Facilitation of epinephrine-induced afterdepolarizations by class III antiarrhythmic drugs

Journal of Electrocardiology Vol. 30 No. 3 1997

Facilitation of Epinephrine-Induced Afterdepolarizations by Class III

Antiarrhythmic Drugs

Eugene Patterson, PhD, Benjamin J. Scherlag, PhD, Bela Szabo, MD, PhD, and Ralph Lazzara, MD

Abstract: The electrophysiologic actions of epinephrine (lO-9M, 10-8M, and 10-7M) were evaluated in canine Purkinie fibers pretreated with the class III antiarrhythmic drugs clofilium (10-7M) or d,l-sotalol (10-6M). Clofilium and d,l-sotalol prolonged action potential duration at 50% and 90% of repolarization without provoking early afterdepolarization (EAD) or delayed afterdepolarization (DAD). Subsequent administration of epinephrine provoked both bradycardia-dependent EADs and tachycardia-dependent DADs in clofilium- treated Purkinje fibers, with predominantly EADs observed in d,l-sotalol- treated Purkinje fibers. A temporary increase in Ca0 +2 from 1.35 mM to 5 mM suppressed both EADs and DADs. The data demonstrate facilitation of epinephrine-induced EADs and DADs by class III antiarrhythmic drugs. The acute suppression of both EADs and DADs observed following an acute increase in Ca0 +2 suggests inward Na+-Cao +2 exchange current as a basis for both EADs and DADs observed in the presence of class III antiarrhythmic drugs and epinephrine. Key Words: early afterdepolarizations, delayed afterdepolarizations, ventricular arrhythmias, antiarrhythmic drugs, epinephrine.

Class III ant iarrhythmic action has been defined as prolongation of action potential duration, wi thout alteration of the rate of rise of phase 0 of the action potential in myocardial tissues; myocardial refrac- toriness is prolonged wi thout alteration of myocardial conduct ion velocity (1). Most commonly, pro-

From the Departments of Pharmacology and Medicine, College of Medicine, University of Oklahoma Health Sciences Center, and Research Service, Department of Veterans Affairs Medical Center, Oklahoma City, Oklahoma.

Supported by research funds from the Department of Veterans Affairs and a grant from the Presbyterian Health Foundation.

Reprint requests: Eugene Patterson, PhD, Research Service 151-E Department of Veteran Affairs Medical Center, 921 NE 13th Street, Oklahoma City, OK 73104.

© 1997 Churchill Livingstone Inc.

longation of the action potential is achieved by inhibition of one or more outward potassium currents mediat ing repolarization. Agents with class III electrophysiologic actions have proved superior to class I ant iarrhythmic agents for the t rea tment of ventricular tachyarrhythmias (2-4).

The role for pure class III an t ia r rhy thmic action in the suppression of lethal ventr icular a r rhyth- mias in survivors of myocardia l infarction was evaluated in the SWORD trial (5). The SWORD (survival with oral d-sotalol) trial, using the class III an t ia r rhy thmic agent d-sotalol, was t e rmina ted p rema tu re ly by the trial's safety rev iew commit tee as a result of an increased morta l i ty in the d-sotalol t r ea tmen t group as compared wi th the placebo (control) t r ea tmen t group. No bases for the in-

217

218 Journal of Electrocardiology Vol. 30 No. 3 July 1997

creased incidence of lethal arrhythmia were iden- tified in the abbreviated trial.

Class III antiarrhythmic agents prolonging repolarization and the electrocardiographic QT interval have proved to induce early afterdepolarizations (PADs) and polymorphic ventricular tachycardias (torsades de pointes) in up to 5% of patients (6,7). Prolongation of the action potential by class III agents may also facilitate PADs and arrhythmia under experimental conditions, prolonging action potential duration and/or compromising calcium handling as with subacute myocardial infarction (8,9) or Bay K8644 administration (10). Little is known about the interaction of catecholamines and class III antiarrhythmic agents. Such an interaction may be important, as prolongation of the action potential by experimental subacute myocardial ischemic injury facilitates alpha- and beta- adrenergic induction of afterdepolarizations and triggered arrhythmia (11,12). We have therefore examined the electrophysiologic actions of epinephrine in normal, superfused Purkinje fibers pretreated with the class III antiarrhythmic drugs clofilium (an inhibitor of lKt o and 1Kr) (13,14) and d,l-sotalol (an inhibitor of 1Kr) (I 5).

