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Cardiovascular Research 1999 43(4):901-908; doi:10.1016/S0008-6363(99)00124-8
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Copyright © 1999, European Society of Cardiology

Differences in the electrophysiologic response of four canine ventricular cell types to {alpha}1-adrenergic agonists

Alexander Burashnikov and Charles Antzelevitch*

Masonic Medical Research Laboratory, 2150 Bleecker Street, Utica, NY 13501, USA

* Corresponding author. Tel.: +1-315-735 2217; fax: +1-315-735 5648 CA{at}mmrl.edu

Received 24 December 1998; accepted 19 March 1999


   Abstract
Top
 Abstract
1 Introduction
 2 Methods
 3 Results
 4.1 The effect of...
 4.2 The effect of...
 5 Discussion
 References
 
Objective: The present study was designed to examine regional differences in the response of {alpha}1 adrenoceptor stimulation in the canine ventricle. Methods: Standard microelectrode techniques were used to record transmembrane action potentials from epicardial, M cell, and endocardial as well as Purkinje fiber preparations isolated from the canine left ventricle. Results: Phenylephrine (0.1–10 µM+propranolol 0.2 µM) and methoxamine (1–10 µM) produced dose- and rate-dependent prolongation of action potential duration (APD90) in Purkinje fibers (P<0.05, at 0.1–10 µM, BCL=0.5–2 s), but an abbreviation of APD90 in tissues from the M region (P<0.05, at 10 µM, BCL=0.5–2 s). At slow pacing rates (≥2 s), phenylephrine (1 µM) exerted a small, significant (P<0.05) prolongation of APD90 in epicardium and endocardium which returned to control values when the concentration was increased to 10 µM. The amplitude of phase 1 of the action potential in M and epicardial cells was significantly increased by phenylephrine at concentrations of 10 µM (P<0.05). Prazosin (1 µM), a nonspecific {alpha}1 antagonist, reversed these effects of phenylephrine (10 µM) and methoxamine (10 µM) on APD90 and the action potential notch. The {alpha}1b-antagonist, chloroethylclonidine (0.1–1.0 µM), but not the {alpha}1a-antagonist, WB-4101 (0.1–1.0 µM), reversed the APD-abbreviating effect of methoxamine in the M cell. Conclusion: Our results demonstrate striking regional differences in the electrophysiological response of the four canine ventricular cell types to {alpha}1 adrenergic agonists. Our data provide support for the hypothesis that different adrenoceptor subtypes underlie the opposite response of M cells ({alpha}1b-APD abbreviation) and Purkinje fibers ({alpha}1a-APD prolongation) to {alpha}1-adrenoceptor activation.

KEYWORDS Experimental; Heart; Electrophysiology; Adrenergic agonists; Autonomic nervous system; Canine; M cell; Purkinje fiber

See Editorial of this article by T.J. Colatsky (pages 827–829) in this issue.


   1 Introduction
Top
 Abstract
 1 Introduction
2 Methods
 3 Results
 4.1 The effect of...
 4.2 The effect of...
 5 Discussion
 References
 
Stimulation of cardiac {alpha}1-adrenoceptor is known to prolong action potential duration (APD) in cardiac Purkinje fibers of several species, including rabbit, cat, dog, ferret, and sheep [1–7]. In atrial and ventricular myocardium, {alpha}1-agonists have been reported to either prolong, abbreviate or exert no effect on APD, depending on the species, site of origin, temperature, time of exposure, type of agonist, drug concentration, and other variables [8–16].

The ventricles of the heart consist of four electrophysiologically and pharmacologically distinct cardiac cell types, i.e., epicardial, endocardial, midmyocardial M cells and Purkinje fibers [17,18]. Epicardial and M, but not endocardial, cells commonly display a prominent transient outward current (Ito) [19] which is responsible for the appearance of a notch in the early phase of the epicardial and M cell action potential. M cells when compared to epicardial and endocardial cells display longer action potentials, steeper APD-rate relations and a greater sensitivity to agents with Class III actions [20] due to the presence of a weaker slowly activating delayed rectifier current (IKs) [21] and a more prominent late sodium current [22]. In this respect, M cells resemble Purkinje fibers. M cells and Purkinje fibers respond similarly to most pharmacological agents that abbreviate or prolong APD or that induce early (EAD) and delayed (DAD) afterdepolarizations and triggered activity [20].

