Skip Navigation

Cardiovascular Research 1998 37(2):312-323; doi:10.1016/S0008-6363(97)00256-3
© 1998 by European Society of Cardiology
This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow E-letters: Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when E-letters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Wickenden, A. D
Right arrow Articles by Backx, P. H
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Wickenden, A. D
Right arrow Articles by Backx, P. H
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

Copyright © 1998, European Society of Cardiology

The role of action potential prolongation and altered intracellular calcium handling in the pathogenesis of heart failure

Alan D Wickendena, Roger Kaprieliana, Zamaneh Kassiria, James N Tsoporisa, Robert Tsushimaa, Glenn I Fishmanb and Peter H Backxa,*

aThe Centre for Cardiovascular Research, Division of Cardiology, The Toronto Hospital, The Department of Medicine and The Institute of Medical Sciences, University of Toronto, 101 College Street, CCRW 3-802, Toronto, Ontario M5G 2C4, Canada
bSection of Molecular Cardiology, Albert Einstein College of Medicine, New York, USA

* Corresponding author. Tel. (+1-416) 340 4083; Fax (+1-416) 340 4596; E-mail: p.backx@utoronto.ca

Received 24 July 1997; accepted 17 October 1997


   Abstract
Top
 Abstract
1 Introduction
 2 Action potential prolongation...
 3 Calcium handling in...
 4 The contribution of...
 5 Implications for treatment
 6 Future directions
 7 Summary
 References
 
Action potential prolongation is a common finding in human heart failure and in animal models of cardiac hypertrophy. The mechanism of action potential prolongation involves altered expression of a variety of depolarising and hyperpolarising currents in the myocardium. In particular, decreased density of the transient outward potassium current seems to play a prominent role, regardless of species, precipitating factors or the severity of hypertrophy. The decreased density of the transient outward current appears to be caused by reduced transcription of Kv4.2 and Kv4.3 and may be caused in part by an inhibitory effect of {alpha}-adrenoceptor stimulation. During the early stage of the disease process, action potential prolongation may increase the amplitude of the intracellular calcium transient, causing positive inotropy. We argue therefore, that action prolongation may be a compensatory response which may acutely support the compromised cardiac output. In severe hypertrophy and end-stage heart failure however, despite continued action potential prolongation, the amplitude of the calcium transient becomes severely reduced. The mechanism underlying this event appears to involve reduced expression of calcium handling proteins, and these late events may herald the onset of failure. At present the events leading to the late changes in calcium handling are poorly understood. However, chronic activation of compensatory mechanisms including action potential prolongation may trigger these late events. In the present article we outline a hypothesis which describes a potential role for action potential prolongation, and the associated elevation in the levels of intracellular calcium, in maladaptive gene expression and the progression toward cardiac failure.

KEYWORDS Heart failure; K+ channels; Action potential; Calcium


   1 Introduction
Top
 Abstract
 1 Introduction
2 Action potential prolongation...
 3 Calcium handling in...
 4 The contribution of...
 5 Implications for treatment
 6 Future directions
 7 Summary
 References
 
Cardiac failure has numerous etiologies including myocardial infarction, hypertension, myocarditis and cardiomyopathy resulting from genetic abnormalities (such as mutations in the β-myosin heavy chain, dystrophin or mitochondrial t-RNA genes). About 50% of heart failure cases result from coronary artery disease with the remainder arising from non-ischaemic, and often unknown, etiologies.

Myocyte loss or systolic dysfunction is typically associated with activation of the sympathetic nervous system, inducing positive inotropy and chronotropy, which acutely support the compromised cardiac output. Myocyte adaptation including concentric myocyte hypertrophy and altered gene expression, further attempt to reverse diminished cardiac function [1–4]. However, in spite of the compensatory response, cardiac function may continue to decline. Chronic myocyte adaptation appears to be associated with diminished systolic and diastolic function and myocyte loss, perhaps as a result of maladaptive hypertrophy and ongoing apoptosis, and these factors have been postulated to be involved in the progressive decline in pump function and the onset of heart failure [5–9]. In addition, myocyte adaptation seems to predispose the heart toward lethal ventricular arrhythmia, a leading cause of death (50–80%) in patients with dilated or hypertrophic heart disease. Thus, whilst myocyte hypertrophy and remodelling may compensate for the original changes in load, these adaptations may ultimately contribute to arrhythmogenesis, mechanical dysfunction and progressive cardiac dysfunction.

The mechanism by which myocyte adaptation leads ultimately to failure is unclear. However, an understanding of the molecular events that occur following an insult to pump function may shed some light on this process. One of the most commonly reported aspects of the remodelling process is action potential prolongation. In the present article we review the data on action potential duration in hypertrophy and failure and it's probable causes. We conclude that action potential prolongation represents an early compensatory event. A second common finding in human and animal models of heart failure is altered calcium handling. In the present article we also review the calcium handling literature and show that, unlike action potential prolongation, calcium handling is most severely impaired late in the progression of heart disease. In the final section of the article we present a hypothesis that links the early compensatory action potential prolongation to the eventual impairment of calcium handling, via chronically elevated intracellular calcium, and provide a model for the progression from compensated hypertrophy to heart failure.


   2 Action potential prolongation in human cardiac failure and in animal models of cardiac failure
Top
 Abstract
 1 Introduction
 2 Action potential prolongation...
3 Calcium handling in...
 4 The contribution of...
 5 Implications for treatment
 6 Future directions
 7 Summary
 References
 
Action potential prolongation is a consistent finding in human heart failure and animal models of cardiac insufficiency. The evidence for action potential prolongation in heart failure has been reviewed in detail previously [10, 11]. In 1970, Coltart and Meldrum reported that action potential duration was prolonged in septal tissue from a patient with hypertrophic cardiomyopathy [12]. Action potential duration was also shown to be prolonged in cardiac trabeculae from the hearts of patients with end-stage heart failure caused by either dilated cardiomyopathy and hypertrophic cardiomyopathy [13, 14]and, more recently, in single cells isolated from hearts of patients with end stage heart failure caused by either dilated cardiomyopathy or ischaemic heart disease [15, 16]. Prolongation of the cardiac action potential duration also occurs in a variety of animal models of cardiac hypertrophy, disease and failure. For example, action potential prolongation was shown in the hypertrophied cat right ventricle following pulmonary artery banding [17–20]. In the rat, action potentials were prolonged in association with hypertrophy induced by hypertension in the Goldblatt [21–23]and SHR models [24, 25]and following deoxycorticosterone acetate treatment [26]. Action potential prolongation is also associated with hypertrophy secondary to left coronary artery ligation [27, 28], pulmonary artery ligation [29], thoracic or abdominal aortic banding [30, 31], acromegaly [32]and catecholamine treatment [33]. Prolongation of action potential duration occurs following pulmonary artery constriction in the ferret [34], in Syrian hamsters with hereditary cardiac hypertrophy [35, 36], in guinea pigs following thoracic or abdominal banding [37, 38], in rabbits with hypertrophy induced by perinephritis hypertension [39]and in dogs with pacing induced heart failure [40]. In our laboratory, we have used a rat model in which ligation of the left anterior descending coronary artery induces a large (>35%) left ventricular infarction leading to the development of a compensatory right sided ventricular hypertrophy [41], and we find that this right ventricular hypertrophy is also associated with action potential prolongation (Fig. 1).


Figure 1
View larger version (16K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 1 (A) Action potentials, (B) the transient outward K+ current (Ito) and (C) calcium transients in rat heart. Action potentials and Ito were recorded from single right ventricular myocytes using the whole cell voltage clamp technique. Calcium transients were recorded from fura-2 loaded trabeculae from the right ventricle. The figure shows that action potential duration is prolonged 6–8 weeks post-myocardial infarction (MI) compared to sham control and that action potential prolongation is associated with a decrease in the density of Ito and an elevation in the amplitude of the calcium transient. Pharmacological inhibition of Ito in control cells with 4-aminopyridine (4-AP, 5 mM) similarly prolongs action potential duration and elevates the calcium transient. Horizontal lines represent (A) 0 mV and (B) 0 pA/pF. Ito density was determined at 70 mV.

 
2.1 The mechanism of action potential prolongation
Action potential profiles depend on a delicate balance between depolarising (L-type calcium current, ICa, sodium current, INa, and the sodium-calcium exchanger, INa/Ca) and hyperpolarising currents (the transient outward potassium current, Ito, the delayed rectifier, IK, the inward rectifier, IK1, chloride current, ICl and the sodium-potassium ATPase). The role of the L-type calcium current has been studied in human heart failure and in animal models and these data have been reviewed in detail previously [11]. In two studies, L-type calcium current has been reported to increase [38, 42]. However, more commonly, the L-type calcium current is either unchanged [15, 20, 28, 31, 41, 43–45], or decreased [46–49]and therefore, appears unlikely to be responsible for the prolongation of action potential duration seen in these studies. INa/Ca may be increased in the hypertrophied heart [38](although contradictory data has been published [50, 51]) and pressure overload can induce increases in NaCa exchanger expression [52], suggesting that this electrogenic exchanger may also contribute to action potential prolongation in some animal models. More importantly, the expression of Na/Ca exchanger is consistently found to increase in end-stage human heart failure (Table 2).


View this table:
[in this window]
[in a new window]

  		Table 2 Altered calcium handling gene expression in end-stage human heart failure

 
Altered background hyperpolarising currents could also impact on the action potential profile of hypertrophied and failing hearts, although the extent to which these currents contribute to action potential prolongation is unclear. Thus, in animal models of cardiac hypertrophy, the activity of the Na+,K+-ATPase is decreased [53–58], along with altered Na+,K+-ATPase isoform expression [59–63]. In human heart failure there is evidence for reduced concentration of the Na+,K+-ATPase (oubain binding sites) but no evidence for any subunit isoform switch [64–66]. One study to date has shown evidence for de-novo expression of a background chloride current (which would tend to counteract action potential prolongation) [67].

Potassium currents are the major repolarising currents active during the plateau of the action potential in myocytes isolated from a variety of model species and human hearts. Several groups have now measured K+ currents in human heart failure and in animals models of cardiac hypertrophy and these data are summarised in Table 1. Of all the mechanisms that may contribute to action prolongation, decreased K+ currents appear to be the most reproducible. Thus, in the studies outlined in Table 1, the density of the transient outward current (Ito) is reduced in hypertrophied hearts, regardless of species, precipitating factors or the disease stage. Indeed, preliminary evidence suggests that reduced Ito density represents a very early event in the response to decreased pump performance [74, 68]. Decreased Ito therefore, would appear to be a significant contributor to action potential prolongation in cardiac hypertrophy and failure. The role of other repolarising K+ currents is not as clear. Delayed rectifier currents (IK) can be separated into several components including a rapid component (IKr), a slow component (IKs) and a poorly characterised sustained component (Isus). Detailed analyses of the expression of each of these components during the development of cardiac hypertrophy have not been performed. In the majority of studies, the density of Isus is not significantly altered in hypertrophied myocytes, although Isus has been reported to be decreased in one report (see Table 1 for references). The inward rectifier (IK1) contributes to the late phase of repolarisation and, more importantly, to the setting of the resting membrane potential. The density of IK1 has been shown to be decreased in human heart failure and in some animal models (see Table 1 for references). Decreased IK1 density may contribute to the reduced resting membrane potential which accompanies cardiac hypertrophy in some models [17, 20, 37, 41, 43]. In other studies however, IK1 is either unchanged, or increased.


