel Kv1.5 current. Life Sci. (2001) 68:2017–2024.[CrossRef][Web of Science][Medline]
91. Choe H., Lee Y.K., Lee Y.T., et al. Papaverine blocks hKv1.5 channel current and human atrial ultrarapid delayed rectifier K⁺ currents. J. Pharmacol. Exp. Ther. (2003) 304:706–712.[Abstract/Free Full Text]
92. Kang J., Wang L., Cai F., et al. High affinity blockade of the HERG cardiac K⁺ channel by the neuroleptic pimozide. Eur. J. Pharmacol. (2000) 392:137–140.[CrossRef][Web of Science][Medline]
93. Franqueza L., Valenzuela C., Delpon E., et al. Effects of propafenone and 5-hydroxy-propafenone on hKv1.5 channels. Br. J. Pharmacol. (1998) 125:969–978.[CrossRef][Web of Science][Medline]
94. Snyders D., Knoth K., Roberds S., et al. Time-, voltage-, and state-dependent block by quinidine of a cloned human cardiac channel. Mol. Pharmacol. (1992) 41:322–330.[Abstract]
95. Valenzuela C., Delpon E., Franqueza L., et al. Effects of ropivacaine on a potassium channel (hKv1.5) cloned from human ventricle. Anesthesiology (1997) 86:718–728.[Web of Science][Medline]
96. Yeola S.W., Rich T.C., Uebele V.N., et al. Molecular analysis of a binding site for quinidine in a human cardiac delayed rectifier K⁺ channel. Role of S6 in antiarrhythmic drug binding. Circ. Res. (1996) 78:1105–1114.[Abstract/Free Full Text]
97. Franqueza L., Longobardo M., Vicente J., et al. Molecular determinants of stereoselective bupivacaine block of hKv1.5 channels. Circ. Res. (1997) 81:1053–1064.[Abstract/Free Full Text]
98. Longobardo M., Delpon E., Caballero R., et al. Structural determinants of potency and stereoselective block of hKv1.5 channels induced by local anesthetics. Mol. Pharmacol. (1998) 54:162–169.[Abstract/Free Full Text]
99. Caballero R., Moreno I., Gonzalez T., et al. Putative binding sites for benzocaine on a human cardiac cloned channel (Kv1.5). Cardiovasc. Res. (2002) 56:104–117.[Abstract/Free Full Text]
100. Zhang X., Anderson J.W., Fedida D. Characterization of nifedipine block of the human heart delayed rectifier, hKv1.5. J. Pharmacol. Exp. Ther. (1997) 281:1247–1256.[Abstract/Free Full Text]
101. Decher N., Pirard B., Bundis F., et al. Molecular basis for Kv1.5 channel block: conservation of drug binding sites among voltage-gated K+ channels. J. Biol. Chem. (2004) 279:394–400.[Abstract/Free Full Text]
102. Honoré E., Barhanin J., Attali B., et al. External blockade of the major cardiac delayed-rectifier K⁺ channel (Kv1.5) by polyunsaturated fatty acids. Proc. Natl. Acad. Sci. U. S. A. (1994) 91:1937–1941.[Abstract/Free Full Text]
103. Longobardo M., Gonzalez T., Navarro-Polanco R., et al. Effects of a quaternary bupivacaine derivative on delayed rectifier K⁺ currents. Br. J. Pharmacol. (2000) 130:391–401.[CrossRef][Web of Science][Medline]
104. Brendel J., Peukert S. Blockers of the Kv1.5 channels for treatment of atrial arrhythmias. Exp. Opin. Ther. Pat. (2002) 12:1589–1598.[CrossRef]
105. Yamashita T., Murakawa Y., Hayami N., et al. Short-term effects of rapid pacing on mRNA level of voltage-dependent K⁺ channels in rat atrium. Electrical remodeling in paroxysmal atrial tachycardia. Circulation (2000) 101:2007–2014.[Abstract/Free Full Text]
106. Knobloch K., Brendel J., Peukert S., et al. Electrophysiological and antiarrhythmic effects of the novel I_Kur channel blockers, S9947 and S20951, on left vs. right pig atrium in vivo in comparison with the I_Kr blockers dofetilide, azimilide, D,L-sotalol and ibutilide. Naunyn Schmiedeber's Arch. Pharmacol. (2002) 366:482–487.[CrossRef]
107. Guo W., Kamiya K., Yasui K., et al. Alpha1-adrenoceptor agonists and IGF-1, myocardial hypertrophic factors, regulate the Kv1.5 K⁺ channel expression differentially in cultured newborn rat ventricular cells. Pfügers Arch. (1998) 436:26–32.[CrossRef][Web of Science][Medline]
108. Matsubara H., Suzuki J., Inada M. Shaker-related potassium channel, Kv1.4, mRNA regulation in cultured rat heart myocytes and differential expression of Kv1.4 and Kv1.5 genes in myocardial development and hypertrophy. J. Clin. Invest. (1993) 92:1659–1666.[Web of Science][Medline]
109. Li G.R., Feng J., Wang Z., et al. Adrenergic modulation of ultrarapid delayed rectifier K⁺ current in human atrial myocytes. Circ. Res. (1996) 78:903–915.[Abstract/Free Full Text]
110. Timpe L.C., Fantl W.J. Modulation of a voltage-activated potassium channel by peptide growth factor receptors. J. Neurosci. (1994) 14:1195–1201.[Abstract]
111. Holmes T.C., Gaddol D.A., Ren R., et al. Association of Src tyrosine kinase with a human potassium channel mediated by SH3 domain. Science (1996) 274:2089–2091.[Abstract/Free Full Text]
112. Williams C.P., Hu N., Shen W., et al. Modulation of the human Kv1.5 channel by protein kinase C activation: role of the Kvbeta1.2 subunit. J. Pharmacol. Exp. Ther. (2002) 302:545–550.[Abstract/Free Full Text]
113. González T., Navarro-Polanco R., Longobardo M., et al. Assembly with the Kvβ1.3 subunit modulates drug block of hKv1.5 channels. Mol. Pharmacol. (2002) 62:1456–1463.[Abstract/Free Full Text]
114. Spector P.S., Curran M.E., Zou A., et al. Fast inactivation causes rectification of the I_Kr channel. J. Gen. Physiol. (1996) 107:611–619.[Abstract/Free Full Text]
115. Verheijck E.E., van Ginneken A.C., Bourier J., et al. Effects of delayed rectifier current blockade by E-4031 on impulse generation in single sinoatrial nodal myocytes of the rabbit. Circ. Res. (1995) 76:607–615.[Abstract/Free Full Text]
116. Pond A.L., Scheve B.K., Benedict A.T., et al. Expression of distinct ERG proteins in rat, mouse, and human heart. Relation to functional I_Kr channels. J. Biol. Chem. (2000) 275:5997–6006.[Abstract/Free Full Text]
117. Liu D.-W., Antzelevitch C. Characteristics of the delayed rectifier current (I_Kr and I_Ks) in canine ventricular epicardial, mid-myocardial, and endocardial myocytes. Circ. Res. (1995) 76:351–365.[Abstract/Free Full Text]
118. Bryant S.M., Wan X., Shipsey S.J., et al. Regional differences in the delayed rectifier current (I_Kr and I_Ks) contribute to the differences in action potential duration in basal left ventricular myocytes in guinea-pig. Cardiovasc. Res. (1998) 40:322–331.[Abstract/Free Full Text]