Materials and Methods

Male dogs were anesthetized with intravenous sodium pentobarbital, 25-30 mg/kg. Endocardial tissue sections containing free-running Purkinje fiber strands (1 x 1 cm) were obtained from left or right ventricular endocardium following excision of the heart via a left thoracotomy. The tissues were superfused with Tyrode's solution (115 mM sodium chloride, 4.0 mM potassium chloride, 1.0 mM sodium dihydrogen phosphate, 1.5 mM mag- nesium chloride, 24 mM sodium bicarbonate, and 1.35 mM calcium chloride) bubbled with 95% oxygen 5% carbon dioxide (pH = 7.4). A Grass S- 88 stimulator (Grass Instruments, West Warwick, RI), was used to initiate electrical activity at the proximal insertion of a free-running Purkinje fiber (2-4 ms stimuli, twice the diastolic threshold). A glass microelectrode (10-20 Mohm resistance) was used to record intracellular potentials from the free-running Purkinje fber. A bipolar electrode was used to record activation of the same fiber at its distal insertion. A differentiating amplifier with peak-and-hold detector was used to record Vmax. Differentiation was linear in the range of 50-i000 V/s. Electrical recordings were performed at a vari- ety of rates from the spontaneous rate to 4.0 Hz. Permanent records were obtained using a Gould

TA 1000 recording system (Gould Electronics, Cleveland, OH).

Measured parameters included (1) resting membrane potential, (2) action potential amplitude, (3) overshoot potential, (4) maximum potential (5) action potential amplitude at 50% and 90% ot repolarization, and (6) stimulus-action potential conduction time. Unless otherwise specified, data are obtained at a paced cycle length of 1,000 ms.

Clofilium tosylate or d,l-sotalol hydrochloride was administered after a 30-minute stabilization period. All electrophysiologic parameters were redetermined after a 1-hour superperfusion period. Epinephrine was then administered in incremen- tally increasing concentrations of 10-9M, 10-SM, and 10-7M (20 minutes at each dosage level), d,I- Sotalol administration was continued during epinephrine administration; clofilium administration was terminated immediately before epinephrine administration was started. Extractable calcium ion concentration was altered by direct addition ot calcium chloride to the perfusate. An acute increase in the extracellular calcium ion concentration reduces the intracellular/extracellular calcium ion gradient driving Na-Ca exchange during periods of high intraceliular calcium and would thereby reduce the inward Na-Ca exchange current (16}.

Clofilium was generously supplied by Eli, Lilly (Indianapolis, IN). d,l-Sotalol was generously supplied by Bristol-Myers (Evansville, IN) and d,l-epinephrine was obtained from Sigma Chemical (St. Louis, MO). M1 other chemicals were reagent grade.

Data are reported as means + SEM. Differences between groups were obtained by analysis of vari- ance followed by Scheffe's test, with P < .05 the cri- terion for significance.

Results

Clofilium

Administration of clofilium (10-7M) prolonged the action potential duration at 50% and 90% of repolarization without altering the maximal diastolic potential, action potential amplitude, overshoot potential, or maximum potential in free-running Purkinje fibers (Table 1). An example is shown in Figure 1. No PADs or DADs were observed at cycle lengths ranging from 3,996 + 953 ms (spontaneous rate) to paced cycle lengths of 250 ms (Fig. 2).