View this table:
[in this window]
[in a new window]

  		Table 1 K+ channel alterations in animal models of hypertrophy and human heart failure

 
2.2 Altered K+ channel gene transcription
Recently, we and others [41, 77–79]have applied molecular and biochemical techniques to address the mechanism underlying the reduced K+ current density in cardiac hypertrophy. These studies show that compensated hypertrophy following MI in the rat is associated with a decrease in the transcription of Kv4.2 and Kv4.3, the probable molecular correlates of Ito in rat. The transcription of some K+ channel genes encoding IK-like currents (Kv2.1, ERG) is also decreased during hypertrophy in animals and human hearts [79]although the functional consequences of decreased transcription have not been identified. In contrast, we find that mRNA levels for genes encoding inward rectifiers, IRK1 and IRK2, are unchanged in the hypertrophied heart, despite electrophysiological evidence for decreased IK1 in the same model [41]. These findings suggest that decreased K+ current density (and action potential prolongation) may be the result of reduced K+ channel gene expression at both the transcriptional and post-transcriptional level. Interestingly, the fetal K+ channel gene, Kv1.4 [80, 81]appears to be re-expressed in the hypertrophied myocyte [41, 82]suggesting that altered K+ channel gene expression represents yet another facet of the re-expression of fetal genes in cardiac hypertrophy.

2.3 The role of the sympathetic nervous system
The mechanism by which K+ channel expression is reduced (and action potential duration is increased) in hypertrophy and failure is not clear. However, reflex activation of the sympathetic nervous system occurs immediately in response to an insult to pump function. Acute administration of {alpha}-adrenergic agonists is known to prolong action potential duration [83–85]by a mechanism that involves inhibition of repolarising K+ currents (Ito [86–88], IK [89, 90]and IK1[91]) without significant effects on ICa [86, 92–94]. Thus, while chronic activation of the sympathetic nervous system is associated with a reduction in the positive inotropic effects of {alpha}-agonists [95], it seems plausible that {alpha}1-adrenoreceptor stimulation following activation of the sympathetic nervous system contributes to the initial action potential prolongation following acute alterations in loading of the myocardium.

2.4 The consequences of action potential prolongation-elevated intracellular calcium and positive inotropy: a compensatory response
It has long been recognised that action potential height and/or duration is an important regulator of the amount of calcium released from intracellular storage sites [96–100]. Furthermore, interventions that induce a prolongation of the action potential, such as {alpha}-adrenoreceptor stimulation, increase the amplitude of the calcium transient in cardiac myocytes [86]. In rat cardiac trabeculae, we find that inhibition of the transient outward potassium current (Ito) and prolongation of the action potential with 4-aminopyridine also enhances the amplitude of the calcium transient (Fig. 1). Prolongation of simulated action potentials using the action potential clamp technique has shown unequivocally that prolonged depolarisation can directly increase the amplitude of the calcium transient [101]. The mechanism by which action potential duration influences the amount of calcium released during cardiac excitation probably involves the two key sarcolemmal proteins involved in calcium cycling, the L-type calcium channel and the Na/Ca exchanger, since the function of both these proteins is directly influenced by the membrane potential. Prolonged depolarisation during the plateau of extended action potentials enhances calcium entry via the L-type calcium channel and retards calcium extrusion via the Na/Ca exchanger, thereby loading the cell with calcium [101, 102].

Elevated calcium transients have also been recorded in animal models of moderate cardiac hypertrophy. Differences in systolic calcium that exist between hypertrophied and normal myocytes are abolished under voltage clamp conditions where the duration of depolarisation is normalised [103], suggesting that action potential prolongation is responsible for the elevated systolic calcium seen in the hypertrophied myocyte. Since increases in the amplitude of the calcium transient are inotropic, it seems plausible that the reduction in K+ channel expression and action potential prolongation represents and early compensatory response of the heart to an increased load, thereby increasing contractility.

Compensatory action potential prolongation is, however, potentially arrhythmogenic and as such this compensatory mechanism may predispose the heart to lethal arrhythmias [104]. In addition, in Section 4we propose that chronic elevation in intracellular calcium (as a result of action potential prolongation) may potentiate mitogenic signalling cascades, leading to maladaptive gene expression (see below), over-riding any short term benefit and contributing to disease progression.


   3 Calcium handling in hypertrophy and failure
Top
 Abstract
 1 Introduction
 2 Action potential prolongation...
 3 Calcium handling in...
4 The contribution of...
 5 Implications for treatment
 6 Future directions
 7 Summary
 References
 
Release and reuptake of intracellular calcium are essential for efficient contraction and relaxation of the heart. Intracellular calcium is released via ryanodine sensitive calcium channels located in the SR, in response to calcium entering during the plateau phase of the action potential. The two main pathways for calcium removal are the SR CaATPase, which resequesters calcium into the SR, and the sarcolemmal NaCa exchanger. The available data from animal models suggest that the calcium handling properties of hypertrophied myocytes are highly stage dependent. In moderate hypertrophy in animal models the expression of genes encoding calcium handling proteins is relatively normal [105–109]. Indeed, during compensated hypertrophy, we and others find that systolic calcium is actually increased [41, 103, 110–112]without slowing in the rate of relaxation of the calcium transient. The elevation in the amplitude of the intracellular calcium transient could result from prolongation of the cardiac action potential, as observed following adrenoreceptor stimulation [86]and may represent a compensatory response (see Section 2.4).

Despite continued action potential prolongation however, systolic calcium is severely reduced [15], the calcium transient is significantly prolonged [13–15, 112]and Ca2+ uptake activity may be reduced [113–115]in more advanced stages of hypertrophy in animal models and in end-stage heart failure in humans. In animal models of severe hypertrophy, these events correlate with the finding that the expression of genes encoding calcium handling proteins is markedly reduced [105–109]. Although the mechanisms underlying altered calcium handling in end-stage human heart failure are not entirely clear, and there is currently controversy concerning the extent to which RNA levels are predictive of protein levels, a number of studies have demonstrated altered expression of genes encoding calcium handling proteins (including SR CaATPase (SERCA2), ryanodine receptor (RYR2), NaCa exchanger and phospholamban genes), and these are summarised in Table 2.

Unlike the changes that lead to action potential prolongation (see Section 2.1Section 2.2) therefore, impaired calcium handling appears to be a relatively late event in the progression toward failure. In contrast to altered K+ channel expression, it appears that changes in calcium handling may be maladaptive rather than compensatory, and may lead to severely impaired systolic and diastolic cardiac function, heralding the onset of failure [105].

At present the events leading to the late changes in calcium handling are poorly understood. However, chronic activation of compensatory mechanisms including action potential prolongation may trigger these late events. In the following sections we outline a hypothesis which describes a potential role for action potential prolongation, and the associated elevation in the levels of intracellular calcium, in the regulation of calcium handling gene expression.


   4 The contribution of action potential prolongation and elevated intracellular calcium to altered gene expression and the progression of heart failure: a hypothesis
Top
 Abstract
 1 Introduction
 2 Action potential prolongation...
 3 Calcium handling in...
 4 The contribution of...
5 Implications for treatment
 6 Future directions
 7 Summary
 References
 
The potential role for prolonged action potential duration in the progression of heart failure is outlined in Fig. 2. Decreased pump function as a result of myocardial infarction, hypertension or genetic abnormalities triggers a compensatory response which involves altered K+ channel gene expression. Prolonged action potential depolarisation results in elevated intracellular calcium which may acutely support the compromised heart. Elevated intracellular calcium however, may also potentiate mitogenic signalling cascades, leading to maladaptive gene expression, which may initially blunt the compensatory response and ultimately depress cardiac function, accelerating the progression toward failure.


Figure 2
View larger version (17K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 2 The role of action potential prolongation in the response to decreased pump function. Decreased pump function from numerous causes is associated with action potential prolongation. The increased amplitude of the intracellular calcium transient as a result of action potential prolongation is inotropic and may acutely compensate for the reduced cardiac output. Chronic elevations in the amplitude of the calcium transient however, may trigger maladaptive gene expression (such as decreased SR Ca2+ ATPase expression), which blunt the compensatory response and ultimately contribute to the progression from compensatory hypertrophy to cardiac failure. ----- shows the compensatory response which supports cardiac output, ——— shows the maladaptation which may contribute to failure.

 
Membrane depolarisation and calcium entry are important determinants of gene expression in a number of excitable cells [127–132]. Similarly, and consistent with the hypothesis, gene expression in cardiac myocytes has also been shown to be dependent on calcium. For example, NE treatment of cultured neonatal myocytes induces a decreased expression of SERCA2 and the decrease in SERCA2 can be abolished in contractile arrested and verapamil treated myocytes [133], implying that excitation-contraction coupling and calcium current through the L-type calcium channel are important in the phenotypic response to {alpha}-adrenergic agonists. Furthermore, the induction of the immediate early genes c-fos and Egr-1 by ET and ANGII in cultured adult cardiocytes is inhibited by the calcium antagonist, nisoldipine [134]and in neonatal myocytes, induction of the muscle specific genes MLC-2, {alpha}-actin and troponin I by ET could be mimicked by the calcium ionophore, ionomycin [135].

Given the potential role for altered gene expression in the pathogenesis of heart failure, the signalling cascades that lead to altered gene expression in heart failure have been the subject of intense research over the last decade. In-vitro and in-vivo studies have shown that altered gene expression can be induced by a number of stimuli including {alpha}- and β-adrenergic agonists, angiotensin II, endothelin, growth factors and mechanical activity. These diverse stimuli converge on the MAPK cascade [136–139]. Once activated, MAPK may translocate to the nucleus, where it can phosphorylate transcription factors and regulate gene expression [140, 141].The MAPK cascade can be activated by calcium [127, 142–148]and calcium sensitive mechanisms seem important for activation of the MAPK cascade by the hypertrophic stimuli, mechanical stretch [138], β-adrenergic agonists [148]and ANG II [149]in cardiac myocytes.

Additional calcium dependent second messenger systems may also play a role in altered gene expression in response to mitogenic stimuli. For example, over-expression of calmodulin in transgenic mice causes myocyte hypertrophy [150]while the calmodulin antagonist W-7 can inhibit the induction of ANF by PE in cultured neonatal myocytes [151]. Calmodulin, when activated by calcium (CaM), modulates the activity of a number of enzymes including CaM-dependent protein kinases (CaM kinases) and adenylate cyclases, both of which are capable of phosphorylating transcription factors and regulating gene expression [152, 153]. A role for PKC-dependent pathways has also been suggested [154, 155]and the activation of many isoforms of PKC is calcium dependent [156]. PKC may directly regulate gene expression following translocation to the nucleus [157]or may regulate gene expression via activation of the MAPK cascade [158].