119. Cheng J., Kamiya K., Liu W., et al. Heterogeneous distribution of the two components of delayed rectifier K⁺ current: a potential mechanism of the proarrhtyhmic effects of methanesulfonanilide class III agents. Cardiovasc. Res. (1999) 43:135–147.[Abstract/Free Full Text]
120. Abbott G.W., Sesti F., Splawski I., et al. MiRP1 forms I_Kr potassium channels with HERG and is associated with cardiac arrhythmia. Cell (1999) 97:175–187.[CrossRef][Web of Science][Medline]
121. Cui J., Melman Y., Palma E., et al. Cyclic AMP regulates the HERG K⁺ channel by dual pathways. Curr. Biol. (2000) 10:671–674.[CrossRef][Web of Science][Medline]
122. Weerapura M., Nattel S., Chartier D., et al. A comparison of currents carried by HERG, with and without coexpression of MiRP1, and the native rapid delayed rectifier current. J. Physiol. (2002) 540:15–27.[Abstract/Free Full Text]
123. Yang T., Kupershmidt S., Roden D.M. Anti-minK antisense decreases the amplitude of the rapidly activating cardiac delayed rectifier K⁺ current. Circ. Res. (1995) 77:1246–1253.[Abstract/Free Full Text]
124. Splawski I., Shen J., Timothy K.W., et al. Spectrum of mutations in long-QT syndrome genes. KVLQT1, HERG, SCN5A, KCNE1, and KCNE2. Circulation (2000) 102:1178–1185.[Abstract/Free Full Text]
125. Kass R.S., Moss A.J. Long QT sndrome: novel insights into the mechanisms of cardiac arrhythmias. J. Clin. Invest. (2003) 112:810–815.[CrossRef][Web of Science][Medline]
126. Zhou Z., Gong Q., Epstein M.L., et al. HERG channel dysfunction in human long QT syndrome. Intracellular transport and functional defects. J. Biol. Chem. (1998) 273:2106–21061.
127. Rajamani S., Anderson C.L., Anson B.D., et al. Pharmacological rescue of human K⁺ channel long-QT2 mutations: human ether-a-go-go-related gene rescue without block. Circulation (2002) 105:2830–2835.[Abstract/Free Full Text]
128. Busch A., Eigenberger B., Jurkiewicz N., et al. Blockade of HERG channels by the class III antiarrhythmic azimilide: mode of action. Br. J. Pharmacol. (1998) 123:23–30.[CrossRef][Web of Science][Medline]
129. Mitcheson J.S., Chen J., Lin M., et al. A structural basis for drug-induced long QT syndrome. Proc. Natl. Acad. Sci. U. S. A. (2000) 97:12329–12333.[Abstract/Free Full Text]
130. Kamiya K., Nishiyama A., Yasui K., et al. Short- and long-term effects of amiodarone on the two components of cardiac delayed rectifier K⁺ current. Circulation (2001) 103:1317–1324.[Abstract/Free Full Text]
131. Kiehn J., Thomas D., Karle C., et al. Inhibitory effects of the class III antiarrhythmic drug amiodarone on cloned HERG potassium channels. Naunyn-Schmiedeberg's Arch. Pharmacol. (1999) 359:212–219.[CrossRef][Web of Science][Medline]
132. Davies M.P., Freeman L.C., Lass R.S. Dual actions of the novel class III antiarrhythmic drug NE-10064 on delayed potassium channel currents in guinea pig ventricular and sinoatrial node cells. J. Pharmacol. Exp. Ther. (1996) 276:1149–1154.[Abstract/Free Full Text]
133. Chouabe C., Drici M., Romey G., et al. HERG and KvLQT1/IsK, the cardiac K⁺ involved in long QT syndromes, are targets for calcium channels blockers. Mol. Pharmacol. (1998) 54:695–703.[Abstract/Free Full Text]
134. González T., Arias C., Caballero R., et al. Effects of levobupivacaine, ropivacaine, and bupivacaine on HERG channels. Br. J. Pharmacol. (2002) 137:1269–1279.[CrossRef][Web of Science][Medline]
135. Caballero R., Moreno I., González T., et al. Spironolactone and its main metabolite, canrenoic acid, block human ether-a-go-go-related gene channels. Circulation (2003) 107:889–895.[Abstract/Free Full Text]
136. Sánchez-Chapula J.A., Navarro-Polanco R.A., et al. Molecular determinants of voltage dependent HERG K⁺ channel block. J. Biol. Chem. (2002) 277:23587–23595.[Abstract/Free Full Text]
137. Wang D.W., Kiyouse T., Sato T., et al. Comparison of the effects of class 1 anti-arrhythmic drugs, cibenzoline, mexiletine and flecainide, on the delayed rectifier K⁺ current of guinea-pig ventricular myocytes. J. Mol. Cell. Cardiol. (1996) 28:893–903.[CrossRef][Web of Science][Medline]
138. Drolet B., Khalifa M., Daleau P., et al. Block of the rapid component of the delayed rectifier potassium current by the prokinetic agent cisapride underlies drug-related lengthening of the QT interval. Circulation (1998) 97:204–210.[Abstract/Free Full Text]
139. Zhang S., Rajamani S., Chen Y., et al. Cocaine blocks HERG, but not KvLQT1+ minK, potassium channels. Mol. Pharmacol. (2001) 59:1069–1076.[Abstract/Free Full Text]
140. Paul A., Witchel H., Hancox J. Inhibition of HERG potassium channel current by the class 1a antiarrhythmic agent disopyramide. Biochem. Biophys. Res. Commun. (2001) 280:1243–1250.[CrossRef][Web of Science][Medline]
141. Krafte D.S., Volberg W.A. Voltage dependence of cardiac delayed rectifier block by methanesulfonamide class III antiarrhythmic agents. J. Cardiovasc. Pharmacol. (1994) 23:37–41.[Web of Science][Medline]
142. Gautier P., Guillemare E., Marion A., et al. Electrophysiologic characterization of dronedarone in guinea pig ventricular cells. J. Cardiovasc. Pharmacol. (2003) 41:191–202.[CrossRef][Web of Science][Medline]
143. Paul A.A., Witchel H.J., Hancox J.C. Inhibition of the current of heterologously expressed HERG potassium channels by flecainide and comparison with quinidine, propafenone and lignocaine. Br. J. Pharmacol. (2002) 136:717–729.[CrossRef][Web of Science][Medline]
144. Milnes J.T., Crociani O., Arcangeli A., et al. Blockade of HERG potassium currents by fluvoxamine: incomplete attenuation by S6 mutations at F656 or Y652. Br. J. Pharmacol. (2003) 139:887–898.[CrossRef][Web of Science][Medline]
145. Yang T., Snyders D., Roden D. Ibutilide, a methanesulfonanilide antiarrhythmic, is a potent blocker of the rapidly activating delayed rectifier K⁺ current (I_Kr) in AT-1 cells: concentration-, time-, voltage-, and use-dependent effects. Circulation (1995) 91:1799–1806.[Abstract/Free Full Text]