{alpha}1-Adrenoceptor stimulation has been shown to affect several ionic currents including Ito [23], IKs [24], IK1 [25], INa/K [26], ICa-L [27], and ICa-T [28]. In view of these multiple actions of {alpha}1-adrenoceptor stimulation and taking into consideration differences in the ionic currents that contribute to electrical heterogeneity among cells spanning the ventricular wall, we hypothesized that {alpha}1-agonists may produce different effects on the action potential of the four ventricular cell types. The present study was designed to test this hypothesis.


   2 Methods
Top
 Abstract
 1 Introduction
 2 Methods
3 Results
 4.1 The effect of...
 4.2 The effect of...
 5 Discussion
 References
 
2.1 Experimental preparation
The present study conforms with the Guide for the Care and Use of Laboratory Animals (NIH publication No.85-23). Free running Purkinje fiber, epicardial, endocardial, and subepicardial M cell preparations (strips approximately 1x0.5x0.1 cm) were isolated from left ventricle of hearts removed from anesthetized (30 mg/kg sodium pentobarbital) mongrel dogs. M cell preparations were cut parallel to the epicardial surface at a depth of 1.5–3 mm. The preparations, isolated using a dermatome (Davol Simon Dermatome, Cranston, RI, USA), were placed in a tissue bath (5 ml volume with flow rate of 14 ml/min) and allowed to equilibrate for at least 3 h while superfused with an oxygenated Tyrode’s solution (37±0.5°C, pH=7.35) and stimulated at 2 Hz using field or point stimulation (rectangular stimuli 1- to 3-ms duration, two to three times diastolic threshold intensity). The composition of the Tyrode’s solution was (in mM) as follows: NaCl 129, KCl 4, NaH2PO4 0.9, NaHCO3 20, CaCl2 1.8, MgSO4 0.5, and D-glucose 5.5.

2.2 Action potential recordings
Transmembrane potentials were recorded using standard glass microelectrodes filled with 2.7 M KCl (10 to 20 M{Omega} DC resistance) connected to a high input-impedance amplification system (World Precision Instruments, Sarasota, FL, USA). Signals were displayed on Tektronix (Beaverton, OR, USA) oscilloscopes and amplified (model 1903-4 programmable amplifiers; Cambridge Electronic Designs (C.E.D.), Cambridge, England), digitized [model 1401 AD/DA system (C.E.D.)], analyzed [Spike 2 acquisition and analysis module (C.E.D.), and stored on magnetic media (personal computer)]. The following action potential parameters were analyzed: maximum diastolic membrane potential (MDP), magnitude of phase 1, amplitude of phases 0, 1, and 2, and action potential duration at 90% repolarization (APD90). The maximal rate of rise of the action potential upstroke (Vmax) was measured with a differentiator adjusted for linearity within the range of 50 to 500 V/s.

2.3 Drugs
We used phenylephrine, an {alpha}1-adrenergic agonist with weak β-adrenergic stimulation properties and methoxamine, a more selective {alpha}1-adrenoceptor agonist. Propranolol was used to block the β-adrenergic effects of phenylephrine. A nonselective {alpha}1-antagonist (with {alpha}1a and {alpha}1b blocking actions) prazosin as well as the selective {alpha}1a-antagonist WB-4101 and the {alpha}1b antagonist chloroethylclonidine (CEC) were used to reverse the effects of phenylephrine and methoxamine. All drugs were obtained from Sigma (St.Louis, MO) and freshly prepared before each experiment as stock solutions of 1 mM. Data collection was started 20 min after addition of drugs.

2.4 Statistics
Statistical analysis was performed using one way repeated measures analysis of variance (ANOVA) followed by Bonferroni’s test.


   3 Results
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
4.1 The effect of...
 4.2 The effect of...
 5 Discussion
 References
 
Figs. 1 and 2Go show the dose-dependent effects of phenylephrine (0.1, 1.0, 10.0 µM; in the presence of 0.2 µM propranolol) on APD90 in epicardial, M region, endocardial, and Purkinje fiber preparations at BCLs of 500 and 2000 ms, respectively. Phenylephrine produced significant dose-dependent prolongation of APD90 in Purkinje fibers, but an abbreviation of APD90 in M cells at both fast and slow rates. The early phases of repolarization were affected by phenylephrine in epicardial and M cell preparations, but not in Purkinje or endocardium (Fig. 2). This effect was more pronounced at the slower rate (c.f., Figs. 1 and 2Go). At BCLs ≥2000 ms, high concentration of phenylephrine (10 µM) significantly increased the amplitude of Phase 1 (voltage between MDP and the end of Phase 1, in M cells from 87.9±4.4 to 90.8±5.5 mV, P<0.05, n=12; in epicardium from 88.7±4.9 to 91.5±4.1 mV, P<0.05, n=10), significantly decreasing the magnitude of the action potential notch in M cells (from 21.4±5.7 to 19.2±3.8 mV, P<0.05, n=12), but not in epicardium (from 13.6±3.9 to 12.2±3.8 mV, n.s., n=10). These effects are consistent with drug-induced block of Ito. Phenylephrine (1–10 µM) also showed a tendency to increase the amplitude of phase 0 and phase 2 of the M cell action potential.