   5 Implications for treatment
Top
 Abstract
 1 Introduction
 2 Action potential prolongation...
 3 Calcium handling in...
 4 The contribution of...
 5 Implications for treatment
6 Future directions
 7 Summary
 References
 
Morbidity and mortality in heart failure remain unacceptably high. Despite recent advances in medical treatment, heart failure remains a highly lethal disease. As we have argued, action potential prolongation and the associated elevation in systolic calcium may contribute to maladaptive gene expression and the progression toward cardiac failure, as well as to the high incidence of sudden cardiac death in patients with heart failure. Accordingly, it is possible to predict that agents that further prolong action potential duration (such as class III anti-arrhythmic agents) or increase calcium availability (such as positive inotropic agents) would be detrimental in the setting of cardiac hypertrophy and failure. Indeed, clinical practise supports this contention since the class III anti-arrhythmic agent, d-sotalol [159]and positive inotropic agents [160, 161]have generally been found to be detrimental in this patient group. On the contrary, agents that normalise action potential duration or reduce the availability of calcium may be beneficial. Reductions in the availability of calcium may explain some recent findings showing the long acting calcium antagonist, amlodipine [162], and the T-type calcium channel antagonist, mibefridil [163], are beneficial in human heart failure and in animal models of cardiac hypertrophy.

Since action potential prolongation in heart failure involves a reduction the net outward repolarising K+ current, a novel approach to the treatment of heart failure would be to normalise K+ channel gene expression. Conceivably, this could be achieved by gene transfer [164]or pharmacologically. With regard to the latter we and others have recently shown that thyroid hormone is capable of increasing K+ channel expression at the transcriptional level in rat ventricular myocytes [81, 165]. The possibility exists therefore, that agents with thyroid hormone-like properties may find a role in the treatment of heart failure.


   6 Future directions
Top
 Abstract
 1 Introduction
 2 Action potential prolongation...
 3 Calcium handling in...
 4 The contribution of...
 5 Implications for treatment
 6 Future directions
7 Summary
 References
 
In order to determine the role of action potential prolongation in the pathogenesis of cardiac failure we have created transgenic mice which over-express an N-terminus fragment of the rat Kv4.2 gene in a cardiac restricted manner [166]. Over-expression of this fragment in-vitro abolishes functional expression of full length Kv4.2 in heterologous expression systems. We hypothesised that in mice this construct should suppress functional expression of Ito, leading to action potential prolongation in the absence of any other trophic stimuli. Preliminary data suggest that these mice develop frank congestive heart failure resulting in death at 2–3 months of age [166]. An understanding of the mechanism by which dominant negative inhibition of K+ channels in the mouse heart leads to failure may help clarify the role of K+ channel down-regulation in the pathogenesis of heart disease.

Since action potential prolongation and the associated increase in intracellular calcium may play a central role in the pathogenesis and progression of heart failure, it is of particular interest to note that membrane depolarisation and intracellular calcium may also be capable of regulating K+ channel gene expression [82, 129, 167]. It is possible therefore, that elevated intracellular calcium may reduce expression of adult K+ channel isoforms, further prolonging action potential duration and accelerating disease progression. This possibility warrants further study.

A number of recent studies have implicated myocyte loss as an important factor in the progressive mechanical dysfunction that leads ultimately to cardiac failure [5]. While cell death can occur by necrosis or apoptosis, the latter appears predominant in the dog model of chronic pacing induced heart failure [6], in dogs with heart failure induced by multiple intracoronary microemboli [7]and in rats following experimental left ventricular infarction [8, 9]. The factors that trigger apoptosis in the hypertrophied myocardium are unknown. However, studies using non-cardiac cells have identified intracellular calcium as an important regulator of programmed cell death [168, 169]. In cardiac myocytes, stretch [170]and angiotensin II [171]have been shown capable of inducing apoptosis and, consistent with an important role for calcium, apoptosis induced by angiotensin II in adult rat ventricular myocytes can be inhibited by the calcium chelator BAPTA/AM and mimicked by the calcium ionophore, A23187 [GenBank] [171]. Further studies to explore the possible link between increases in intracellular calcium (secondary to action potential prolongation) and apoptosis in the overloaded heart are clearly warranted.


   7 Summary
Top
 Abstract
 1 Introduction
 2 Action potential prolongation...
 3 Calcium handling in...
 4 The contribution of...
 5 Implications for treatment
 6 Future directions
 7 Summary
References
 
Altered K+ channel expression and action potential prolongation is a common finding in heart disease. Previous studies have focused on the arrhythmogenic consequences of these alterations. However, given the connection between action potential profile, intracellular calcium concentration and myocyte gene expression, it seems plausible that altered K+ channel expression and action potential prolongation may also play a more insidious role in disease progression.

Time for primary review 38 days.


   Acknowledgements
 
This work was supported by the Heart & Stroke Foundation of Canada and a scholarship from the Medical Research Council of Canada (PHB). Equipment funding from the Tiffin Trust is gratefully acknowledged.


   References
Top
 Abstract
 1 Introduction
 2 Action potential prolongation...
 3 Calcium handling in...
 4 The contribution of...
 5 Implications for treatment
 6 Future directions
 7 Summary
 References
 