146. Lynch J.J. Jr., Baskin E.P., Nutt E.M., et al. Comparison of binding to rapidly activating delayed rectifier K⁺ channel, I_Kr, and effects on myocardial refractoriness for class III antiarrhythmic agents. J. Cardiovasc. Pharmacol. (1995) 25:336–340.[Web of Science][Medline]
147. Valenzuela C., Sánchez-Chapula J., Delpon E., et al. Imipramine blocks rapidly activating and delays slowly activating K⁺ current activation in guinea pig ventricular myocytes. Circ. Res. (1994) 74:687–699.[Abstract/Free Full Text]
148. Dumaine R., Roy M., Brown A. Blockade of HERG and Kv1.5 by ketoconazole. J. Pharmacol. Exp. Ther. (1998) 286:727–735.[Abstract/Free Full Text]
149. Crumb W.J. Jr. Loratadine blockade of K⁺ channels in human heart: comparison with terfenadine under physiological conditions. J. Pharmacol. Exp. Ther. (2000) 292:261–264.[Abstract/Free Full Text]
150. Suessbrich H., Schönherr R., Heinemann S., et al. Specific block of cloned HERG channels by clofilium and its tertiary analog LY97241. FEBS Lett. (1997) 414:435–438.[CrossRef][Web of Science][Medline]
151. Bachmann A., Mueller S., Kopp K., et al. inhibition of cardiac potassium currents by pentobarbital. Naunyn-Schmiedeberg's Arch. Pharmacol. (2002) 365:29–37.[CrossRef][Web of Science][Medline]
152. Delpon E., Valenzuela C., Pérez O., et al. Propafenone preferentially blocks the rapidly activating component of delayed rectifier K⁺ current in guinea pig ventricular myocytes. Voltage-independent and time-dependent block of the slowly activating component. Circ. Res. (1995) 76:223–235.[Abstract/Free Full Text]
153. Arias C., González T., Moreno I., et al. Effects of propafenone and its main metabolite, 5-hydroxypropafenone, on HERG channels. Cardiovasc. Res. (2003) 57:660–669.[Abstract/Free Full Text]
154. Yang T., Roden D. Extracellular potassium modulation of drug block of I_Kr: implication for torsade de pointes and reverse use-dependence. Circulation (1996) 93:407–411.[Abstract/Free Full Text]
155. Kongsamut S., Kang J., Chen X.-L., et al. A comparison of the receptor binding and HERG channel affinities for a series of antipsychotic drugs. Eur. J. Pharmacol. (2002) 450:37–41.[CrossRef][Web of Science][Medline]
156. Jurkiewicz N., Wang J., Fermini B., et al. Mechanism of action potential prolongation by RP58866 and its active enantiomer, terikalant. Block of the rapidly activating delayed rectifier K⁺ current, I_Kr. Circulation (1996) 94:2938–2946.[Abstract/Free Full Text]
157. Rampe D., Murawsky M., Grau J., et al. The antipsychotic agent sertindole is a high affinity antagonist of the human cardiac potassium channel HERG. J. Pharmacol. Exp. Ther. (1998) 286:788–793.[Abstract/Free Full Text]
158. Rampe D., Wible B., Fedida D., et al. Verapamil blocks a rapidly activating delayed rectifier K⁺ channel cloned from human heart. Mol. Pharmacol. (1993) 44:642–648.[Abstract]
159. Sanguinetti M., Salata J. Potassium channels and their modulators. From synthesis to clinical experience. Evans J., Hamilton T., Longman S., Stemp G., eds. (1996) London: Taylor & Francis. 221–256.
160. Nattel S., Singh B.N. Evolution, mechanisms, and classification of antiarrhythmic drugs: focus on class III actions. Am. J. Cardiol. (1999) 84:11R–19R.[Web of Science][Medline]
161. Ulens C., Daenens P., Tytgat J. Norpropoxyphene-induced cardiotoxicity is associated with changes in ion-selectivity and gating of HERG currents. Cardiovasc. Res. (1999) 44:568–578.[Abstract/Free Full Text]
162. Jiang M., Dun W., Fan J.-S., et al. Use-dependent "agonist" effect of azimilide on the HERG channel. J. Pharmacol. Exp. Ther. (1999) 291:1324–1336.[Abstract/Free Full Text]
163. Malykhina A.P., Shoeb F., Akbarali H.I. Fenamate-induce enhancement of heterologously expressed HERG currents in Xenopus oocytes. Eur. J. Pharmacol. (2002) 452:269–277.[CrossRef][Web of Science][Medline]
164. Wang J., Wang H., Han H., et al. Phospholipid metabolite 1-palmitoyl-lysophosphatidylcholine enhances human Ether-a-go-go-related gene (HERG) K⁺ channel function. Circulation (2001) 104:2645–2648.[Abstract/Free Full Text]
165. Haverkamp W., Breithardt G., Camm A.J., et al. The potential for QT prolongation and pro-arrhythmia by non antiarrhythmic drugs: clinical and regulatory implications. Report on a Policy Conference of the European Society of Cardiology. (2000) vol. 47:219–233. Cardiovasc. Res.
166. Redfern W.S., Carlsson L., Davis A.S., et al. Relationships between preclinical cardiac electrophysiology, clinical QT interval prolongation and torsade de pointes for a broad rage of drugs: evidence for a provisional safety margin in drug development. Cardiovasc. Res. (2003) 58:32–45.[Abstract/Free Full Text]
167. Mitcheson J.S., Chen J., Sanguinetti M. Trapping of a methanesulfonanilide by closure of the HERG potassium channel activation gate. J. Gen. Physiol. (2000) 115:229–239.[Abstract/Free Full Text]
168. Chen J., Seebohm G., Sanguinetti M.C. Position of aromatic residues in the S6 domain, not inactivation, dictates cisapride sensitivity of HERG and eag potassium channels. Proc. Natl. Acad. Sci. U. S. A. (2002) 99:12461–12466.[Abstract/Free Full Text]
169. Ficker E., Jarolimek W., Brown A.M. Molecular determinants of inactivation and dofetilide block in ether a-go-go (EAG) channels and EAG-related K⁺ channels. Mol. Pharmacol. (2001) 60:1343–1348.[Abstract/Free Full Text]
170. Etheridge S.P., Compton S., Tristani-Firouzi M., et al. A new oral therapy for long QT syndrome. J. Am. Coll. Cardiol. (2003) 42:1777–1782.[Abstract/Free Full Text]
171. Kiehn J. Regulation of the cardiac repolarizing HERG potassium channel by protein kinase A. Trends Cardiovasc. Med. (2000) 10:205–209.[CrossRef][Web of Science][Medline]
172. Lei M., Brown H.F., Terrar D.A. Modulation of delayed rectifier potassium current, iK, by isoprenaline in rabbit isolated pacemaker cells. Exp. Physiol. (2000) 85:27–35.[Abstract]
173. Thomas D., Zhang W., Wu K., et al. Regulation of HERG potassium channel activation by protein kinase C independent of direct phosphorylation of the channel protein. Cardiovasc. Res. (2003) 59:14–26.[Abstract/Free Full Text]