The subsequent administration of epinephrine (10-SM, IO-TM, but not 10-gM) produced rate- dependent PADs and DADs (Table 1). The PADs

Epinephrine-Induced EarlyAfterdepolarizations • Patterson et al. 219

Table 1. Administration of Clofilium Plus Epinephrine

Parameter Predrug Clofi l ium (10 7M) + EPI (10-gM) + EPI (10-aM) + EPI (10-7M)

MDP (mY) -89 ± I -89 ± 1 -90 ± 1 -90 ± 1 -89-+ 1 APA (mY) 120 +_ 2 121 ± 2 121 ± 3 121 ± 2 120_+ 2 OS(mV) 3 1 ± 2 32_+2 31_+3 3 1 ± 2 3 1 ± 2 Vmax (V/s) 71I ± 59 706 + 6 714 + 79 722 ± 86 702 ± 78 APDS0 (ms) 268 ± 61 364 ± 88* 349 ± 82* 360 ± 73* 368 ± 69* APD90 (ms) 402 ± 76 508 ± 107" 489 ± 81" 502 ± 84J- 488 ± 88* CT (ms) 8.4 ± 1.3 8.4 ± 1.4 8.3 ± 1.4 8.4 ± 1.4 8.3 ± 1.3 Cycle length (ms) 3,996 ± 953 4,063 ± 887 3,898 ± 967 3,567 ± 862* 3,156 ± 826* EAD incidence 0/11 0/11 0/11 11/115 11/115 DAD incidence 0/11 0/11 0/11 5/11" 6/11"

EPI, epinephrine; MDE m a x i m u m diastolic potential; APA, action potential amplitude; OS, overshoot potential; Vmax, maximal rate of phase 0 depolarization; APD50, action potential durat ion at 50% of repolarization; APD90, action potential durat ion at 90% of repolarization; CT = conduction time; EAD, early atterdepolarization; DAD, delayed atterdepolarization. * P < .05 vs control; -]- P < .01 vs control; $ P < .001 vs control. Paced cycle length, 1,000 ms.

(Fig. 1) were bradycardia-dependent, being present at spontaneous and paced cycle lengths of 2,000 ms or greater. The EADs and triggered potentials were suppressed at paced cycle lengths of 1,000 ms or less. The takeoff potentials for EADs facilitated by epinephrine occurred both during the plateau phase of the Purkinje action potential (-25 to -40 mV) and during late repolarization (-60 to -70 mV). The DADs and triggered rhythms were observed with the cessation of pacing at cycle lengths of 333 ms or less (Fig. 2). Adding suffident calcium chloride to

increase Ca +2 to 5 mM immediately (within 30 seconds) suppressed both EADs and DADs.

d,/-Sotalol

Administration of d,l-sotalol (lO-8M) prolonged the action potential duration at 50% and 90% of repolarization wi thout altering the maximal diastolic potential, action potential amplitude, overshoot potential, or Vmax in free-running Purkinje fibers (Table 2). Neither (EADs) nor DADs were

+2s] mV 0J

- 25 J -50 -75

- 100 2

PRE-DRUG

+25 ]

mV OJ

-25 t -50 -75

- 1 0 0 - -

400 MSEC

10-7M CLOFILIUM

mV 0J

-25 t -50 -75

- 100

~ ~ ~1010-7M CLOFILIUM

-SM EPINEPHRINE

Fig. 1. Administration of epinephrine in a clofilium pretreated canine Purkinje fiber. In the upper panel (Predrug), a Purkinje fiber action potential is shown. Prolongation of the action potential by dofilium (10-7M) is shown in the middle panel. No early or delayed afterdepolarizations were present over a 3,890-3,333 ms range of cycle lengths. With subsequent administration of 10-aM epinephrine (lower panel), pronounced formation of early afterdepolarizations is present at cycle lengths greater than 1,000 ms. The recordings shown above were obtained at a paced cycle length of 2,000 ms.