Figure 1
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  		Fig. 1 Dose-dependent effect of phenylephrine on action potential duration (APD90) in epicardial, M cell, endocardial, and Purkinje fiber preparations (BCL=500 ms). The top panels show superimposed transmembrane potentials recorded from four ventricular cell types before and 20 min after the addition of 0.1, 1.0, and 10.0 µM phenylephrine. Bottom panel: Graphic plot of APD90 under control conditions and after increasing concentrations of phenylephrine. All experiments were performed in the presence of 0.2 µM propranolol. Data are expressed as mean±SD. *=P<0.05.

 

Figure 2
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  		Fig. 2 Dose-dependent effect of phenylephrine on action potential duration (APD90) in epicardial, M cell, endocardial, and Purkinje fiber preparations (BCL=2000 ms). The top panels show superimposed transmembrane potentials recorded from four ventricular cell types before and 20 min after the addition of 0.1, 1.0, and 10.0 µM phenylephrine. Bottom panel: Graphic plot of APD90 under control conditions and after increasing concentrations of phenylephrine. All experiments were performed in the presence of 0.2 µM propranolol. Data are expressed as mean±SD. *=P<0.05.

 
At a BCL of 500 ms, phenylephrine produced little or no effect on epicardial and endocardial tissues (Fig. 1). At slower pacing rates (BCLs≥2000 ms), 1 µM phenylephrine caused a small but significant (P<0.05 vs control) prolongation of APD90 in epicardium and endocardium which returned to control values when the concentration was increased to 10 µM (Fig. 2). Vmax was not affected by phenylephrine in any of the four tissue types. Phenylephrine and methoxamine produced a non-significant hyperpolarization of resting membrane potential in the M cell preparations (from –87.4±2.5 mV in control to –88.5±2.2 mV at phenylephrine 10 µM, n=12) with no effect in epicardium, endocardium, and Purkinje fibers.

Rate- and concentration-dependent effects of phenylephrine on APD90 of Purkinje fiber and M cell preparations are presented in Fig. 3. The phenylephrine-induced prolongation of APD90 in Purkinje fibers as well as abbreviation of APD90 in M cell preparations were more accentuated at slow rates and at higher concentrations of the drug.


Figure 3
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  		Fig. 3 Rate-, and concentration-dependence of phenylephrine’s action to alter action potential duration in M cell and Purkinje fiber preparations. Top panels show transmembrane action potentials recorded from a Purkinje (A) and an M cell preparation (B) under control conditions and 20 min after 10 µM phenylephrine at BCLs of 500, 1000, 2000, and 5000 ms. C: Graph of phenylephrine-induced changes in action potential duration at 90% repolarization ({Delta}APD90). All experiments were performed in the presence of 0.2 µM propranolol. Data are expressed as mean±SE. Due to spontaneous automaticity, observations in Purkinje at a BCL of 5000 ms were limited to an n of 5.

 
The effect of methoxamine, a more specific {alpha}1-adrenergic agonist, was evaluated in another series of experiments involving Purkinje fibers and M cell preparations. Methoxamine (1–10 µM), like phenylephrine, produced opposite effects on the APD90 of M cells and Purkinje fibers. Like phenylephrine, methoxamine increased the amplitude of phase 1 in M cells, but not in Purkinje fibers. The rate- and dose-dependent effects of methoxamine on APD90 of Purkinje fiber and M cell tissues are summarized in Fig. 4.


Figure 4
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  		Fig. 4 Rate-, and dose-dependent effects of methoxamine on action potentials recorded from M cell and Purkinje fiber preparations. Top panels show transmembrane action potentials recorded from a Purkinje (A) and an M cell preparation (B) under control conditions and 20 min after 10 µM methoxamine at BCLs of 500, 1000, 2000, and 5000 ms. C: Graph of methoxamine-induced changes in action potential duration measured at 90% repolarization ({Delta}APD90). Data are expressed as mean±SE. Due to spontaneous automaticity, observations in Purkinje at a BCL of 5000 ms were limited to an n of 4.