174. Bian J., Cui J., McDonald T.V. HERG K⁺ channel activity is regulated by changes in phosphatidyl inositol 4,5-biphosphate. Circ. Res. (2001) 89:1168–1176.[Abstract/Free Full Text]
175. Magyar J., Iost N., Kortvely A., et al. Effects of endothelin-1 on calcium and potassium currents in undiseased human ventricular myocytes. Pflügers Arch. (2000) 441:144–149.[CrossRef][Web of Science][Medline]
176. Li G.-R., Lau C.P., Ducharme A., et al. Transmural action potential and ionic current remodeling in ventricles of failing canine hearts. Am. J. Physiol. (2002) 283:H1031–H1041.[Web of Science]
177. Zhang Y., Han H., Wang J., et al. Impairment of human ether-a-go-go-related gene (HERG) K⁺ channel function by hypoglycemia and hyperglycemia. Similar phenotypes but different mechanisms. J. Biol. Chem. (2003) 278:10417–10426.[Abstract/Free Full Text]
178. Jiang M., Cabo C., Yao J.-A., et al. Delayed rectifier K currents have reduced amplitudes and altered kinetics in myocytes from infarcted canine ventricle. Cardiovasc. Res. (2000) 48:34–43.[Abstract/Free Full Text]
179. Kurokawa J., Abriel H., Kass R.S. Molecular basis of the delayed rectifier current I(ks) in heart. J. Mol. Cell. Cardiol. (2001) 33:873–882.[CrossRef][Web of Science][Medline]
180. Jurkiewicz N.K., Sanguinetti M.C. Rate-dependent prolongation of cardiac action potentials by a metanosulfonanilide class III antiarrhythmic agent. Specific block of rapidly activating delayed rectifier K⁺ current by dofetilide. Circ. Res. (1993) 72:75–83.[Abstract/Free Full Text]
181. Chen H., Kim L.A., Rajan S., et al. Charybdotoxin binding in the I(Ks) pore demonstrates two MinK subunits in each channel complex. Neuron (2003) 40:15–23.[CrossRef][Web of Science][Medline]
182. Sanguinetti M.C., Curran M.E., Zou A., et al. Coassembly of KvLQT1 and minK (IsK) proteins to form cardiac I_Ks potassium channel. Nature (1996) 384:80–83.[CrossRef][Medline]
183. Suessbrich H., Busch A.E. The I_Ks channel: coassembly of IsK (minK) and KvLQT1 proteins. Rev. Physiol. Biochem. Pharmacol. (1999) 137:191–226.[Medline]
184. Pereon Y., Demolombe S., Baro I., et al. Differential expression of KvLQT1 isoforms across the human ventricular wall. Am. J. Physiol. (2000) 278:H1908–H1915.[Web of Science]
185. Demolombe S., Lande G., Charpentier F., et al. Transgenic mice overexpressing human KvLQT1 dominant-negative isoform: Part I. Phenotypic characterisation. Cardiovasc. Res. (2001) 50:314–327.[Abstract/Free Full Text]
186. Schulze-Bahr E., Wang Q., Wedekind H., et al. KCNE1 mutations cause Jervell and Lange–Nielsen syndrome. Nat. Genet. (1997) 17:267–268.[CrossRef][Web of Science][Medline]
187. Busch A.E., Suessbrich H., Waldegger S., et al. Inhibition of I_Ks in guinea pig cardiac myocytes and guinea pig IsK channels by the chromanol 293B. Pflügers Arch. (1996) 432:1094–1096.[CrossRef][Web of Science][Medline]
188. Turgeon J., Daleau P., Bennett P., et al. Block of I_Ks, the slow component of the delayed rectifier K⁺ current, by the diuretic agent indapamide in guinea pig myocytes. Circ. Res. (1994) 75:879–886.[Abstract/Free Full Text]
189. Heath B., Terrar D. Separation of the components of the delayed rectifier potassium current using selective blockers of I_Kr and I_Ks in guinea-pig isolated ventricular myocytes. Exp. Physiol. (1996) 81:587–603.[Abstract]
190. Lengyel C., Iost N., Virág L., et al. Pharmacological block of the slow component of the outward delayed rectifier current (I_Ks) fails to lengthen rabbit ventricular muscle QT_c and action potential duration. Br. J. Pharmacol. (2001) 132:101–110.[CrossRef][Web of Science][Medline]
191. Seebohm G., Chen J., Strutz N., et al. Molecular determinants of KCNQ1 channel block by a benzodiazepine. Mol. Pharmacol. (2003) 64:70–77.[Abstract/Free Full Text]
192. Yang I.C., Scherz M.W., Bahiski A., et al. Stereoselective interactions of the enantiomers of chromanol 293B with human voltage-gated potassium channels. J. Pharmacol. Exp. Ther. (2000) 294:955–962.[Abstract/Free Full Text]
193. Seebohm G., Lerche C., Pusch M., et al. A kinetic study on the stereospecific inhibition of KCNQ1 and I_Ks by the chromanol 293B. Br. J. Pharmacol. (2001) 134:1647–1654.[CrossRef][Web of Science][Medline]
194. Busch A.E., Malloy K., Groh W.J., et al. The novel class III antiarrhythmics NE-10064 and NE-10133 inhibit IsK channels expressed in Xenopus oocytes and I_Ks in guinea pig cardiac myocytes. Biochem. Biophys. Res. Commun. (1994) 202:265–270.[CrossRef][Web of Science][Medline]
195. Loussouarn G., Charpentier F., Mohammad-Panah R., et al. KvLQT1 potassium channel but not IsK is the molecular target for trans-6-cyano-4-(N-ethylsulfonyl-N-methylamino)-3-hydroxy-2,2-dimethyl-chromane. Mol. Pharmacol. (1997) 52:1131–1136.[Abstract/Free Full Text]
196. Varró A., Balati B., Iost N., et al. The role of the delayed rectifier component I_Ks in dog ventricular muscle and Purkinje fibre repolarization. J. Physiol. (2000) 523:67–81.[Abstract/Free Full Text]
197. Shimizu W., Antzelevitch C. Cellular basis for the ECG features of the LQT1 form of the long-QT syndrome: effects of beta-adrenergic agonists and antagonists and sodium channel blockers on transmural dispersion of repolarization and torsade de pointes. Circulation (1998) 98:2314–2322.[Abstract/Free Full Text]
198. Schwartz P.J., Priori S.G., Spazzolini C., et al. Genotype–phenotype correlation in the long-QT syndrome: gene-specific triggers for life-threatening arrhythmias. Circulation (2001) 103:89–95.[Abstract/Free Full Text]
199. Biliczki P., Virag L., Iost N., et al. Interaction of different potassium channels in cardiac repolarization in dog ventricular preparations: role of repolarization reserve. Br. J. Pharmacol. (2002) 137:361–368.[CrossRef][Web of Science][Medline]
200. Busch A.E., Busch G.L., Ford E., et al. The role of IsK protein in the specific pharmacological properties of the I_Ks channel complex. Br. J. Pharmacol. (1997) 122:187–189.[CrossRef][Web of Science][Medline]
201. Wang H.S., Brown B.S., McKinnon D., et al. Molecular basis for differential sensitivity of KCNQ and I_Ks channels to the cognitive enhancer XE991. Mol. Pharmacol. (2000) 57:1218–1223.[Abstract/Free Full Text]