  1. Scheuer J, Buttrick P. The cardiac hypertrophic response to pathologic and physiologic loads. Circulation (1987) 75(Suppl_I):I63–I68.[Medline]
  2. Chien K.R, Knowlton K.U, Zhu H, Chen S. Regulation of cardiac gene expression during myocardial growth and hypertrophy: molecular studies of an adaptive physiologic response. FASEB J (1991) 5:3037–3046.[Abstract]
  3. Nadal-Ginard B, Mahdavi V. Molecular basis of cardiac performance: plasticity of the myocardium generated through protein isoform switches. J Clin Invest (1989) 84:1693–1700.[Web of Science][Medline]
  4. Boheler K, Schwartz K. Gene expression in cardiac hypertrophy. Trends Cardiovasc Med (1992) 2:172–182.
  5. Anversa P, Kajstura J, Olivetti G. Myocyte cell death in heart failure. Curr Opin Cardiol (1996) 11:245–251.[CrossRef][Web of Science][Medline]
  6. Lui Y, Cigola E, Cheng W, Kajstura J, Olivetti G, Hintze T.H, Anversa P. Myocyte nuclear mitotic division and programmed myocyte cell death characterise the cardiac myopathy induced by rapid ventricular pacing in dogs. Lab Invest (1995) 73:771–787.[Web of Science][Medline]
  7. Sharov V.G, Sabbah H.N, Shimoyama H, Goussev A.V, Lesch M, Goldstein S. Evidence of cardiocyte apoptosis in myocardium of dogs with chronic heart failure. Am J Pathol (1996) 148:141–149.[Abstract]
  8. Kajstura J, Cheng W, Reiss K, Clark W.A, Sonnenblick E.H, Krajewski S, Reed J.C, Olivetti G, Anversa P. Apoptotic and necrotic myocyte cell deaths are independent contributing variables of infarct size in rats. Lab Invest (1996) 74:86–107.[Web of Science][Medline]
  9. Cheng W, Kajstura J, Nitahara J.A, Li B, Reiss K, Liu Y, Clark W.A, Krajewski S, Reed J.C, Olivetti G, Anversa P. Programmed myocyte cell death affects the viable myocardium after infarction in rats. Exp Cell Res (1996) 226:316–327.[CrossRef][Web of Science][Medline]
  10. Ten Eick RE, Basset AL. Cardiac hypertrophy and altered cellular electrical activity of the myocardium. Possible electrophysiologic basis for myocardial contractility changes. In: Sperelakis N, editor. Physiology and pathophysiology of the heart. The Hague: Martinus Nijhoff Publishing 1984:521-542.
  11. Hart G. Cellular electrophysiology in cardiac hypertrophy and failure. Cardiovascular Res (1994) 28:933–946.[Free Full Text]
  12. Coltart D.J, Meldrum S.J. Hypertrophic cardiomyopathy: An electrophysiological study. BMJ (1970) 4:217–218.[Abstract/Free Full Text]
  13. Gwathmey J.K, Copelas L, MacKinnon R, Schoen F.J, Feldman M.D, Grossman W, Morgan J.P. Abnormal intracellular calcium handling in myocardium from patients with end-stage heart failure. Circ Res (1987) 61:70–76.[Abstract/Free Full Text]
  14. Gwathmey J.K, Slawsky M.T, Hajjar R.J, Briggs G.M, Morgan J.P. Role of intracellular calcium handling in force-interval relationship of human ventricular myocardium. J Clin Invest (1990) 85:1599–1613.[Web of Science][Medline]
  15. Beuckelmann D.J, Nabauer M, Erdmann E. Intracellular calcium handling in isolated ventricular myocytes from patients with terminal heart failure. Circulation (1992) 85:1046–1055.[Abstract/Free Full Text]
  16. Beuckelmann D.J, Nabauer M, Erdmann E. Alterations of K+ currents in isolated human ventricular myocytes from patients with terminal heart failure. Circ Res (1993) 73:379–385.[Abstract/Free Full Text]
  17. Gelband H, Basset A.L. Depressed transmembrane potentials during experimentally induced ventricular failure in cats. Circ Res (1973) 32:625–634.[Abstract/Free Full Text]
  18. Tritthart H, Leudeke H, Bayer R, Stierle H, Kaufmann R. Right ventricular hypertrophy in the cat — an electrophysiological and anatomical study. J Mol Cell Cardiol (1975) 7:163–174.[CrossRef][Web of Science][Medline]
  19. Houser S.R, Freeman A.R, Jaegger J.M, Breisch E.A, Coulson R.L, Carey R, Spann J.F. Resting potential changes associated with Na-K pump in failing heart muscle. Am J Physiol (1981) 240:H168–H176.[Web of Science][Medline]
  20. Kleiman R.B, Houser S.R. Calcium currents in normal and hypertrophied isolated feline ventricular myocytes. Am J Physiol (1988) 255:H1434–H1442.[Web of Science][Medline]
  21. Gulch R.W, Baumann R, Jacob R. Analysis of myocardial action potential in left ventricular hypertrophy of Goldblatt rats. Basic Res Cardiol (1979) 74:69–82.[CrossRef][Web of Science][Medline]
  22. Aronson R.S. Characteristics of action potentials of hypertrophied myocardium from rats with renal hypertension. Circ Res (1980) 47:443–454.[Free Full Text]
  23. Capasso J.M, Malhotra A, Scheuer J, Sonnenblick E.H. Myocardial biochemical, contractile and electrical performance after imposition of hypertension in young and old rats. Circ Res (1986) 58:445–460.[Abstract/Free Full Text]
  24. Hayashi H, Shibata S. Electrical property of cardiac cell membrane of spontaneously hypertensive rat. Eur J Pharmacol (1974) 27:355–359.[CrossRef][Web of Science]
  25. Brooksby P, Levi A.J, Jones J.V. The electrophysiological characteristics of hypertrophied ventricular myocytes from the spontaneously hypertensive rat. J Hypertens (1993) 11:611–622.[CrossRef][Web of Science][Medline]
  26. Heller L.J, Stauffer E.K. Membrane potentials and contractile events of hypertrophied cardiac muscle. Proc Soc Exp Biol Med (1981) 166:141–147.[CrossRef][Medline]
  27. Thollon C, Kreher P, Carlton V, Rossi A. Hypertrophy induced alteration of action potential and effects of the inhibition of angiotensin converting enzyme by perindopril in infarcted rat hearts. Cardiovasc Res (1989) 23:224–230.[Web of Science][Medline]
  28. Qin D, Zhang Z.H, Caref E.B, Boutjdir M, Jain P, El-Sherif N. Cellular and ionic basis of arrhythmias in postinfarction remodeled ventricular myocardium. Circ Res (1996) 79:461–473.[Abstract/Free Full Text]
  29. Schouten V.J.A, Vliegen H.W, van der Laarse A, Huysmans H.A. Altered calcium handling at normal contractility in hypertrophied rat heart. J Mol Cell Cardiol (1990) 22:987–998.[CrossRef][Web of Science][Medline]
  30. Kohya T, Kimura S, Myerburg R.J, Basset A.L. Suceptibility of hypertrophied rat hearts to ventricular fibrillation during acute ischaemia. J Mol Cell Cardiol (1988) 20:159–168.[CrossRef][Web of Science][Medline]
  31. Scamps F, Mayoux E, Charlemagne D, Vassort G. Calcium current in single cells isolated from normal and hypertrophied rat heart. Effects of β-adrenergic stimulation. Circ Res (1990) 67:199–208.[Abstract/Free Full Text]
  32. Xu X, Best P.M. Decreased transient outward K+ current in ventricular myocytes from acromegalic rats. Am J Physiol (1991) 260:H935–H942.[Web of Science][Medline]
  33. Meszaros J, Ryder K.O, Hart G. Transient outward current in catecholamine-induced cardiac hypertrophy in the rat. Am J Physiol (1996) 271:H2360–H2367.[Web of Science][Medline]
  34. Potreau D, Gomez J.P, Fares N. Depressed transient outward current in single hypertrophied cardiomyocytes isolated from the right ventricle of ferret heart. Cardiovasc Res (1995) 30:440–448.[Abstract/Free Full Text]
  35. Rossner K.L, Sachs H.G. Electrophysiological study of Syrian hamster hereditary cardiomyopathy. Am J Physiol (1991) 260:H1179–H1186.[Web of Science][Medline]
  36. Capasso J.M, Sonnenblick E.H, Anversa P. Chronic calcium channel blockade prevents the progression of myocardial and electrical dysfunction in the cardiomyopathic Syrian hamster. Circ Res (1990) 67:1381–1393.[Abstract/Free Full Text]
  37. Nordin C, Siri F, Aronson R.S. Electrophysiological characteristics of single myocytes isolated from hypertrophied guinea pig hearts. J Mol Cell Cardiol (1989) 21:729–739.[CrossRef][Web of Science][Medline]
  38. Ryder K.O, Bryant S.M, Hart G. Membrane current changes in left ventricular myocytes isolated from guinea pigs after abdominal aortic coarctation. Cardiovasc Res (1993) 27:1278–1287.[Abstract/Free Full Text]
  39. Hicks M.N, McIntosh M.A, Kane K.A, Rankin A.C, Cobbe S.M. The electrophysiology of rabbit hearts with left ventricular hypertrophy under normal and ischaemic conditions. Cardiovasc Res (1995) 30:181–186.[Abstract/Free Full Text]
  40. Kaab S, Nuss B, Chiamvimonvat N, O'Rourke B, Pak P.H, Kass D.A, Marban E, Tomaselli G.F. Ionic mechanism of action potential prolongation in ventricular myocytes from dogs with pacing-induced heart failure. Circ Res (1996) 78:262–273.[Abstract/Free Full Text]
  41. Kaprielian R, Kassiri Z, Tsoporis J, Dawood F, Liu P, Parker T.G, Backx P.H. Electrical, ionic and mechanical alterations in right ventricular myocardium isolated from rats with left coronary infarcts. Circulation (1996) 94(8):1–159. (Abstract).[Free Full Text]
  42. Keung E.C. Calcium current is increased in isolated adult myocytes from hypertrophied rat myocardium. Circ Res (1989) 64:753–763.[Abstract/Free Full Text]
  43. Bouron A, Potreau D, Raymond G. The L-type calcium current in single hypertrophied cardiomyocytes isolated from the right ventricle of ferret heart. Cardiovasc Res (1992) 26:662–670.[Abstract/Free Full Text]
  44. Cerbai E, Barbieri M, Li Q, Mugelli A. Ionic basis of action potential prolongation of hypertrophied cardiac myocytes isolated from hypertensive rats of different ages. Cardiovasc Res (1994) 28:1180–1187.[Abstract/Free Full Text]
  45. Meszaros J, Coutinho J.J, Bryant S.M, Ryder K.O, Hart G. L-type calcium current in catecholamine-induced cardiac hypertrophy in the rat. Exp Physiol (1997) 82:71–83.[Abstract]
  46. Nuss H.B, Houser S.R. Voltage dependence of contraction and calcium current in severely hypertrophied feline ventricular myocytes. J Mol Cell Cardiol (1991) 23:717–726.[CrossRef][Web of Science][Medline]
  47. Rossner K.L. Calcium current in congestive heart failure of hamster cardiomyopathy. Am J Physiol (1991) 260:H1179–H1186.[Web of Science][Medline]
  48. Ming Z, Nordin C, Siri F, Aronson R.S. Reduced calcium current density in single myocytes isolated from hypertrophied failing guinea pig hearts. J Mol Cell Cardiol (1994) 26:1133–1143.[CrossRef][Web of Science][Medline]
  49. Legrand B, Hatem S, Deroubaix E, Couetil J.P, Coraboeuf E. Depressed transient outward and calcium currents in dilated human atria. Cardiovasc Res (1994) 28:548–556.[Abstract/Free Full Text]
  50. Zhang X.-Q, Tillotson D.L, Moore R.L, Zelis R, Cheung J.Y. Na+/Ca2+ exchange currents and SR Ca2+ contents in postinfarction myocytes. Am J Physiol (1996) 271:C1800–C1807.[Web of Science][Medline]
  51. Momtaz A, Coulombe A, Richer P, Mercadier J.J, Coraboeuf E. Action potential and plateau ionic currents in moderately and severely DOCA-salt hypertrophied rat hearts. J Mol Cell Cardiol (1996) 28:2511–2522.[CrossRef][Web of Science][Medline]
  52. Kent R.L, Rozich J.D, McCollam P.L, McDermott D.E, Thacker U.F, Menick D.R, et al. Rapid expression of the Na+-Ca2+ exchanger in response to cardiac pressure overload. Am J Physiol (1993) 265:H1024–H1029.[Web of Science][Medline]
  53. Yazaki Y, Fujji J. Depressed Na-K-ATPase activity in the failing rabbit heart. Jpn Heart J (1972) 13:73–83.[Medline]
  54. Whitmer K.R, Lee J.H, Martin A.F, Lane L.K, Lee S.W, Schwartz A, et al. Myocardial Na,K-ATPase in one kidney, one clip hypertensive rats. J Mol Cell Cardiol (1986) 18:1085–1095.[CrossRef][Web of Science][Medline]
  55. Norgaard A, Baandrup U, Larsen J.S, Kjeldsen K. Heart Na,K-ATPase activity in cardiomyopathic hamsters as estimated from K-dependent 3-O-MFPase activity in crude homogenates. J Mol Cell Cardiol (1987) 19:589–594.[CrossRef][Web of Science][Medline]
  56. Dixon I.M, Hata T, Dhalla N.S. Sarcolemmal Na+-K+-ATPase activity in congestive heart failure due to myocardial infarction. Am J Physiol (1992) 262:C664–C671.[Web of Science][Medline]
  57. Spinale F.G, Clayton C, Tanaka R, Fulbright B.M, Mukherjee R, Schulte B.A, et al. Myocardial Na+,K+-ATPase in tachycardia induced cardiomyopathy. J Mol Cell Cardiol (1992) 24:277–294.[Web of Science][Medline]
  58. Fan T.H, Frantz R.P, Elam H, Sakamoto S, Imai N, Liang C.S. Reductions of myocardial Na-K-ATPase activity and oubain binding sites in heart failure: prevention by nadolol. Am J Physiol (1993) 265:H2086–H2093.[Web of Science][Medline]
  59. Tsuruya Y, Ikeda U, Yamamoto K, Seimo Y, Kanbe T, Shimada K. Decreased Na,K-ATPase gene expression in cardiomyopathic hamster hearts. Life Sci (1994) 54:71–77.[CrossRef][Web of Science][Medline]
  60. Kim C.H, Fan T.H, Kelly P.F, Himura Y, Delehanty J.M, Hang C.L, Liang C.S. Isoform-specific regulation of myocardial Na,K-ATPase alpha-subunit in congestive heart failure. Role of norepinephrine. Circulation (1994) 89:313–320.[Abstract/Free Full Text]
  61. Charlemagne D, Orlowski J, Olivero P, Rannou F, Sainte Beuve C, Swynghdauw B, Lane L.K. Alteration of Na,K-ATPase subunit mRNA and protein levels in hypertrophied rat heart. J Biol Chem (1994) 269:1541–1547.[Abstract/Free Full Text]