 

   4.1 The effect of prazosin
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 Abstract
 1 Introduction
 2 Methods
 3 Results
 4.1 The effect of...
4.2 The effect of...
 5 Discussion
 References
 
The {alpha}1 antagonist prazosin (1 µM) blocked the effects of phenylephrine and methoxamine to prolong APD90 in Purkinje as well as their effect to abbreviate APD90 of the M cell preparation (Fig. 5). Prazosin also reversed the {alpha}-agonist-induced diminution of the M cell action potential notch (Fig. 5B).


Figure 5
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  		Fig. 5 Prazosin reverses the effects of phenylephrine and methoxamine in M cell and Purkinje fiber preparations. Superimposed action potentials recorded from Purkinje (A) and M cell (B) preparations in control, in the presence of phenylephrine (10 µM), and following the addition of the {alpha}1 antagonist, prazosin (1 µM), in the continued presence of phenylephrine. BCL=2000 ms. C: Graphic plot of APD90 under control conditions, after 10 µM phenylephrine or methoxamine and following addition of prazosin (1 µM). All experiments involving phenylephrine were performed in the presence of 0.2 µM propranolol. Data are expressed as mean±SD. *=P<0.05.

 

   4.2 The effect of WB-4101 and CEC
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 Abstract
 1 Introduction
 2 Methods
 3 Results
 4.1 The effect of...
 4.2 The effect of...
5 Discussion
 References
 
Because it is well established that {alpha}1-agonists induce APD prolongation in canine Purkinje fibers via activation of the {alpha}1a (WB-4101-sensitive) subtype of {alpha}1-adrenoceptor [6,15], we sought to determine the receptor subtype present in the M cell. As illustrated in Fig. 6, the {alpha}1b-antagonist, chloroethylclonidine (0.1–1.0 µM), but not the {alpha}1a-antagonist, WB-4101 (0.1–1.0 µM), reversed the APD-abbreviating effect of methoxamine (10 µM) in M cells (Fig. 6).


Figure 6
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  		Fig. 6 Chloroethylclonidine (CEC) but not WB-4101 reverses the effect of methoxamine (MTX) on M cell action potential duration (APD90). The graph illustrates APD90 of M cell preparations under control conditions, after 10 µM methoxamine and following addition of either CEC (0.1, 1.0 µM) or WB-4101 (0.1, 1.0 µM). BCL=2000 ms. Data are expressed as mean±SD. *=P<0.05 vs. control.

 

   5 Discussion
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
 4.1 The effect of...
 4.2 The effect of...
 5 Discussion
References
 
The chief finding of the present study is that {alpha}1-adrenoceptor stimulation produces opposite effects on M cells and Purkinje fibers, and little or no effect in epicardium and endocardium. Our data indicate that phenylephrine and methoxamine abbreviate the APD of the M cell via {alpha}1b-adrenoceptor activation. This is in contrast to the APD prolongation observed in Purkinje as a result of {alpha}1a activation [6,15].

It has long been appreciated that {alpha}1-adrenoceptor stimulation produces prolongation of APD in mammalian cardiac Purkinje fibers in a variety of species including rabbit, cat, dog, ferret, and sheep [3–7]. In contrast, variable and even opposite responses to {alpha} agonists have been observed in atrial and ventricular tissues and cells. Depending on the species, origin of tissues or cells, time of exposure, temperature and other variables, stimulation of {alpha}1-adrenoceptors has been shown to either increase, decrease, or exert no effect on APD. APD of rat, rabbit and guinea pig atria prolongs in response to {alpha}1-adrenoceptors stimulation [3,11,29]. A similar response has been reported in canine ventricular epicardium [15]; cow and rabbit ventricular endocardium [3,10]; and canine and rat ventricular myocytes [23,30]. Other studies report that {alpha}1-agonists do not affect APD in dog ventricular endocardium [15] or human papillary muscle [13]. Still others report a reduction of APD as a result of exposure to methoxamine [9], but no effect in response to a similar concentration of phenylephrine [8] in guinea pig papillary muscles. A small reduction of APD90 in response to phenylephrine was also observed in human atrium [14].