202. Doolan G.K., Panchal R.G., Fonnes E.L., et al. Fatty acid augmentation of the cardiac slowly activating delayed rectifier current (I_Ks) is conferred by hminK. FASEB J. (2002) 16:1662–1664.[Abstract/Free Full Text]
203. Salata J.J., Jurkiewicz N.K., Wang J., et al. A novel benzodiazepine that activates cardiac slow delayed rectifier K⁺ currents. Mol. Pharmacol. (1998) 54:220–230.[Abstract/Free Full Text]
204. Xu X., Salata J.J., Wang J., et al. Increasing I_Ks corrects abnormal repolarization in rabbit models of acquired LQT2 and ventricular hypertrophy. Am. J. Physiol. (2002) 283:H664–H670.[Web of Science]
205. Abitbol I., Peretz A., Lerche C., et al. Stilbenes and fenamates rescue the loss of I_Ks channel function induced by an LQT5 mutation and other IsK mutants. EMBO J. (1999) 18:4137–4148.[CrossRef][Web of Science][Medline]
206. Lo C.F., Numann R. Independent and exclusive modulation of cardiac delayed rectifying K⁺ current by protein kinase C and protein kinase A. Circ. Res. (1998) 83:995–1002.[Abstract/Free Full Text]
207. Marx S.O., Kurokawa J., Reiken S., et al. Requirement of a macromolecular signaling complex for beta adrenergic receptor modulation of the KCNQ1–KCNE1 potassium channel. Science (2002) 295:496–499.[Abstract/Free Full Text]
208. Yang T., Kauki H., Roden D. Phosphorylation of the I_Ks channel complex inhibits drug block. Novel mechanisms underlying variable antiarrhythmic drug actions. Circulation (2003) 108:132–134.[Abstract/Free Full Text]
209. Washizuka T., Horie M., Watanuki M., et al. Endothelin-1 inhibits the slow component of cardiac delayed rectifier K⁺ currents via a pertussis toxin-sensitive mechanism. Circ. Res. (1997) 81:211–218.[Abstract/Free Full Text]
210. Wible B.A., De Biasi M., Majumder K., et al. Cloning and functional expression of an inwardly rectifying K⁺ channel from human atrium. Circ. Res. (1995) 76:343–350.[Abstract/Free Full Text]
211. Miake J., Marbán E., Nuss H.B. Functional role of inward rectifier current in heart probed by Kir2.1 overexpression and dominant-negative suppression. J. Clin. Invest. (2003) 111:1529–1536.[CrossRef][Web of Science][Medline]
212. Yang J., Jan Y.N., Jan L.Y. Control of rectification and permeation by residues in two distinct domains in an inward rectifier K⁺ channel. Neuron (1995) 14:1047–1054.[CrossRef][Web of Science][Medline]
213. Sato R., Koumi S., Singer D.H., et al. Amiodarone blocks the inward rectifier potassium channel in isolated guinea pig ventricular cells. J. Pharmacol. Exp. Ther. (1994) 269:1213–1219.[Abstract/Free Full Text]
214. Koumi S., Wasserstrom J.A., Ten Eick R.E. Beta-adrenergic and cholinergic modulation of inward rectifier K⁺ channel function and phosphorylation in guinea-pig ventricle. J. Physiol. (1995) 486:661–678.[Abstract/Free Full Text]
215. Karle C.A., Zitron E., Zhang W., et al. Human cardiac inwardly-rectifying K⁺ channel Kir_2.1b is inhibited by direct protein kinase C-dependent regulation in human isolated cardiomyocytes and in an expression system. Circulation (2002) 106:1493–1499.[Abstract/Free Full Text]
216. Sato R., Koumi S., Hisatome I., et al. A new class III antiarrhythmic drug, MS-551, blocks the inward rectifier potassium channel in isolated guinea pig ventricular myocytes. J. Pharmacol. Exp. Ther. (1995) 274:469–474.[Abstract/Free Full Text]
217. Tong Y., Brandt G.S., Li M., et al. Tyrosine decaging leads to substantial membrane trafficking during modulation of an inward rectifier potassium channel. J. Gen. Physiol. (2001) 117:103–118.[Abstract/Free Full Text]
218. Koumi S., Backer C.L., Arentzen C.E. Characterization of inwardly rectifying K⁺ channel in human cardiac myocytes. Alterations in channel behavior in myocytes isolated from patients with idiopathic dilated cardiomyopathy. Circulation (1995) 92:164–174.[Abstract/Free Full Text]
219. Dobrev D., Graf E., Wettwer E., et al. Molecular basis of downregulation of G-protein-coupled inward rectifying K(+) current (IK,ACh) in chronic human atrial fibrillation: decrease in GIRK4 mRNA correlates with reduced IK,ACh and muscarinic receptor-mediated shortening of action potentials. Circulation (2001) 104:2551–2557.[Abstract/Free Full Text]
220. Plaster N.M., Tawil R., Tristani-Firouzi M., et al. Mutations in Kir2.1 cause the developmental and episodic electrical phenotypes of Andersen's Syndrome. Cell (2001) 105:511–519.[CrossRef][Web of Science][Medline]
221. Corey S., Krapivinsky G., Krapivinsky L., et al. The native inwardly rectifying atrial K⁺ channel, I_KAch, is a tetramer composed of 2 GIRK1 subunits and 2 GIRK4 subunits. J. Biol. Chem. (1998) 273:5271–5278.[Abstract/Free Full Text]
222. Cho H., Hwang J.Y., Kim D., et al. Acetylcholine-induced phosphatidylinositol 4,5-bisphosphate depletion does not cause short-term desensitization of G protein-gated inwardly rectifying K⁺ current in mouse atrial myocytes. J. Biol. Chem. (2002) 277:27742–27747.[Abstract/Free Full Text]
223. Guillemare E., Marion A., Nisato D., et al. Inhibitory effects of dronedarone on muscarinic K⁺ current in guinea pig atrial cells. J. Cardiovasc. Pharmacol. (2000) 36:802–805.[CrossRef][Web of Science][Medline]
224. Inomata N., Ohno T., Ishihara T., et al. Antiarrhythmic agents act differently on the activation phase of the ACh-response in guinea-pig atrial myocytes. Br. J. Pharmacol. (1993) 108:111–115.[Web of Science][Medline]
225. Brandts B., Van Bracht M., Tuttelmann F., et al. Inhibition of muscarinic potassium current by the class III antiarrhythmic drug RP58866 in guinea-pig atrial myocytes. Pacing Clin. Electrophysiol. (2000) 23:1812–1815.[Medline]
226. Ji S., John S.A., Lu Y., et al. Mechanosensitivity of the cardiac muscarinic potassium channel. A novel property conferred by Kir3.4 subunit. J. Biol. Chem. (1998) 273:1324–1328.[Abstract/Free Full Text]
227. Liu L., Nattel S. Differing sympathetic and vagal effects on atrial fibrillation in dogs: role of refractoriness heterogeneity. Am. J. Physiol. (1997) 273:H805–H816.[Web of Science][Medline]