P R E - D R U G 10-7M CLOFILIUM

Fig. 2. Epinephrine-induced delayed afterdepolarizations and tachycardia fadlitated by dofilium administration. Prior to clofilium administration (Predrug) and 1 hour following clofilium administration (10-7M dofilium) (upper two panels), bursts of rapid ventricular pacing (333 and 250 ms) failed to induce delayed afterdepolarization or spontaneous arrhythmia. With subsequent administration of epinephrine (10-7M dofilium + 10-8M epinephrine), rapid pacing initiated a sustained rhythm terminated by rapid pacing and ending in a delayed afterdepolarization.

+2; t -201 -40

- 6 0

- 80

i

RAPID PACING 4 Hz

, , i I ]

2 SEC

?2 t - 6 0

- 8 0

t J

RAPID PACING 3 Hz

i i i I

RAPID PACING RAPID PACING 3 Hz 5 Hz

10-7M CLOFILIUM +

1 0 -8 M EPINEPHRINE

observed at cycle length ranging from 4,128 _ 2,034 ms (spontaneous rate) to paced cycle lengths of 250 ms (Fig. 3).

Subsequent administration of epinephrine (10-8M, 10-TM, but not 10-9M) produced rate-dependent EADs and DADs (Table 2). The takeoff potentials for EADs facilitated by epinephrine occurred both during the plateau phase of the Purkinje action potential (-25 to -40 mV) and during late repolarization (-60 to -70 mY). As observed with clofil-

ium, EADs were bradycardia-dependent and were present at both spontaneous and paced cycle lengths greater than 1,000 ms. Paced cycle lengths of 1,000 ms and less suppressed EADs. With d,l- sotalol (in contrast to clofilium), DADs and triggered rhythms were not observed following the cessation of pacing at cycle lengths of 333 ms or less. Adding calcium chloride sufficient to increase Ca0 +2 to 5 mM immediately (within 30 seconds) suppressed EADs (Fig. 3).

Table 2. A d m i n i s t r a t i o n of d, l -Sotalol P lus E p i n e p h r i n e

Parameter Predrug d,l-Sotalol (10-6M) + EPI (10-9M) + EPI (10-SM) + EPI (10-7M)

MDP (mV) -90_+ 1 - 9 i _+ I -91 4- 1 - 9 0 + 1 -90_+ I APA (mV) 122 _+ 2 122 4- 2 121 _+ 3 121 +_ 2 120 _+ 2 OS (mV) 32_+2 3 2 + 2 31 _+2 31 _+2 30_+2 Vmax (V/sec) 688 + 62 673 _+ 69 693 + 79 687 _+ 90 668 + 87 APD50 (ms) 257 -+ 61 367 -+ 88* 360 _+ 77* 370 _+ 67* 385 _+ 82* APD90 (ms) 419 _+ 77 521 _+ 90* 504 _+ 90* 502 -- 96"t" 490 _+ 87* CT (ms) 8.4_+ 1.3 8.4_+ 1.4 8.3 _+ 1.4 8.4+- 1.4 8.3 + 1.3 Cycle l eng th (ms) 4,128 -+ 2,034 4,358 4- 1,993 4,269 _ 1,921 3,999 4- 1,689" 3,987 _+ 1,834" EAD incidence 0/9 0/9 0/9 8/95 9/95 DAD incidence 0/9 0/9 0/9 1/9 219

EPI, epinephrine; MDP, m a x i m u m diastolic potential; APA, action potential ampli tude; OS, overshoot potential; Vmax, max ima l rate of phase 0 depolarization; APDS0, act ion potential dura t ion at 50% of repolarization; APD90, act ion potential dura t ion at 90% of repolarization; CT conduc t ion time; EAD, early after depolarization; DAD, delayed after depolarization. * P < .05 vs control; t P < .01 vs control; $ P < .001 vs control. Paced cycle length, 1,000 ms.