  62. Book C.B, Moore R.L, Semanchik A, Ng Y.C. Cardiac hypertrophy alters expression of Na+,K+-ATPase subunit isoforms at mRNA and protein levels in rat myocardium. J Mol Cell Cardiol (1994) 26:591–600.[CrossRef][Web of Science][Medline]
  63. Sweadner K.J, Herrera V.L, Amato S, Moellmann A, Gibbons D.K, Repke K.R. Immunologic identification of Na+,K+-ATPase isoforms in myocardium. Isoform change in deoxycorticosterone acetate-salt hypertension. Circ Res (1994) 74:669–678.[Abstract/Free Full Text]
  64. Shamraj O.I, Grupp I.L, Grupp G, Melvin D, Gradoux N, Kramers W, et al. Characterisation of NA/K-ATPase, its isoforms, and the inotropic response to ouabain in isolated failing human hearts. Cardiovasc Res (1993) 27:2229–2237.[Abstract/Free Full Text]
  65. Ellingsen O, Holthe M.R, Svindland A, Aksnes G, Sejersted O.M, Ilebekk A. Na,K-pump concentration in hypertrophied human hearts. Eur Heart J (1994) 15:1184–1190.[Abstract/Free Full Text]
  66. Allen P.D, Schmidt T.A, Marsh J.D, Kjeldsen K. Na,K-ATPase expression in normal and failing human left ventricle. Basic Res Cardiol (1987) 192(1):87–94. Suppl.
  67. Benitah J.-P, Gomez A.M, Delgardo C, Lorente P, Lederer W.J. A chloride current component induced by hypertrophy in rat ventricular myocytes. Am J Physiol (1997) 272:H2500–H2506.[Web of Science][Medline]
  68. Yao J.-A, Zhou Y.-Y, Jiang M, Fan J.-S, Tseng G.-N. Differential effects of myocardial infarction on transient outward, delayed rectifier and inward rectifier currents in rat ventricle. Biophys J (1997) 72:A143. (Abstract).
  69. Benitah J.-P, Gomez A.M, Bailly P, DaPointe J.P, Berson G, Delgardo C, Lorente P. Heterogeneity of the early outward current in ventricular cells isolated from normal and hypertrophied rat hearts. J Physiol (1993) 469:111–138.[Abstract/Free Full Text]
  70. Tomita F, Bassett A.L, Myerberg R.J, Kimura S. Diminished transient outward currents in rat hypertrophied ventricular myocytes. Circ Res (1994) 75:296–303.[Abstract/Free Full Text]
  71. Li Q, Keung E.C. Effects of myocardial hypertrophy on transient outward current. Am J Physiol (1994) 266:H1738–H1745.[Web of Science][Medline]
  72. Coulombe A, Momtaz A, Richer P, Swynghedauw B, Coraboeuf E. Reduction of calcium independent transient outward potassium current density in DOCA salt hypertrophied rat ventricular myocytes. Pflugers Arch (1994) 427:47–55.[CrossRef][Web of Science][Medline]
  73. Kleiman R.B, Houser S.R. Outward currents in normal and hypertrophied feline ventricular myocytes. Am J Physiol (1989) 256:H1450–H1461.[Web of Science][Medline]
  74. Lue W.-M, Boyden P.A. Abnormal electrical properties of myocytes from chronically infarcted canine heart. Alterations in Vmax and the transient outward current. Circulation (1992) 85:1175–1188.[Abstract/Free Full Text]
  75. Thuringer D, Coulombe A, Deroubaix E, Coraboeuf E, Mercadier J.J. Depressed transient outward current density in ventricular myocytes from cardiomyopathic Syrian hamsters of different ages. J Mol Cell Cardiol (1996) 28:387–401.[CrossRef][Web of Science][Medline]
  76. Thuringer D, Coulombe A, Deroubaix E, Coraboeuf E, Mercadier J.J. Ionic basis of the action potential prolongation in ventricular myocytes from Syrian hamsters with dilated cardiomyopathy. Cardiovasc Res (1996) 31:747–757.[Abstract/Free Full Text]
  77. Gigh-Jain M, Huang B, El-Sherif N. Differential expression of voltage-gated K+ channel genes in left ventricular remodeled myocardium after experimental myocardial infarction. Circ Res (1996) 79:669–675.[Abstract/Free Full Text]
  78. Jiang M, Yao J.-A, Zhou Y.-Y, Tseng G.-N. Differential effects of myocardial infarction on K channel expression in rat heart. Biophys J (1997) 72:A143. (Abstract).
  79. Kaab S.H, Duc J, Ashen D, Nabauer M, Beuckelmann D.J, Dixon J, McKinnon D, Tomaselli G.F. Quantitative analysis of K+ channel mRNA expression in normal and failing human ventricle reveals the molecular identity of Ito1. Circulation (1996) 94(Suppl. I):592. (Abstract).[Free Full Text]
  80. Xu H, Dixon J.E, Barry D.M, Trimmer J.S, Merlie J.P, McKinnon D, Nerbonne J.M. Developmental analysis reveals mismatches in the expression of K+ channel {alpha}-subunits and voltage-gated K+ channel currents in rat ventricular myocytes. J Gen Physiol (1996) 108:405–419.[Abstract/Free Full Text]
  81. Wickenden A.D, Kapriellian R, Parker T.G, Jones O.T, Backx P.H. Effects of development and thyroid hormone on K+ currents and K+ channel gene expression in rat ventricle. J Physiol (1997) 504:271–286.[Abstract/Free Full Text]
  82. Matsubara H, Susuki 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]
  83. Pappano A.J. Propranolol-insensitive effects of epinephrine on action potential repolarisation in electrically driven atria of the guinea pig. J Phamacol Exp Ther (1971) 177:85–95.[Abstract/Free Full Text]
  84. Hescheler J, Nawrath H, Tang M, Trautwein W. Adrenoceptor mediated changes of excitation and contraction in ventricular heart muscle from guinea pigs and rabbits. J Physiol (1988) 397:657–670.[Abstract/Free Full Text]
  85. Giotti A, Ledda F, Mannaioni P.F. Effects of noradrenaline and isoprenaline, in combination with {alpha}- and β-receptor blocking substances, on the action potential of cardiac Purkinje fibres. J Physiol (1973) 229:99–113.[Abstract/Free Full Text]
  86. Fedida D, Bouchard R.A. Mechanisms for the positive inotropic effect of {alpha}1-adrenoceptor stimulation in rat cardiac myocytes. Circ Res (1992) 71:673–688.[Abstract/Free Full Text]
  87. Apkon M, Nerbonne J.M. {alpha}1-Adrenergic agonists selectively suppress voltage dependent K+ currents in rat ventricular myocytes. Proc Natl Acad Sci USA (1988) 85:8756–8760.[Abstract/Free Full Text]
  88. Tohse N.H, Nakaya H, Hattori Y, Endou M, Kanno M. Inhibitory effect mediated by {alpha}1-adrenoceptors on transient outward current in isolated rat ventricular cells. Pflugers Arch. (1990) 415:575–581.[Web of Science][Medline]
  89. Ravens U, Wang X.L, Wettwer E. Alpha adrenoceptor stimulation reduces outward currents in rat ventricular myocytes. J Pharmacol Exp Ther (1989) 250:364–370.[Abstract/Free Full Text]
  90. Van Wagoner D, Kirian M, Lamorgese M. Phenylephrine suppresses outward K+ currents in rat atrial myocytes. Am J Physiol (1996) 271:H937–H946.[Medline]
  91. Braum A.P, Fedida D, Giles W.R. Activation of {alpha}1-adrenoceptors modulates the inwardly rectifying potassium currents of mammalian atrial myocytes. Pflugers Arch. (1992) 421:431–439.[CrossRef][Web of Science][Medline]
  92. Fedida D, Shimoni Y, Giles W.R. {alpha}-Adrenergic modulation of the transient outward current in rabbit atrial myocytes. J Physiol (1990) 423:257–277.[Abstract/Free Full Text]
  93. Ravens U, Wang X.-L, Wettwer E. Alpha adrenoceptor stimulation reduces outward currents in rat ventricular myocytes. J Pharmacol Exp Ther (1989) 250:364–370.[Abstract/Free Full Text]
  94. Hartmann H.A, Mazzocca N.J, Kleimann R.B, Houser S.R. Effects of phenylephrine on calcium current and contractility of feline ventricular myocytes. Am J Physiol (1988) 255:H1173–H1180.[Web of Science][Medline]
  95. Steinfath M, Danielsen S, von der Leyen H, Mende U, Meyer W, Neumann J, et al. Reduced alpha-1 and beta-2-adrenoceptor-mediated positive inotropic effects in human end-stage heart failure. Br J Pharmacol (1992) 105:463–469.[Web of Science][Medline]
  96. Wood E.H, Heppner R, Weidmann S. Inotropic effects of electric currents. Circ Res (1969) 24:409–445.[Abstract/Free Full Text]
  97. Morad M, Goldman Y. Excitation-contraction coupling in heart muscle: membrane control of development of tension. Prog Biophys Mol Biol (1973) 27:257–313.[CrossRef]
  98. Allen D.G. On the relationship between action potential duration and tension in cat papillary muscle. Cardiovasc Res (1977) 11:210–218.[Abstract/Free Full Text]
  99. Wolfhart B. Relationship between peak force, action potential duration and stimulus interval in rabbit myocardium. Acta Physiol Scand (1979) 106:395–409.[Web of Science][Medline]
  100. Schouten V.J.A. The negative correlation between action potential duration and force of contraction during restitution in rat myocardium. J Mol Cell Cardiol (1986) 18:1033–1045.[CrossRef][Web of Science][Medline]
  101. Bouchard R.A, Clark R.B, Giles W.R. Effects of action potential duration on excitation-contraction coupling in rat ventricular myocytes. Action potential voltage-clamp measurements. Circ Res (1995) 76:790–801.[Abstract/Free Full Text]
  102. Bouchard R.A, Clark R.B, Giles W.R. Role of sodium-calcium exchange in activation of contraction in rat ventricle. J Physiol (1995) 472:391–413.[Web of Science]
  103. Brooksby P, Levi A.J, Jones J.V. Investigation of the mechanisms underlying the increased contraction of hypertrophied ventricular myocytes isolated from the spontaneously hypertensive rat. Cardiovasc Res (1993) 27:1268–1277.[Abstract/Free Full Text]
  104. Tomaselli G.F, Beuklemann D.J, Calkins H.G, Berger R.D, Kessler P.D, Lawrence J.H, Kass D, Feldman A.M, Marban E. Sudden cardiac death in heart failure: The role of abnormal repolarisation. Circulation (1994) 90:2534–2539.[Abstract/Free Full Text]
  105. Feldman A.M, Weinberg E.O, Ray P.E, Lorell B.H. Selective changes in cardiac gene expression during compensated hypertrophy and the transition to cardiac decompensation in rats with chronic aortic banding. Circ Res (1993) 73:184–192.[Abstract]
  106. De la Bastie D, Levitsky D, Rappaport L, Mercadier J.-J, Marotte F, Wisnewsky C, Brovkovich V, Schwartz K, Lompre A.-M. Function of the sarcoplasmic reticulum and expression of its Ca2+-ATPase gene in pressure overload-induced cardiac hypertrophy in the rat. Circ Res (1990) 66:554–564.[Abstract/Free Full Text]
  107. Kiss E, Ball N.A, Kranias E.G, Walsh R.A. Differential changes in cardiac phospholamban and sarcoplasmic reticular Ca(2+)-ATpase protein levels. Effects on Ca2+ transport and mechanics in compensated pressure- overload hypertrophy and congestive cardiac failure. Circ Res (1995) 77(4):759–764.[Abstract/Free Full Text]
  108. Arai M, Suzuki T, Nagai R. Sarcoplasmic reticulum genes are upregulated in mild cardiac hypertrophy but down regulated in severe cardiac hypertrophy induced by pressure overload. J Mol Cell Cardiol (1996) 28(8):1583–1590.[CrossRef][Web of Science][Medline]
  109. Qi M, Shannon T.R, Euler D.E, Bers D.M, Samarel A.M. Downregulation of sarcoplasmic reticulum Ca2+-ATPase during progression of left ventricular hypertrophy. Am J Physiol (1997) 272:H2416–H2424.[Web of Science][Medline]
  110. Litwin S.E, Morgan J.P. Captopril enhances intracellular calcium handling and β-adrenergic responsiveness of myocardium from rats with post-infarction failure. Circ Res (1992) 71:797–807.[Abstract/Free Full Text]
  111. Kagaya Y, Hajjar R.J, Gwathmey J.K, Barry W.H, Lorell B.H. Long term angiotensin-converting enzyme inhibition with fosinopril improves depressed responsiveness to Ca2+ in myocytes from aortic-banded rats. Circulation (1996) 94:2915–2922.[Abstract/Free Full Text]
  112. Siri F.M, Krueger J, Nordin C, Ming Z, Aronson R.S. Depressed intracellular calcium transients and contraction in myocytes from hypertrophied and failing guinea pig hearts. Am J Physiol (1991) 261:H514–H530.[Web of Science][Medline]
  113. Flesch M, Schwinger R.H, Schnabel P, Schiffer F, van Gelder I, Bavendiek U, et al. Sarcoplasmic reticulum Ca2+-ATPase and phospholamban mRNA and protein levels in end-stage human heart failure due to ischaemic or dilated cardiomyopathy. J Mol Med (1996) 74:321–332.[CrossRef][Web of Science][Medline]
  114. Limas C.J, Olivari M.-T, Goldenberg I.F, Levine T.B, Benditt D.G, Simon A. Calcium uptake by cardiac sarcoplasmic reticulum in human dilated cardiomyopathy. Cardiovasc Res (1987) 21:601–605.[Web of Science][Medline]
  115. Pieske B, Kretschmann B, Meyer M, Holubarsch C, Weirich J, Posival H, et al. Alterations in intracellular calcium handling associated with the inverse force-frequency relation in human dilated cardiomyopathy. Circulation (1995) 92:1169–1178.[Abstract/Free Full Text]
  116. Hasenfuss G, Meyer M, Schillinger W, Preuss M, Pieske B, Just H. Calcium handling proteins in the failing human heart. Basic Res Cardiol (1997) 92(1):87–93. Suppl.[CrossRef][Web of Science][Medline]
  117. Flesch M, Schwinger R.H, Schiffer F, Frank K, Sudkamp M, Kuhn-Regnier F, et al. Evidence for functional relevance of an enhanced expression of the Na+-Ca2+ exchanger in failing human myocardium. Circulation (1996) 94:992–1002.[Abstract/Free Full Text]
  118. Reinecke H, Studer R, Vetter R, Holtz J, Drexler H. Cardiac Na+/Ca2+ exchange activity in patients with end-stage heart failure. Cardiovasc Res (1996) 31:48–54.[Abstract/Free Full Text]