228. Yokoshiki H., Sunagawa M., Seki T., et al. ATP-sensitive K⁺ channels in pancreatic, cardiac, and vascular smooth muscle cells. Am. J. Physiol. (1998) 274:C25–C37.[Web of Science][Medline]
229. Horie M., Irisawa H., Noma A. Voltage-dependent magnesium block of adenosine-triphosphate-sensitive potassium channel in guinea-pig ventricular cells. J. Physiol. (1987) 387:251–272.[Abstract/Free Full Text]
230. Tucker S.J., Gribble F.M., Zhao C., et al. Truncation of Kir6.2 produces ATP-sensitive K⁺ channels in the absence of the sulphonylurea receptor. Nature (1997) 387:179–183.[CrossRef][Medline]
231. Conti L.R., Radeke C.M., Shyng S.L., et al. Transmembrane topology of the sulfonylurea receptor SUR1. J. Biol. Chem. (2001) 276:41270–41278.[Abstract/Free Full Text]
232. Zerangue N., Schwappach B., Jan Y.N., et al. A new ER trafficking signal regulates the subunit stoichiometry of plasma membrane KATP channels. Neuron (1999) 22:537–548.[CrossRef][Web of Science][Medline]
233. Grover G.J., Garlid K.D. ATP-Sensitive potassium channels: a review of their cardioprotective pharmacology. J. Mol. Cell. Cardiol. (2000) 32:677–695.[CrossRef][Web of Science][Medline]
234. Gögelein H. Inhibition of cardiac ATP-dependent potassium channels by sulfonylurea drugs. Curr. Opin. Investig. Drugs (2001) 2:72–80.[Medline]
235. Zingman L.V., Hodgson D.M., Bast P.H., et al. Kir6.2 is required for adaptation to stress. Proc. Natl. Acad. Sci. U. S. A. (2002) 99:13278–13283.[Abstract/Free Full Text]
236. Moreau C., Jacquet H., Prost A.L., et al. The molecular basis of the specificity of action of K_ATP channel openers. EMBO J. (2000) 19:6644–6651.[CrossRef][Web of Science][Medline]
237. Di Diego J.M., Antzelevitch C. Pinacidil-induced electrical heterogeneity and extrasystolic activity in canine ventricular tissues. Does activation of ATP-regulated potassium current promote phase 2 reentry? Circulation (1993) 88:1177–1189.[Abstract/Free Full Text]
238. Shimizu W., Kurita T., Matsuo K., et al. Improvement of repolarization abnormalities by a K⁺ channel opener in the LQT1 form of congenital long QT syndrome. Circulation (1998) 97:1581–1588.[Abstract/Free Full Text]
239. Sakuta H., Okamoto K., Watanabe Y. Blockade by antiarrhythmic drugs of glibenclamide-sensitive K⁺ channels in Xenopus oocytes. Br. J. Pharmacol. (1992) 107:1061–1067.[Web of Science][Medline]
240. Sakuta H., Okamoto K., Watanabe Y. Antiarrhythmic drugs, clofilium and cibenzoline are potent inhibitors of glibenclamide-sensitive K⁺ currents in Xenopus oocytes. Br. J. Pharmacol. (1993) 109:866–872.[Web of Science][Medline]
241. Wang D.W., Sato T., Arita M. Voltage-dependent inhibition of ATP sensitive potassium channels by flecainide in guinea pig ventricular cells. Cardiovasc. Res. (1995) 29:520–525.[CrossRef][Web of Science][Medline]
242. Ripoll C., Lederer W., Nichols C. On the mechanism of inhibition of KATP channels by glibenclamide in rat ventricular myocytes. J. Cardiovasc. Electrophysiol. (1993) 4:38–47.[Web of Science][Medline]
243. Liu Y., Ren G., O'Rourke B., et al. Pharmacological comparison of native mitochondrial K_ATP channels with molecularly defined surface K_ATP channels. Mol. Pharmacol. (2001) 59:225–230.[Abstract/Free Full Text]
244. Babenko A.P., González G., Bryan J. Two regions of sulfonylurea receptor specify the spontaneous bursting and ATP inhibition of K_ATP channel isoforms. J. Biol. Chem. (1999) 274:11587–11592.[Abstract/Free Full Text]
245. Brady P., Terzic A. The sulfonylurea controversy: more questions from the heart. J. Am. Coll. Cardiol. (1998) 31:950–956.[Abstract/Free Full Text]
246. Grover G.J., D'Alonzo A.J., Garlid K.D., et al. Pharmacologic characterization of BMS-191095, a mitochondrial K_ATP opener with no peripheral vasodilator or cardiac action potential shortening activity. J. Pharmacol. Exp. Ther. (2001) 297:1184–1192.[Abstract/Free Full Text]
247. Matsuoka T., Matsushita K., Katayama Y., et al. C-terminal tails of sulfonylurea receptors control ATP-induced activation and diazoxide modulation of ATP-sensitive K⁺ channels. Circ. Res. (2000) 87:873–880.[Abstract/Free Full Text]
248. Suzuki M., Saito T., Sato T., et al. Cardioprotective effect of diazoxide is mediated by activation of sarcolemmal but not mitochondrial ATP-sensitive potassium channels in mice. Circulation (2003) 107:682–685.[Abstract/Free Full Text]
249. Light P.E., Sabir A.A., Allen B.G., et al. Protein kinase C-induced changes in the stoichiometry of ATP binding activate cardiac ATP-sensitive K⁺ channels: a possible mechanistic link to ischemic preconditioning. Circ. Res. (1996) 79:399–406.[Abstract/Free Full Text]
250. Ito K., Sato T., Arita M. Protein kinase C isoform-dependent modulation of ATP-sensitive K⁺ channels during reoxygenation in guinea-pig ventricular myocytes. J. Physiol. (2001) 532:165–174.[Abstract/Free Full Text]
251. Fan Z., Makielski J.C. Anionic phospholipids activate ATP-sensitive potassium channels. J. Biol. Chem. (1997) 272:5388–5395.[Abstract/Free Full Text]
252. Xie L.H., Takano M., Kakei M., et al. Wortmannin, an inhibitor of phosphatidylinositol kinases, blocks the MgATP-dependent recovery of Kir6.2/SUR2A channels. J. Physiol. (1999) 514:655–665.[Abstract/Free Full Text]
253. Stadnicka A., Kwok W.-M., Warltier D.C., et al. Protein tyrosine kinase-dependent modulation of isoflurane effects on cardiac sarcolemmal K_ATP channel. Anesthesiology (2002) 97:1198–1208.[CrossRef][Web of Science][Medline]
254. Han J., Kim N., Joo H., et al. ATP-sensitive K⁺ channel activation by nitric oxide and protein kinase G in rabbit ventricular myocytes. Am. J. Physiol. (2002) 283:H1545–H1554.[Web of Science]
255. Ping P., Takano H., Zhang J., et al. Isoform-selective activation of protein kinase C by nitric oxide in the heart of conscious rabbits: a signalling mechanism for both nitric oxide-induced and ischemia induced preconditioning. Circ. Res. (1999) 84:587–604.[Abstract/Free Full Text]
256. Nishio M., Habuchi Y., Tanaka H., et al. Tyrosine kinase-dependent modulation by interferon-alpha of the ATP-sensitive K⁺ current in rabbit ventricular myocytes. FEBS Lett. (1999) 445:87–91.[CrossRef][Web of Science][Medline]