+25]

mV 01 25J -50 -75

- 1 0 0

+25] mV 01

-25] -50 -75 -100

PRE-DRUG

d ,1- SOTALOL (10-6M)

i i

400 MSEC

+25] + ~ % ~p,(~0-8~ ~~__ mV 0J

-25 t -50 75

- 100

+25] mV O]

-25] -50 -75

- 100

+2 +ca o =5 mM

Fig. 3. Suppression of epinephrine-induced early afterdepolarization by increasing extracellular calcium in a d,l-sotalol-pretreated fiber, d,l-Sotalol administration (d,l- sotalol (lO-6M), second panel from top) prolonged action potential amplitude as compared with Predrug {upper panel). Subsequent epinephrine administration (addition of 10-8M epinephrine) induced early afterdepolarizations and triggered arrhythmias {second panel from bottom). Subsequent administration of external calcium to 5 mM suppressed early afterdepolarization Iormation and triggered arrhythmia (bottom panel). The recordings shown above were obtained at a paced cycle length of 2,000 ms.

Epinephrine Administration in Control Fibers

Epinephrine was administered in increasing dosages of 10-9M, 10-SM, and 10-7M to free-running canine Purkinje fiber preparations, decreasing the spontaneous cycle length from 3,886 + 787 ms under control conditions to 3,668 + 852 ms, 3,551 + 910 ms (P < .05), and 3150 + 938 ms (P < .01), respectively. The same pacing protocols were used in control and clofilium- and d,l-sotalol-treated Purkinje fibers. No EADs or DADs were observed in each of six fibers studied over a period of 1 hour.

Discussion

Prolongation of the action potential by the IKr blocker d,l-sotalol or the (IKto + IK~) blocker clofilium is necessary but not sufficient to produce afterdepolarizations and triggered arrhythmia in normal canine Purkinje tissues. Elicitation of bradycardia-dependent EADs and spontaneous arrhythmia in drug-treated fibers is dependent on the additional administration of epinephrine. In the absence of class III drug pretreatment, the identical dosages of epinephrine fail to evoke either afterdepolarizations or arrhythmia in normal superfused canine cardiac Purkinje fibers.

The alpha- and beta-adrenoreceptor-mediated actions of epinephrine in Purkinje tissues were not separated in the present experiments. Both alpha-adrenoreceptor stimulation (via activation of phospholipase A and formation of inositol-3- phosphate) (17) and beta-adrenoreceptor stimulation (18) (via increased entry of calcium through the phosphorylated L-type calcium channel and via increased sarcoplasmic reticular calcium uptake through phosphorylation of phospholam- ban) can alter intracellular calcium metabolism. Intense alpha-adrenoreceptor stimulation facilitates EADs and bradycardia-dependent rhythms in ventricular myocytes isolated from normal canine hearts (19). Similarly, beta-adrenergic stimulation also facilitates DADs and triggered arrhythmia in canine ventricular myocytes {20,21). In normal canine Purkinje tissues, however, afferdepolariza- tions and triggered activity are not initiated by alpha- and beta-adrenoreceptor agonists over the same range of drug concentrations (22 and this study).

Clofilium but not d,l-sotalol facilitated tachycardia-dependent DADs and tachycardia-dependent arrhythmia produced by epinephrine. The basis for the differential development of DADs with epinephrine administration in the presence of clofilium versus d,l-sotalol is unknown, but could result either from nonselective beta-adrenoreceptor antagonism by d,l-sotalol or from competitive antagonism of dif- ferent subsets of potassium channels by the two class III antiarrhythmic drugs. This may have occurred propitiously as d,l-sotalol combines beta- adrenoreceptor block with a competitive inhibition of IKr (44). The potential role of pure beta-adrenoreceptor activation, with consequent fadlitation ot DADs in clofilium- or d-sotalol-treated fibers, was not addressed in this study. The role of beta- adrenoreceptor stimulation is important, as isoproterenol can evoke both EADs and DADs in canine ventricular myocytes, with EADs and DADs pre- ceded by unstimulated increases in intracellular calcium (23) and cell shortening (24).