  119. Lo G, Moschella M.C, Watras J, Handa K.K, Fyfe B.S, Marks A.R. Differential regulation of two types of intracellular calcium release channels during end-stage heart failure. J Clin Invest (1995) 95:888–894.[Web of Science][Medline]
  120. Movsesian M.A, Karimi M, Green K, Jones L.R. Ca2+-transporting ATPase, phospholamban, and calsequestrin levels in nonfailing and failing human myocardium. Circulation (1994) 90:653–657.[Abstract/Free Full Text]
  121. Studer R, Reinecke H, Bilger J, Eschenhagen T, Böhm M, Hasenfuß G, Just H, Holtz J, Drexler H. Gene expression of the cardiac Na+-Ca2+ exchanger in end-stage human heart failure. Circ Res (1994) 75:443–453.[Abstract/Free Full Text]
  122. Mercadier J.-J, Lompre A.-M, Duc P, Boheler K.R, Fraysse J.-B, Wisnewsky C, Allen P.D, Komajda M, Schwartz K. Altered sarcoplasmic reticulum Ca2+-ATPase gene expression in the human ventricle during end-stage heart failure. J Clin Invest (1990) 85:305–309.[Web of Science][Medline]
  123. Feldman A.M, Ray P.E, Silan C.M, Mercer J.A, Minobe W, Bristow M.R. Selective gene expression in failing human heart: Quantification of steady-state levels of messenger RNA in endomyocardial biopsies using the polymerase chain reaction. Circulation (1991) 83:1866–1872.[Abstract/Free Full Text]
  124. Meyer M, Schillinger W, Pieske B, Holubarsch C, Heilmann C, Posival H, et al. Alterations of sarcoplasmic reticulum proteins in failing human dilated cardiomyopathy. Circulation (1995) 92:778–784.[Abstract/Free Full Text]
  125. Arai M, Alpert N.R, Maclennan D.H, Barton P, Periasamy M. Alterations in sarcoplasmic reticulum gene expression in human heart failure. A possible mechanism for alterations in systolic and diastolic properties of the failing myocardium. Circ Res (1993) 72:463–469.[Abstract/Free Full Text]
  126. Linck B, Boknik P, Eschenhagen T, Muller F.U, Neumann J, Nose M, et al. Messenger RNA expression and immunological quantification of phospholamban and SR-Ca2+-ATPase in failing and nonfailing human hearts. Cardiovasc Res (1996) 31:625–632.[Abstract/Free Full Text]
  127. Finkbeiner S, Greenberg M.E. Ca2+-dependent routes to Ras: Mechanisms for neuronal survival, differentiation and plasticity. Neuron (1996) 16:233–236.[CrossRef][Web of Science][Medline]
  128. Levitan E.S, Gealy R, Trimmer J.S, Takimoto K. Membrane depolarisation inhibits Kv1.5 voltage-gated K+ channel gene transcription and protein expression in pituatory cells. J Biol Chem (1995) 270:6036–6041.[Abstract/Free Full Text]
  129. Schmidt J. Depolarization-transcription coupling in excitable cells. Rev Physiol Biochem Pharmacol (1996) 127:251–279.[Web of Science][Medline]
  130. Offord J, Catterall W.A. Electrical activity, cAMP, and cytosolic calcium regulate mRNA encoding sodium channel alpha subunits in rat muscle cells. Neuron (1989) 2:1447–1452.[CrossRef][Web of Science][Medline]
  131. Huang C.F, Schmidt J. Calcium influx blocks the skeletal muscle acetylcholine receptor alpha-subunit gene in vivo. FEBS Lett. (1994) 338:277–280.[CrossRef][Web of Science][Medline]
  132. Abu-Shakra S.R, Cole A.J, Adams R.N, Drachmann D.B. Cholinergic stimulation of skeletal muscle cells induces rapid immediate early gene expression: role of intracellular calcium. Bran Res Mol Brain Res (1994) 26:55–60.[CrossRef]
  133. Muller A, Zuidwijk M.J, Simonides W.S, Van Hardeveld C. Modulation of SERCA2 expression by thyroid hormone and norepinephrine in cardiocytes: role of contractility. Am J Physiol (1997) 272:H1876–H1885.[Web of Science][Medline]
  134. Grohe C, Nouskas J, Vetter H, Neyses L. Effects of nisoldipine on endothelin-1 and angiotensin II-induced immediate/early gene expression and protein synthesis in adult rat ventricular cardiomyocytes. J Cardiovasc Pharmacol (1994) 24:13–16.[Web of Science][Medline]
  135. Ito H, Hirata Y, Tsujino M, Adachi S, Takamoto T, Nitta M, Taniguchi K, Marumo F. Endothelin-1 induces hypertrophy with enhanced expression of muscle-specific genes in cultured neonatal rat cardiomyocytes. Circ Res (1991) 69:209–215.[Abstract/Free Full Text]
  136. Bogoyevitch M.A, Glennon P.E, Sugden P.H. Endothelin-1, phorbol esters and phenylephrine stimulate MAP kinase activities in ventricular cardiomyocytes. FEBS Lett. (1993) 317:271–275.[CrossRef][Web of Science][Medline]
  137. Sadoshima J.I, Izumo S. Signal transduction pathways of angiotensin II-induced fos gene expression in cardiac myocytes in-vitro. Roles of phospholipid-derived second messengers. Circ Res (1993) 73:424–438.[Abstract/Free Full Text]
  138. Yamazaki T, Tobe K, Hoh E, Maemura K, Kaida T, Komura I, Tamemoto H, Kadowaki T, Nagai R, Yazaki Y. Mechanical loading activates mitogen-activated protein kinase and S6 peptide kinase peptide in cultured rat cardiac myocytes. J Biol Chem (1993) 269:12069–12076.
  139. Bogoyevitch M.A, Glennon P.E, Andersson M.B, Clerk A, Lazou A, Marshall C.J, Parker P.J, Sugden P.H. Endothelin-1 and fibroblast growth factors stimulate the mitogen-activated protein kinase signalling cascade in cardiac myocytes. The potential role of the cascade in the integration of two signalling pathways leading to myocyte hypertrophy. J Biol Chem (1994) 269:1110–1119.[Abstract/Free Full Text]
  140. Bogoyevitch M.A, Sugden P.H. The role of protein kinases in adaptational growth of the heart. Int J Biochem Cell Biol (1996) 1:1–12.[Medline]
  141. Page C, Doubell A.F. Mitogen-activated protein kinase (MAPK) in cardiac tissues. Mol Cell Biochem (1996) 157:49–57.[Web of Science][Medline]
  142. Chao T.-S.O, Byron K.L, Lee K.-M, Villereal M, Rosner M.R. Activation of MAP kinases by calcium-dependent and calcium-independent pathways. Stimulation by thapsigargin and epidermal growth factor. J Biol Chem (1992) 267:19876–19883.[Abstract/Free Full Text]
  143. Chao T.-S.O, Foster D.A, Rapp U.R, Rosner M.R. Differential Raf requirement for activation of mitogen-activated protein kinase by growth factors, phorbol esters and calcium. J Biol Chem (1994) 269:7337–7341.[Abstract/Free Full Text]
  144. Huang S, Maher V.M, McCormick J.J. Extracellular Ca2+ stimulates the activation of mitogen-activated protein kinase and cell growth in human fibroblasts. Biochem J (1995) 310:881–885.[Web of Science][Medline]
  145. Fleming I, Fisslthaler B, Busse R. Calcium signalling in endothelial cells involves activation of tyrosine kinases and leads to activation of mitogen-activated protein kinases. Circ Res (1995) 76:522–529.[Abstract/Free Full Text]
  146. Farnsworth C.L, Freshney N.W, Rosen L.B, Ghosh A, Greenberg M.E, Feig L.A. Calcium activation of Ras mediated by neuronal exchange factor Ras-GRF. Nature (1995) 376:524–527.[CrossRef][Medline]
  147. Rosen L.B, Greenberg M.E. Stimulation of growth factor receptor signal transduction by activation of voltage-sensitive calcium channels. Proc Natl Acad Sci USA (1996) 93:1113–1118.[Abstract/Free Full Text]
  148. Bogoyevitch M.A, Andersson M.B, Gillespie-Brown J, Clerk A, Glennon P.E, Fuller S.J, Sugden P.H. Adrenergic receptor stimulation of the mitogen-activated protein kinase cascade and cardiac hypertrophy. Biochem J (1996) 314:115–121.[Web of Science][Medline]
  149. Sadoshima J, Qui Z, Morgan J.P, Izumo S. Angiotensin II and other hypertrophic stimuli medited by G protein-coupled receptors activate tyrosine kinase, mitogen-activated protein kinase, and 90-kD S6 kinase in cardiac myocytes. The critical role of Ca2+-dependent signaling. Circ Res (1995) 76:1–15.[Abstract/Free Full Text]
  150. Gruver C.L, DeMayo F, Goldstein A, Means A.R. Targeted overexpression of calmodulin induces proliferative and hypertrophic growth of cardiomyocytes in transgenic mice. Endocrinology (1993) 133:376–388.[Abstract/Free Full Text]
  151. Sei C.A, Irons C.E, Sprenkle A.B, McDonough P.M, Brown J.H, Glembotski C.C. The {alpha}-adrenergic stimulation of atrial natriuretic factor expression in cardiac myocytes requires calcium influx, protein kinase C, and calmodulin-regulated pathways. J Biol Chem (1991) 266:15910–15916.[Abstract/Free Full Text]
  152. Miranti C.K, Ginty D.D, Huang G, Chatila T, Greenberg M.E. Calcium activates serum response factor-dependent transcription by a Ras- and Elk-1 independent mechanism that involves a Ca2+/calmodulin-dependent kinase. Mol Cell Biol (1995) 15:3672–3684.[Abstract]
  153. Corneliussen B, Holm M, Waltersson Y, Onions J, Hallberg B, Thornell A, Grundström T. Calcium/calmodulin inhibition of basic-helix-loop-helix transcription factor domains. Nature (1994) 368:760–764.[CrossRef][Medline]
  154. Allo S.N, Carl L.L, Morgan H.E. Acceleration of growth of cultured cardiomyocytes and translocation of protein kinase C. Am J Physiol (1992) 263:C319–325.[Web of Science][Medline]
  155. Henrich C.J, Simpson P.C. Differential acute and chronic response of protein kinase C in cultured neonatal rat heart myocytes due to {alpha}1-adrenergic and phorbol ester stimulation. J Mol Cell Cardiol (1988) 20:1081–1085.[CrossRef][Web of Science][Medline]
  156. Newton A.C. Protein kinase C: Structure, function and regulation. J.Biol Chem (1995) 270:28495–28498.[Free Full Text]
  157. Disatnik M.-H, Buraggi G, Mochly-Rosen D. Localisation of protein kinase C isozymes in cardiac myocytes. Exp Cell Res (1994) 210:287–297.[CrossRef][Web of Science][Medline]
  158. Kolch W, Heidecker G, Kochs G, Hummel R, Vahidi H, Mischak H, Finkenceller G, Marne D, Rapp U. Protein kinase C{alpha} activates Raf-1 by direct phosphorylation. Nature (1993) 364:249–251.[CrossRef][Medline]
  159. Waldo A.L, Camm A.J, deRuyter H, Friedman P.L, MacNeil D.J, Pauls J.F, Pitt B, Pratt C.M, Schwartz P.J. Veltri EP for the SWORD investigators. Effect of d-sotalol on mortality in patients with left ventricular dysfunction after recent and remote myocardial infarction. Lancet (1996) 348:7–12.[CrossRef][Web of Science][Medline]
  160. Packer M, Carver J.R, Chesbro J.H, Ivanhoe R.J, Dibianco R, Zeldis S.M, Hendrix G.H, Bommer W.J, Elkayam U, Kukin M.L, Mallis G.I, Sollano J.A, Shannon J, Tandon P.K. DeMets DL and the PROMISE investigators. Effect of milrinone on mortality in severe chronic heart failure. The Prospective Randomised Milrinone Survival Evaluation (PROMISE). N Engl J Med (1991) 325:1468–1475.[Abstract]
  161. PROFILE Investigators and Coordinators. Packer M, Rouleau J, Swedberg K, Pitt B, Fisher L, Klepper M. Effect of flosequinan on survival in chronic heart failure: preliminary results of the PROFILE study. Circulation (1993) 88(1):I301.
  162. Packer M, Frid D, Wertheimer J.H, Cropp A.B, DeMets D.L. Effect of amlodipine on morbidity and mortality in severe chronic heart failure. Prospective randomised amlodipine survival evaluation study group. N Engl J Med (1996) 335:1107–1114.[Abstract/Free Full Text]
  163. Mulder P, Richard V, Compagnon P, Henry J.-P, Lallemand F, Clozel J.-P, Koen R, Mace B, Thuillez C. Increased survival after long term treatment with mibefradil, a selective T-channel calcium antagonist, in heart failure. J Am Col Cardiol (1997) 29:416–421.[Abstract]
  164. Johns D.C, Nuss H.B, Chiamvimonvat N, Ramza B.M, Marban E, Lawrence J.H. Adenovirus-mediated expression of a voltage-gated potassium channel in-vitro (rat cardiac myocytes) and in-vivo (rat liver). A novel strategy for modifying excitability. J Clin Invest (1995) 95:1152–1158.
  165. Shimoni Y, Fiset C, Clark R.B, Dixon J.E, MacKinnon D, Giles W.R. Thyroid hormone regulates postnatal expression of transient K+ channel isoforms in rat ventricle. J Physiol (1997) 500:65–73.[Abstract/Free Full Text]
  166. Wickenden AD, Huang Q, Factor S, Backx PH, Fishman GI. Expression of a dominant negative Kv4.2 channel in the hearts of transgenic mice (Abstract). Circulation 1997; In Press.
  167. Shin K.S, Park J.Y, Kwon H, Chung C.H, Kang M.S. Opposite effects of intracellular Ca2+ and protein kinase C on the expression of inwardly rectifying K+ channel 1 in mouse skeletal muscle. J Biol Chem (1997) 272:21227–21232.[Abstract/Free Full Text]
  168. McConkey D.J, Orrenius S. The role of calcium in the regulation of apoptosis. J Leukocyte Biol (1996) 59:775–783.[Abstract]
  169. Trump B.F, Berezesky I.K. The role of altered [Ca2+]i regulation in apoptosis, oncosis and necrosis. Biochim Biophys Acta (1996) 131:173–178.
  170. Cheng W, Li B, Kajstura J, Li P, Wolin M.S, Sonnenblick E.H, Hintze T.H, Olivetti G, Anversa P. Stretch-induced programmed myocyte cell death. J Clin Invest (1995) 96:2247–2259.[Web of Science][Medline]
  171. Kajstura J, Cigola E, Malhotra A, Li P, Cheng W, Meggs L.G, Anversa P. Angiotensin II induces apoptosis of adult ventricular myocytes in vitro. J Mol Cell Cardiol (1997) 29:859–870.[CrossRef][Web of Science][Medline]