Our results differ from those of Lee et al [15] who reported an effect of phenylephrine (0.1–10.0 µM) to prolong the APD of canine epicardial, but not endocardial preparations. In the present study, phenylephrine (1 µM) produced a small, but statistically significant APD prolongation in both epicardial and endocardial tissues at a slow pacing rate (BCL=2000 ms), while lower (0.1µM) and higher (10.0 µM) concentrations of the {alpha}1-agonist caused no effect. The reason for this discrepancy is not clear. Of note, control values for epicardial and endocardial APD90 reported by Lee and co-workers [15] were much shorter (120±9 and 167±6, respectively, BCL=1.5 s) than those reported by us and others for dog myocardium (Epi 202±12, Endo 201±10 ms at BCL=2 s in present study; Epi 249±10, Endo 229±5 ms, CL=2 s, Anyukhovsky et al. [31]) [32,33].

Recent studies indicate that ventricular myocardium in many mammalian species consists of at least four electrophysiologically and pharmacologically distinct cell types (for review see [17,18,22]). M cells differ from epicardial and endocardial cells with respect two ionic currents. M cells display a weaker IKs [21] but a more prominent late INa [22]. Ito is prominent in canine ventricular epicardial and M cells, but relatively weak in endocardial cells [19]. In contrast to the electrophysiological differences between the M cell and epicardial or endocardial cells, M cells and Purkinje fibers have many features in common. Like Purkinje fibers, M cells display (1) a higher Vmax than epicardium and endocardium, (2) a relatively steep rate-dependence of APD, and (3) a greater response than epicardium and endocardium to drugs that abbreviate or prolong APD and produce EADs or DADs [20,33]. Unlike Purkinje fibers, M cells (1) display no phase 4 or diastolic depolarization, even in the presence of β-agonists [17]; (2) show a greater hyperpolarization when [K+]o is reduced [34]; (3) display DADs in response to the calcium agonist BAY K 8644 [35]; and (4) develop EADs that are exquisitely sensitive to intracellular calcium activity [22].

Although major pharmacological differences between M cells and epicardial/endocardial cells have been reported previously, the present study is the first to demonstrate a major pharmacological distinction between M cells and Purkinje fibers. The opposite effects of phenylephrine and methoxamine on the APD of the M cell and Purkinje fiber are mediated by {alpha}1-adrenoceptor activation, since both APD prolongation in Purkinje fiber and abbreviation in M cell could be reversed with the nonspecific {alpha}1-antagonist prazosin.

Using a pharmacological approach, Lee and Rosen [36] presented evidence that {alpha}1 adrenoceptor-induced APD prolongation in canine Purkinje fibers is due to block of IK via a WB 4101-sensitive {alpha}1a-adrenergic receptor subtype activation [15]. Our data indicate that APD abbreviation in the M cell involves CEC-sensitive {alpha}1b-subtype activation. While IK inhibition can explain the effect of {alpha}1-agonists to prolong APD in Purkinje fibers, it cannot account for the abbreviation seen in M cells. Abbreviation of APD of the M cell may be due to number of mechanisms, including {alpha}1-agonist induced block of Ito [23,37], increase in IKs [24,38] and/or increase of Na/K pump activity [26].

Specific block of Ito using low concentrations of 4-AP (≤ 0.5 mM) [39] has been shown to abbreviate APD in Purkinje, M, and epicardial tissues [18,36,40]. In the present study, it is interesting that significant abbreviation of the M cell action potential was recorded at concentrations at which the {alpha}1-agonists reduced the magnitude of the action potential notch, consistent with Ito block. Little information is available regarding the receptor subtype responsible for Ito inhibition. Wang et al. [41] report that stimulation of both {alpha}1a- and {alpha}1b-receptor subtypes contributes to inhibition of Ito in rat ventricular myocytes.

{alpha}1-agonists have been shown to alter the intensity of delayed rectifier current. Walsh and Kass demonstrated that {alpha}1-adrenoreceptor stimulation could enhance IK [38]. Tohse et al. subsequently showed that it is the slowly activating component (IKs) that is augmented [24]. The greater sensitivity of M cell preparations to the {alpha}-agonists may be due to the presence of an initially low level of IKs in this cell type [21]. In support of this hypothesis are the observations of Gintant et al. that stimulation of protein kinase C (PKC) with either PMA or phenylephrine in canine ventricular myocytes results in an increase in IKs in ventricular cells possessing an intrinsically low density of this current [42]. IKs density was unaffected in myocytes with IKs density ≥3 pA/pF, but showed large increases of IKs in cells in which basal level of the current was relatively small. These findings argue for a preferential effect of {alpha}-agonists to increase IKs in the M cell, thus causing a selective abbreviation of the action potential of the M cell, and a decrease in transmural dispersion of action potential duration, as observed in our preparations.