Three possible mechanisms may be proposed for EADs observed during the plateau phase of the action potential in canine Purkinje fibers: (1) recovery and reactivation of L-type calcium channels (25,26), (2) calcium-activated chloride currents (27,28), and (3) activation of sodium-calcium exchange by unstimulated release of calcium from sarcoplasmic reticulum (23,24,29). The takeoff potentials for plateau phase EADs (-25 to -40 mV) are consistent with calcium win- dow current (23,24) and inward calcium-activated chloride current positive to the chloride current reversal potential (25-27). Overloading of the sarcoplasmic reticulum by increased calcium entry through the slow channel (beta-adrenergic stimulation) and decreased sequestration of intracellular calcium by the sarcoplasmic reticulum (alpha-adrenoreceptor stimulation) in response to epinephrine could also produce nonstimulated release of calcium from the sarcoplasmic reticulum. The transient elevation of cytosolic calcium ion concentrations stimulates the sarcolemmal sodium- calcium exchanger and provides for a transient inward current (23,24,30,31). The suppression of both DADs and EADs during phase 3 of the action potential by an acute increase in Ca0 +2 in the present study is consistent with several previous stud- ies suggesting sodium-calcium exchange as a basis for transient inward current giving rise to both EADs (10,23,24,29) and DADs (10,23,24, 30,31). This transient increase in Ca +2 (reducing the calcium gradient driving sodium-calcium exchange) must, however, be differentiated from prolonged exposure to elevated Ca0 +2, a procedure facilitating intracellular calcium accumulation and DADs (11).

Cesium chloride, an inhibitor of I k currents, pro- longs the action potential and initiates EADs and DADs. Triggered arrhythmias observed following cesium administration, both bradycardia-dependent and tachycardia-dependent rhythms, are associated with EADs and DADs, respectively (32,33). Alpha- adrenoreceptor agonists (34) and stellate ganglion stimulation (35,36) facilitate both EADs and bradycardia-dependent triggered arrhythmias following cesium pretreatment. Inasmuch as cesium chloride alone is well documented to produce EADs and triggered arrhythmia (29,32,33,37), the findings are less clear than in this study concerning the relationship between action potential prolongation and catecholamines as a basis for the facilitation of afterdepolarizations and triggered rhythms.

A more direct study of the electrophysiologic actions of sympathetic stimulation in the presence of a class III antiarrhythmic drug (d-sotalo]) was performed by Vanoli et al (38). Although the

authors noted a dramatic shortening of the d-sotalol-prolonged ventricular monophasic action potential with sympathetic stimulation, afterdepolarizations and rate-dependent ventricular ectopia were conspicuously absent. Class III antiarrhythmic drugs have been demonstrated however, to facilitate EADs and triggered rhythms in the rabbit in the presence of intense alpha-adrenoreceptor stimulation in vivo (39,40). The applicability of the results to dogs and humans is not certain, as the rabbit represents a species with an increased responsiveness to alpha-receptor-mediated positive inotropy (17). However, EADs were observed in d,l-sotalol-treated canine Purkinje fibers in the presence of beta-adrenoreceptor block and in clofilium-treated canine Purkin]e fibers.

With respect to clinical implications, class III antiarrhythmic drugs have been shown to facilitate EADs and ventricular arrhythmia in the dog during the recovery period of myocardial infarction (8,9). This study demonstrates that the class III antiarrhythmic drugs facilitate EADs and DADs by epinephrine in normal canine Purkinje tissues. Fur- thermore, EADs and/or DADs in Purkinje tissues may contribute to the increased incidence of lethal arrhythmia and the overall increased mortality observed in survivors of myocardial infarction who comprised the d-sotalol treatment group in the SWORD trial (5). Prolongation of the action potential by inhibition of repolarizing potassium currents may place a patient at an increased risk for EAD- and DAD-mediated arrhythmogenesis by adrenergic stimulation and may reduce the efficacy of a promising class of antiarrhythmic agents.

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Facilitation of epinephrine-induced afterdepolarizations by class III antiarrhythmic drugs