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


This article has been cited by other articles:


Home page
 Am. J. Physiol. Heart Circ. Physiol.Home page
G. S. Hoeker, R. P. Katra, L. D. Wilson, B. N. Plummer, and K. R. Laurita
Spontaneous calcium release in tissue from the failing canine heart
Am J Physiol Heart Circ Physiol, October 1, 2009; 297(4): H1235 - H1242.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Cell Physiol.Home page
M.-Q. Zheng, K. Tang, M. C. Zimmerman, L. Liu, B. Xie, and G. J. Rozanski
Role of {gamma}-glutamyl transpeptidase in redox regulation of K+ channel remodeling in postmyocardial infarction rat hearts
Am J Physiol Cell Physiol, August 1, 2009; 297(2): C253 - C262.
[Abstract] [Full Text] [PDF]

Home page
 Cardiovasc ResHome page
U. Mackiewicz, M. Maczewski, A. Konior, J. O. Tellez, D. Nowis, H. Dobrzynski, M. R. Boyett, and B. Lewartowski
Sarcolemmal Ca2+-ATPase ability to transport Ca2+ gradually diminishes after myocardial infarction in the rat
Cardiovasc Res, February 15, 2009; 81(3): 546 - 554.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Heart Circ. Physiol.Home page
X. Li, K. Tang, B. Xie, S. Li, and G. J. Rozanski
Regulation of Kv4 channel expression in failing rat heart by the thioredoxin system
Am J Physiol Heart Circ Physiol, July 1, 2008; 295(1): H416 - H424.
[Abstract] [Full Text] [PDF]

Home page
 Cardiovasc ResHome page
M. Maczewski and U. Mackiewicz
Effect of metoprolol and ivabradine on left ventricular remodelling and Ca2+ handling in the post-infarction rat heart
Cardiovasc Res, July 1, 2008; 79(1): 42 - 51.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
M. C. G. Daniels, T. Naya, V. L. M. Rundell, and P. P. de Tombe
Development of contractile dysfunction in rat heart failure: hierarchy of cellular events
Am J Physiol Regulatory Integrative Comp Physiol, July 1, 2007; 293(1): R284 - R292.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Heart Circ. Physiol.Home page
J. Altamirano and D. M. Bers
Effect of intracellular Ca2+ and action potential duration on L-type Ca2+ channel inactivation and recovery from inactivation in rabbit cardiac myocytes
Am J Physiol Heart Circ Physiol, July 1, 2007; 293(1): H563 - H573.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Heart Circ. Physiol.Home page
M. Dong, X. Sun, A. A. Prinz, and H.-S. Wang
Effect of simulated Ito on guinea pig and canine ventricular action potential morphology
Am J Physiol Heart Circ Physiol, August 1, 2006; 291(2): H631 - H637.
[Abstract] [Full Text] [PDF]

Home page
 Cardiovasc ResHome page
M. A.G. van der Heyden, T. J.M. Wijnhoven, and T. Opthof
Molecular aspects of adrenergic modulation of the transient outward current
Cardiovasc Res, August 1, 2006; 71(3): 430 - 442.
[Abstract] [Full Text] [PDF]

Home page
 Circ. Res.Home page
H. Sun, B.-G. Kerfant, D. Zhao, M. G. Trivieri, G. Y. Oudit, J. M. Penninger, and P. H. Backx
Insulin-Like Growth Factor-1 and PTEN Deletion Enhance Cardiac L-Type Ca2+ Currents via Increased PI3K{alpha}/PKB Signaling
Circ. Res., June 9, 2006; 98(11): 1390 - 1397.
[Abstract] [Full Text] [PDF]

Home page
 J. Physiol.Home page
X. Sun and H.-S. Wang
Role of the transient outward current (Ito) in shaping canine ventricular action potential - a dynamic clamp study
J. Physiol., April 15, 2005; 564(2): 411 - 419.
[Abstract] [Full Text] [PDF]

Home page
 Circ. Res.Home page
D. M. Harris, G. D. Mills, X. Chen, H. Kubo, R. M. Berretta, V. S. Votaw, L. F. Santana, and S. R. Houser
Alterations in Early Action Potential Repolarization Causes Localized Failure of Sarcoplasmic Reticulum Ca2+ Release
Circ. Res., March 18, 2005; 96(5): 543 - 550.
[Abstract] [Full Text] [PDF]

Home page
 CirculationHome page
D. Lebeche, R. Kaprielian, F. del Monte, G. Tomaselli, J. K. Gwathmey, A. Schwartz, and R. J. Hajjar
In Vivo Cardiac Gene Transfer of Kv4.3 Abrogates the Hypertrophic Response in Rats After Aortic Stenosis
Circulation, November 30, 2004; 110(22): 3435 - 3443.
[Abstract] [Full Text] [PDF]