{alpha}1-adrenoceptor stimulation has also been shown to increase Na/K pump activity through {alpha}1b-receptor activation [15,26], which can lead to an increase in electrogenic outward current and abbreviation of APD. {alpha}1-agonists induce a small, statistically insignificant hyperpolarization of the resting membrane potential in M cells, consistent with a possible Na/K pump augmentation. {alpha}1-agonists have also been shown to reduce IK1 [25,26] and augment the T-type calcium current [28]. In contrast to Purkinje fibers, canine myocardial cells have little or no T-type calcium current [28]. These differences may contribute to opposite responses of M cells and Purkinje fibers to {alpha}-agonists.

In summary, our data demonstrate remarkable regional differences in the response of the four ventricular cell types to {alpha}1-adrenoceptor simulation. This study is the first to systematically investigate the effects of {alpha}1-adrenergic agonists in all four ventricular cell types in the same species. The opposite effects of {alpha}-adrenergic agents in Purkinje and M cells and the absence of an effect in epicardium and endocardium may aid in our understanding of the actions of these neurohormones. One example is the ability of {alpha} agonists to facilitate the development of spontaneous Torsade de Pointes (TdP) arrhythmias in the acquired long QT syndrome [43]. Our results suggest that in the dog, {alpha} agonists may exert an antiarrhythmic effect by diminishing transmural dispersion of repolarization, but may also exert an arrhythmogenic effect by facilitating prolongation of APD and the development of EADs in Purkinje, thus increasing the incidence of triggered beats responsible for the initiation of reentrant arrhythmias, including TdP [44–46].

Time for primary review 35 days.


   Acknowledgements
 
We are grateful to Judy Hefferon, Robert Goodrow, and Teng-Xian Liu and Di Hou for expert technical assistance. Supported by grant HL47678 from the National Institutes of Health and by the Masons of NYS and Florida. Dr. Burashnikov served as the Eighth Manhattan Masonic District Fellow during the period of this study.


   References
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
 4.1 The effect of...
 4.2 The effect of...
 5 Discussion
 References
 