CiteULike    Connotea    Del.icio.us    What's this?

This article has been cited by other articles:

				C. L. Stables and M. J. Curtis Development and characterization of a mouse in vitro model of ischaemia-induced ventricular fibrillation Cardiovasc Res, July 15, 2009; 83(2): 397 - 404. [Abstract] [Full Text] [PDF]

				R. Gomez, L. Nunez, M. Vaquero, I. Amoros, A. Barana, T. de Prada, C. Macaya, L. Maroto, E. Rodriguez, R. Caballero, et al. Nitric oxide inhibits Kv4.3 and human cardiac transient outward potassium current (Ito1) Cardiovasc Res, December 1, 2008; 80(3): 375 - 384. [Abstract] [Full Text] [PDF]

				J. Sanchez-Quinones, F. Marin, V. Roldan, and G.Y.H. Lip The impact of statin use on atrial fibrillation QJM, November 1, 2008; 101(11): 845 - 861. [Abstract] [Full Text] [PDF]

				E. Delpon, J. M. Cordeiro, L. Nunez, P. E. B. Thomsen, A. Guerchicoff, G. D. Pollevick, Y. Wu, J. K. Kanters, C. T. Larsen, E. Burashnikov, et al. Functional Effects of KCNE3 Mutation and Its Role in the Development of Brugada Syndrome Circ Arrhythm Electrophysiol, August 1, 2008; 1(3): 209 - 218. [Abstract] [Full Text] [PDF]

				M. E. Mangoni and J. Nargeot Genesis and Regulation of the Heart Automaticity Physiol Rev, July 1, 2008; 88(3): 919 - 982. [Abstract] [Full Text] [PDF]

				D. Heitzmann and R. Warth Physiology and Pathophysiology of Potassium Channels in Gastrointestinal Epithelia Physiol Rev, July 1, 2008; 88(3): 1119 - 1182. [Abstract] [Full Text] [PDF]

				G. C. L. Bett and R. L. Rasmusson Modification of K+ channel-drug interactions by ancillary subunits J. Physiol., February 15, 2008; 586(4): 929 - 950. [Abstract] [Full Text] [PDF]

				E. A. Ko, E. D. Burg, O. Platoshyn, J. Msefya, A. L. Firth, and J. X.-J. Yuan Functional characterization of voltage-gated K+ channels in mouse pulmonary artery smooth muscle cells Am J Physiol Cell Physiol, September 1, 2007; 293(3): C928 - C937. [Abstract] [Full Text] [PDF]