Home page
 Br J AnaesthHome page
A. Rithalia, P. M. Hopkins, and S. M. Harrison
Effects of halothane on action potential configuration in sub-endocardial and sub-epicardial myocytes from normotensive and hypertensive rat left ventricle
Br. J. Anaesth., April 1, 2003; 90(4): 501 - 503.
[Abstract] [Full Text] [PDF]

Home page
 Cardiovasc ResHome page
J. Fauconnier, S. Bedut, J.-Y. Le Guennec, D. Babuty, and S. Richard
Ca2+ current-mediated regulation of action potential by pacing rate in rat ventricular myocytes
Cardiovasc Res, March 1, 2003; 57(3): 670 - 680.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Heart Circ. Physiol.Home page
L. M. Semeniuk, D. L. Severson, A. J. Kryski, S. L. Swirp, J. D. Molkentin, and H. J. Duff
Time-dependent systolic and diastolic function in mice overexpressing calcineurin
Am J Physiol Heart Circ Physiol, February 1, 2003; 284(2): H425 - H430.
[Abstract] [Full Text] [PDF]

Home page
 Cardiovasc ResHome page
D. Dong, Y. Duan, J. Guo, D. E Roach, S. L Swirp, L. Wang, J.P Lees-Miller, R.S Sheldon, J. D Molkentin, and H. J Duff
Overexpression of calcineurin in mouse causes sudden cardiac death associated with decreased density of K+ channels
Cardiovasc Res, February 1, 2003; 57(2): 320 - 332.
[Abstract] [Full Text] [PDF]

Home page
 CirculationHome page
C. Zobel, Z. Kassiri, T.-T. T. Nguyen, Y. Meng, and P. H. Backx
Prevention of Hypertrophy by Overexpression of Kv4.2 in Cultured Neonatal Cardiomyocytes
Circulation, October 29, 2002; 106(18): 2385 - 2391.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Heart Circ. Physiol.Home page
G. J. Rozanski and Z. Xu
Glutathione and K+ channel remodeling in postinfarction rat heart
Am J Physiol Heart Circ Physiol, June 1, 2002; 282(6): H2346 - H2355.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Heart Circ. Physiol.Home page
C. Chouabe, J. Amsellem, L. Espinosa, P. Ribaux, S. Blaineau, P. Megas, and R. Bonvallet
Reversibility of electrophysiological changes induced by chronic high-altitude hypoxia in adult rat heart
Am J Physiol Heart Circ Physiol, April 1, 2002; 282(4): H1452 - H1460.
[Abstract] [Full Text] [PDF]

Home page
 Cardiovasc ResHome page
N. N Petrashevskaya, I. Bodi, M. Rubio, J. D Molkentin, and A. Schwartz
Cardiac function and electrical remodeling of the calcineurin-overexpressed transgenic mouse
Cardiovasc Res, April 1, 2002; 54(1): 117 - 132.
[Abstract] [Full Text] [PDF]

Home page
 Circ. Res.Home page
Z. Kassiri, C. Zobel, T.-T. T. Nguyen, J. D. Molkentin, and P. H. Backx
Reduction of Ito Causes Hypertrophy in Neonatal Rat Ventricular Myocytes
Circ. Res., March 22, 2002; 90(5): 578 - 585.
[Abstract] [Full Text] [PDF]

Home page
 Circ. Res.Home page
D. M. Bers
Calcium and Cardiac Rhythms: Physiological and Pathophysiological
Circ. Res., January 11, 2002; 90(1): 14 - 17.
[Full Text] [PDF]

Home page
 Am. J. Physiol. Heart Circ. Physiol.Home page
T. Watanabe, M. Yamaki, S. Yamauchi, O. Minamihaba, T. Miyashita, I. Kubota, and H. Tomoike
Regional prolongation of ARI and altered restitution properties cause ventricular arrhythmia in heart failure
Am J Physiol Heart Circ Physiol, January 1, 2002; 282(1): H212 - H218.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Heart Circ. Physiol.Home page
M. C. G. Daniels, R. S. Keller, and P. P. de Tombe
Losartan prevents contractile dysfunction in rat myocardium after left ventricular myocardial infarction
Am J Physiol Heart Circ Physiol, November 1, 2001; 281(5): H2150 - H2158.
[Abstract] [Full Text] [PDF]

Home page
 CirculationHome page
Z. Wang, W. Kutschke, K. E. Richardson, M. Karimi, and J. A. Hill
Electrical Remodeling in Pressure-Overload Cardiac Hypertrophy: Role of Calcineurin
Circulation, October 2, 2001; 104(14): 1657 - 1663.
[Abstract] [Full Text] [PDF]

Home page
 CirculationHome page
J. D. Harding, V. Piacentino III, J. P. Gaughan, S. R. Houser, and K. B. Margulies
Electrophysiological Alterations After Mechanical Circulatory Support in Patients With Advanced Cardiac Failure
Circulation, September 11, 2001; 104(11): 1241 - 1247.
[Abstract] [Full Text] [PDF]

Home page
 J. Physiol.Home page
R. Sah, R. J Ramirez, R. Kaprielian, and P. H Backx
Alterations in action potential profile enhance excitation-contraction coupling in rat cardiac myocytes
J. Physiol., May 15, 2001; 533(1): 201 - 214.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Heart Circ. Physiol.Home page
G. R. Ferrier and S. E. Howlett
Cardiac excitation-contraction coupling: role of membrane potential in regulation of contraction
Am J Physiol Heart Circ Physiol, May 1, 2001; 280(5): H1928 - H1944.
[Abstract] [Full Text] [PDF]

Home page
 Cardiovasc ResHome page
D. Babuty and M. J Lab
Mechanoelectric contributions to sudden cardiac death
Cardiovasc Res, May 1, 2001; 50(2): 270 - 279.
[Full Text] [PDF]

Home page
 Cardiovasc ResHome page
S. Demolombe, G. Lande, F. Charpentier, M. A van Roon, M. J.B van den Hoff, G. Toumaniantz, I. Baro, G. Guihard, N. Le Berre, A. Corbier, et al.
Transgenic mice overexpressing human KvLQT1 dominant-negative isoform Part I: Phenotypic characterisation
Cardiovasc Res, May 1, 2001; 50(2): 314 - 327.
[Abstract] [Full Text] [PDF]

Home page
 J. Physiol.Home page
T. Volk, T. H.-D. Nguyen, J.-H. Schultz, J. Faulhaber, and H. Ehmke
Regional alterations of repolarizing K+ currents among the left ventricular free wall of rats with ascending aortic stenosis
J. Physiol., February 1, 2001; 530(3): 443 - 455.
[Abstract] [Full Text] [PDF]

Home page
 Pharmacol. Rev.Home page
C.-C. Shieh, M. Coghlan, J. P. Sullivan, and M. Gopalakrishnan
Potassium Channels: Molecular Defects, Diseases, and Therapeutic Opportunities
Pharmacol. Rev., December 1, 2000; 52(4): 557 - 594.
[Abstract] [Full Text] [PDF]

Home page
 Cardiovasc ResHome page
Y. Tsuji, T. Opthof, K. Kamiya, K. Yasui, W. Liu, Z. Lu, and I. Kodama
Pacing-induced heart failure causes a reduction of delayed rectifier potassium currents along with decreases in calcium and transient outward currents in rabbit ventricle
Cardiovasc Res, November 1, 2000; 48(2): 300 - 309.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Heart Circ. Physiol.Home page
G. R. Ferrier, I. M. Redondo, C. A. Mason, C. Mapplebeck, and S. E. Howlett
Regulation of contraction and relaxation by membrane potential in cardiac ventricular myocytes
Am J Physiol Heart Circ Physiol, May 1, 2000; 278(5): H1618 - H1626.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Heart Circ. Physiol.Home page
A. D. Wickenden, R. Kaprielian, X.-M. You, and P. H. Backx
The thyroid hormone analog DITPA restores Ito in rats after myocardial infarction
Am J Physiol Heart Circ Physiol, April 1, 2000; 278(4): H1105 - H1116.
[Abstract] [Full Text] [PDF]

Home page
 J. Physiol.Home page
T. Volk, T. H.-D. Nguyen, J.-H. Schultz, and H. Ehmke
Relationship between transient outward K+ current and Ca2+ influx in rat cardiac myocytes of endo- and epicardial origin
J. Physiol., September 15, 1999; 519(3): 841 - 850.
[Abstract] [Full Text] [PDF]

Home page
 J. Physiol.Home page
R Kaprielian, A D Wickenden, Z Kassiri, T G Parker, P P Liu, and P H Backx
Relationship between K+ channel down-regulation and [Ca2+ ]i in rat ventricular myocytes following myocardial infarction
J. Physiol., May 15, 1999; 517(1): 229 - 245.
[Abstract] [Full Text] [PDF]

Home page
 Cardiovasc ResHome page
E. Cerbai, R. Pino, L. Sartiani, and A. Mugelli
Influence of postnatal-development on If occurrence and properties in neonatal rat ventricular myocytes
Cardiovasc Res, May 1, 1999; 42(2): 416 - 423.
[Abstract] [Full Text] [PDF]

Home page
 Circ. Res.Home page
P. H. Sugden
Signaling in Myocardial Hypertrophy : Life After Calcineurin?
Circ. Res., April 2, 1999; 84(6): 633 - 646.
[Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
Z. Wang, B. Nolan, W. Kutschke, and J. A. Hill
Na+-Ca2+ Exchanger Remodeling in Pressure Overload Cardiac Hypertrophy
J. Biol. Chem., May 18, 2001; 276(21): 17706 - 17711.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Heart Circ. Physiol.Home page
G. Bru-Mercier, E. Deroubaix, D. Rousseau, A. Coulombe, and J.-F. Renaud
Depressed transient outward potassium current density in catecholamine-depleted rat ventricular myocytes
Am J Physiol Heart Circ Physiol, April 1, 2002; 282(4): H1237 - H1247.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Heart Circ. Physiol.Home page
G. J. Rozanski and Z. Xu
Glutathione and K+ channel remodeling in postinfarction rat heart
Am J Physiol Heart Circ Physiol, June 1, 2002; 282(6): H2346 - H2355.
[Abstract] [Full Text] [PDF]

Home page
 Circ. Res.Home page
Z. Kassiri, C. Zobel, T.-T. T. Nguyen, J. D. Molkentin, and P. H. Backx
Reduction of Ito Causes Hypertrophy in Neonatal Rat Ventricular Myocytes
Circ. Res., March 22, 2002; 90(5): 578 - 585.
[Abstract] [Full Text] [PDF]

Home page
 CirculationHome page
R. Sah, G. Y. Oudit, T.-T. T. Nguyen, H. W. Lim, A. D. Wickenden, G. J. Wilson, J. D. Molkentin, and P. H. Backx
Inhibition of Calcineurin and Sarcolemmal Ca2+ Influx Protects Cardiac Morphology and Ventricular Function in Kv4.2N Transgenic Mice
Circulation, April 16, 2002; 105(15): 1850 - 1856.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow E-letters: Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when E-letters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Wickenden, A. D
Right arrow Articles by Backx, P. H
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Wickenden, A. D
Right arrow Articles by Backx, P. H
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?