  1. Burashnikov A., Antzelevitch C. Alpha-agonists produce opposite effect on action potential duration in Purkinje and M cells isolated from the canine left ventricle. PACE (1995) 18:II, 935. Abstract.
  2. Burashnikov A., Antzelevitch C. Differences in the response of four canine ventricular cell types to {alpha}1 adrenergic agonists. PACE (1997) 20:II, 1115. Abstract.
  3. Dukes I.D., VaughamWilliams E.M. Effects of selective {alpha}1-, {alpha}2-, β1- and β2-adrenoceptor stimulation on potentials and contractions in the rabbit heart. J. Physiol. (Lond.) (1984) 355:523–546.[Abstract/Free Full Text]
  4. Kimura S., Cameron J.S., Kozlovskis P.L., Bassett A.L., Myerburg R.J. Delayed afterdepolarizations and triggered activity induced in feline Purkinje fibers by {alpha}-adrenergic stimulation in the presence of elevated calcium levels. Circulation (1984) 70:1074–1082.[Abstract/Free Full Text]
  5. Rosen M.R., Hordof A.J., Ilvento J.P., Danilo P. Jr. Effects of adrenergic amines on electrophysiological properties and automaticity of neonatal and adult canine Purkinje fibers. Circ. Res. (1977) 40:390–400.[Abstract/Free Full Text]
  6. Drouin E., Charpentier F., Gauthier C. {alpha}1-adrenergic stimulation induces early afterdepolarizations in ferret Purkinje fibers. J. Cardiovasc. Pharmacol. (1996) 27:320–326.[CrossRef][Web of Science][Medline]
  7. Ledda F., Marchetti P., Manni A. Influence of phenylephrine on transmembrane potentials and effective refractory period of single Purkinje fibers of sheep heart. Pharmacol. Res. Commun (1971) 3:195–206.[CrossRef]
  8. 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. (Lond.) (1988) 397:657–670.[Abstract/Free Full Text]
  9. Dirksen R.T., Sheu S.-S. Modulation of ventricular action potential by {alpha}1-adrenoceptors and protein kinase C. Am. J. Physiol (1990) 258:H907–H911.[Web of Science][Medline]
  10. Bruckner R., Scholz H. Effects of {alpha}-adrenoceptor stimulation with phenylephrine in the presence of propranolol on force of contraction, slow inward current and cyclic AMP content in the bovine heart. Br. J. Pharmacol. (1984) 82:223–232.[Web of Science][Medline]
  11. Ertl R., Jahnel U., Nawrath H., Carmeliet E., Vereecke J. Differential electrophysiological and inotropic effects of phenylephrine in atrial and ventricular heart muscle preparations from rats. Naunyn-Schmied Arch. Pharmacol. (1991) 344:574–581.[Web of Science][Medline]
  12. Flores N.A., Sheridan D.J. Electrophysiological effects of alpha-adrenoceptor stimulation in perfused and superfused myocardium. J. Mol. Cell. Cardiol (1991) 23:973–985.[CrossRef][Web of Science][Medline]
  13. Jacob H., Nawrath H., Rupp J. Adrenoceptor-mediated changes of action potential and force of contraction in human isolated ventricular heart muscle. Br. J. Pharmacol. (1988) 94:584–590.[Web of Science][Medline]
  14. Jahnel U., Jakob H., Nawrath H. Electrophysiologic and inotropic effects of {alpha}-adrenoceptor stimulation in human isolated atrial heart muscle. Naunyn-Schmied Arch. Pharmacol. (1992) 346:82–87.[CrossRef][Web of Science][Medline]
  15. Lee J.H., Steinberg S.F., Rosen M.R. A WB 4101-sensitive alpha-1 adrenergic receptor subtype modulates repolarization in canine Purkinje fibers. J. Pharmacol. Exp. Ther. (1991) 258:681–687.[Abstract/Free Full Text]
  16. Marchi S., Szabo B., Lazzara R. Adrenergic induction of delayed afterdepolarizations in ventricular myocardial cells: Beta-induction and Alpha-Modulation. J. Cardiovasc. Electrophysiol (1991) 2:476–491.[CrossRef]
  17. Antzelevitch C., Sicouri S., Litovsky S.H., et al. Heterogeneity within the ventricular wall: electrophysiology and pharmacology of epicardial, endocardial and M cells. Circ. Res. (1991) 69:1427–1449.[Free Full Text]
  18. Antzelevitch C., Sicouri S., Lukas A., et al. Cardiac electrophysiology: From cell to bedside. Zipes D.P., Jalife J., eds. (1995) 2nd ed. Philadelphia: W.B. Saunders Co. 228–245.
  19. Liu D.W., Gintant G.A., Antzelevitch C. Ionic bases for electrophysiological distinctions among epicardial, midmyocardial, and endocardial myocytes from the free wall of the canine left ventricle. Circ. Res. (1993) 72:671–687.[Abstract/Free Full Text]
  20. Antzelevitch C., Sicouri S. Clinical relevance of cardiac arrhythmias generated by afterdepolarizations: The role of M cells in the generation of U waves, triggered activity and torsade de pointes. J. Am. Coll. Cardiol. (1994) 23:259–277.[Abstract]
  21. Liu D.W., Antzelevitch C. Characteristics of the delayed rectifier current (IKr and IKs) in canine ventricular epicardial, midmyocardial and endocardial myocytes: A weaker IKs contributes to the longer action potential of the M cell. Circ. Res. (1995) 76:351–365.[Abstract/Free Full Text]
  22. Antzelevitch C. The M cell. J Cardiovasc Pharmacol Therapeut (1997) 2:73–76. Invited Editorial Comment.[Free Full Text]
  23. Apkon M., Nerbonne J.M. a1-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]