				X. Chen, R. M. Wilson, H. Kubo, R. M. Berretta, D. M. Harris, X. Zhang, N. Jaleel, S. M. MacDonnell, C. Bearzi, J. Tillmanns, et al. Adolescent Feline Heart Contains a Population of Small, Proliferative Ventricular Myocytes With Immature Physiological Properties Circ. Res., March 2, 2007; 100(4): 536 - 544. [Abstract] [Full Text] [PDF]

				M. J. Tafreshi and J. Rowles A Review of the Investigational Antiarrhythmic Agent Dronedarone Journal of Cardiovascular Pharmacology and Therapeutics, March 1, 2007; 12(1): 15 - 26. [Abstract] [PDF]

				Z. Mustapha, L. Pang, and S. Nattel Characterization of the cardiac KCNE1 gene promoter Cardiovasc Res, January 1, 2007; 73(1): 82 - 91. [Abstract] [Full Text] [PDF]

				A. S. Tutor, E. Delpon, R. Caballero, R. Gomez, L. Nunez, M. Vaquero, J. Tamargo, F. Mayor Jr., and P. Penela Association of 14-3-3 Proteins to beta1-Adrenergic Receptors Modulates Kv11.1 K+ Channel Activity in Recombinant Systems Mol. Biol. Cell, November 1, 2006; 17(11): 4666 - 4674. [Abstract] [Full Text] [PDF]

				L. Nunez, M. Vaquero, R. Gomez, R. Caballero, P. Mateos-Caceres, C. Macaya, I. Iriepa, E. Galvez, A. Lopez-Farre, J. Tamargo, et al. Nitric oxide blocks hKv1.5 channels by S-nitrosylation and by a cyclic GMP-dependent mechanism Cardiovasc Res, October 1, 2006; 72(1): 80 - 89. [Abstract] [Full Text] [PDF]

				Writing Committee Members, V. Fuster, L. E. Ryden, D. S. Cannom, H. J. Crijns, A. B. Curtis, K. A. Ellenbogen, J. L. Halperin, J.-Y. Le Heuzey, G. N. Kay, et al. ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation: full text: A report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation) Developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society Europace, September 1, 2006; 8(9): 651 - 745. [Full Text] [PDF]

				V. Fuster, L. E. Ryden, D. S. Cannom, H. J. Crijns, A. B. Curtis, K. A. Ellenbogen, J. L. Halperin, J.-Y. Le Heuzey, G. N. Kay, J. E. Lowe, et al. ACC/AHA/ESC 2006 Guidelines for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation) Developed in Collaboration With the European Heart Rhythm Association and the Heart Rhythm Society J. Am. Coll. Cardiol., August 15, 2006; 48(4): e149 - e246. [Full Text] [PDF]

				V. Fuster, L. E. Ryden, D. S. Cannom, H. J. Crijns, A. B. Curtis, K. A. Ellenbogen, J. L. Halperin, J.-Y. Le Heuzey, G. N. Kay, J. E. Lowe, et al. ACC/AHA/ESC 2006 Guidelines for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation): Developed in Collaboration With the European Heart Rhythm Association and the Heart Rhythm Society Circulation, August 15, 2006; 114(7): e257 - e354. [Full Text] [PDF]

				A. Varro and J. Gy. Papp Low penetrance, subclinical congenital LQTS: Concealed LQTS or silent LQTS? Cardiovasc Res, June 1, 2006; 70(3): 404 - 406. [Full Text] [PDF]

				A. Rossokhin, G. Teodorescu, S. Grissmer, and B. S. Zhorov Interaction of d-Tubocurarine with Potassium Channels: Molecular Modeling and Ligand Binding Mol. Pharmacol., April 1, 2006; 69(4): 1356 - 1365. [Abstract] [Full Text] [PDF]

				G.-J. Chang, M.-J. Su, S.-C. Kuo, T.-P. Lin, and Y.-S. Lee Multiple Cellular Electrophysiological Effects of a Novel Antiarrhythmic Furoquinoline Derivative HA-7 [N-Benzyl-7-methoxy-2,3,4,9-tetrahydrofuro[2,3-b]quinoline-3,4-dione] in Guinea Pig Cardiac Preparations J. Pharmacol. Exp. Ther., January 1, 2006; 316(1): 380 - 391. [Abstract] [Full Text] [PDF]

				D. Herrera, A. Mamarbachi, M. Simoes, L. Parent, R. Sauve, Z. Wang, and S. Nattel A Single Residue in the S6 Transmembrane Domain Governs the Differential Flecainide Sensitivity of Voltage-Gated Potassium Channels Mol. Pharmacol., August 1, 2005; 68(2): 305 - 316. [Abstract] [Full Text] [PDF]

				N. W. G. Lambrecht, I. Yakubov, D. Scott, and G. Sachs Identification of the K efflux channel coupled to the gastric H-K-ATPase during acid secretion Physiol Genomics, March 21, 2005; 21(1): 81 - 91. [Abstract] [Full Text] [PDF]

				D. Garcia-Dorado, K.-D. Schluter, E. A. Martinson, and H. M. Piper Which papers are most interesting to the readers of Cardiovascular Research? Information from download monitoring Cardiovasc Res, January 1, 2005; 65(1): 1 - 5. [Full Text] [PDF]

				B. P. Ander, A. R. Weber, P. P. Rampersad, J. S. C. Gilchrist, G. N. Pierce, and A. Lukas Dietary Flaxseed Protects against Ventricular Fibrillation Induced by Ischemia-Reperfusion in Normal and Hypercholesterolemic Rabbits J. Nutr., December 1, 2004; 134(12): 3250 - 3256. [Abstract] [Full Text] [PDF]

This Article Abstract FREE Full Text (PDF) E-letters: Submit a response Alert me when this article is cited Alert me when E-letters are posted Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to My Personal Archive Download to citation manager Request Permissions Disclaimer Google Scholar Articles by Tamargo, J. Articles by Delpón, E. Search for Related Content PubMed PubMed Citation Articles by Tamargo, J. Articles by Delpón, E. Social Bookmarking          What's this?

Online ISSN 1755-3245 - Print ISSN 0008-6363

Copyright © 2009 European Society of Cardiology

Oxford Journals Oxford University Press

• Site Map
• Privacy Policy
• Frequently Asked Questions

Other Oxford University Press sites: Oxford University Press Oxford Journals China Oxford Journals Japan American National Biography Booksellers' Information Service Children's Fiction and Poetry Children's Reference Corporate & Special Sales Dictionaries Dictionary of National Biography Digital Reference English Language Teaching Higher Education Textbooks Humanities International Education Unit Law Medicine Music Online Products Oxford English Dictionary Reference Rights and Permissions Science School Books Social Sciences Very Short Introductions World's Classics