  24. Tohse N., Nakaya H., Kanno M. Alpha1-adrenoceptor stimulation enhances the delayed rectifier K current of guinea pig ventricular cells through the activation of protein kinase C. Circ. Res. (1992) 71:1441–1446.[Abstract/Free Full Text]
  25. Fedida D., Braun A.P., Giles W.R. {alpha}1-adrenoceptors in myocardium: functional aspects and transmembrane signaling mechanisms. Physiological Rev. (1993) 73:469–487.[Free Full Text]
  26. Shah A., Cohen I.S., Rosen M.R. Stimulation of cardiac alpha receptors increases Na/K pump current and decreases gK via a pertussis toxin-sensitive pathway. Biophys. J. (1988) 54:219–225.[Web of Science][Medline]
  27. Liu S.J., Kennedy R.H. Alpha1-Adrenergic activation of L-type Ca current in rat ventricular myocytes: perforated patch-clamp recordings. Am. J. Physiol. (1998) 274:H2203–H2207.[Web of Science][Medline]
  28. Tseng G.N., Boyden P.A. Multiple types of Ca2+ currents in single canine Purkinje cells. Circ. Res. (1989) 65:1735–1750.[Abstract/Free Full Text]
  29. Pappano A.J. Propranolol-insensitive effects of epinephrine in action potential repolarization in electrically driven atria of the guinea pig. J. Pharmacol. Exp. Ther. (1971) 177:85–95.[Abstract/Free Full Text]
  30. Priori S.G., Corr P.B. Mechanisms underlying early and delayed afterdepolarizations induced by catecholamines. Am. J. Physiol. (1990) 258:H1796–H1805.[Web of Science][Medline]
  31. Anyukhovsky E.P., Sosunov E.A., Rosen M.R. Regional differences in electrophysiologic properties of epicardium, midmyocardium and endocardium: In vitro and in vivo correlations. Circulation (1996) 94:1981–1988.[Abstract/Free Full Text]
  32. Samson R.A., Cai J.J., Shibata E.F., Martins J.B., Lee H.-C. Electrophysiological effect of {alpha}2-adrenergic stimulation in canine cardiac Purkinje fibers. Am. J. Physiol. (1995) 268:H2024–H2035.[Web of Science][Medline]
  33. Sicouri S., Antzelevitch C. A subpopulation of cells with unique electrophysiological properties in the deep subepicardium of the canine ventricle: The M cell. Circ. Res. (1991) 68:1729–1741.[Abstract/Free Full Text]
  34. Sicouri S., Antzelevitch C. Electrophysiologic characteristics of M cells in the canine left ventricular free wall. J. Cardiovasc. Electrophysiol (1995) 6:591–603.[Web of Science][Medline]
  35. Sicouri S., Antzelevitch C. Afterdepolarizations and triggered activity develop in a select population of cells (M cells) in canine ventricular myocardium: The effects of acetylstrophanthidin and Bay K 8644. PACE (1991) 14:1714–1720.[Medline]
  36. Lee J.H., Rosen M.R. Alpha 1-adrenergic receptor modulation of repolarization in canine Purkinje fibers. J. Cardiovasc. Electrophysiol (1994) 5:232–240.[Web of Science][Medline]
  37. Fedida D., Shimoni Y., Giles W.R. Alpha-adrenergic modulation of the transient outward current in rabbit atrial myocytes. J. Physiol. (Lond.) (1990) 423:257–277.[Abstract/Free Full Text]
  38. Walsh K.B., Kass R. Distinct voltage-dependent regulation of a heart-delayed IK by protein kinases A and C. Am. J. Physiol. (1991) 261:C1081–C1090.[Web of Science][Medline]
  39. Snyders D.J., VanBogaert P.P. Effects of 4-aminopyridine on inward rectifying and pacemaker currents of cardiac Purkinje fibers. Pflugers Arch. (1982) 394:230–238.[CrossRef][Web of Science][Medline]
  40. Litovsky S.H., Antzelevitch C. Rate dependence of action potential duration and refractoriness in canine ventricular endocardium differs from that of epicardium: The role of the transient outward current. J. Am. Coll. Cardiol. (1989) 14:1053–1066.[Abstract]
  41. Wang X.L., Wettwer E., Gross G.J., Ravens U. Reduction of cardiac outward currents by alpha-1 adrenoceptor stimulation: A subtype-specific effect? J. Pharmacol. Exp. Ther. (1991) 259:783–788.[Abstract/Free Full Text]
  42. Gintant G.A., Vanderpool K.M., VanderHeide R.S. Effects of protein kinase C on canine cardiac IKsdelayed rectifier current: dependence on basal IKs current density. Circulation (1997) 96:I, 293. Abstract.
  43. Carlsson L., Abrahamsson C., Andersson B., Duker G., Schiller-Linhardt G. Proarrhythmic effects of the class III agent almokalant: importance of infusion rate. QT dispersion, and early afterdepolarisations. Cardiovasc. Res. (1993) 27:2186–2193.[Abstract/Free Full Text]
  44. Antzelevitch C., Sun Z.Q., Zhang Z.Q., Yan G.X. Cellular and ionic mechanisms underlying erythromycin-induced long QT and torsade de pointes. J. Am. Coll. Cardiol. (1996) 28:1836–1848.[Abstract]
  45. Shimizu W., Antzelevitch C. Sodium channel block with mexiletine is effective in reducing dispersion of repolarization and preventing torsade de pointes in LQT2 and LQT3 models of the long-QT syndrome. Circulation (1997) 96:2038–2047.[Abstract/Free Full Text]
  46. El-Sherif N., Caref E.B., Yin H., Restivo M. The electrophysiological mechanism of ventricular arrhythmias in the long QT syndrome: Tridimensional mapping of activation and recovery patterns. Circ. Res. (1996) 79:474–492.[Abstract/Free Full Text]

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