Electrophysiologic effects of beta blockers in ventricular arrhythmias

ElectrophysiologicEffects of Beta Blockers in Ventricular Arrhythmias FERDINAND

J. VENDITTI Jr., MD, HASAN GARAN, and JEREMY N. RUSKIN, MD

P-adrenergic receptor blocking agents are effective antiarrhythmic drugs in patients with ventricular arrhythmias. However, these agents exert little or no measurable electrophysiologic effect on normal Purkinje and ventricular muscle fibers when administered acutely. They prevent catecholamine-induced increases in Purkinje fiber automaticity and may interfere with catecholamine-dependent slow responses. @-adrenergic blocking drugs also prevent the decrease in ventricular fibrillation threshold induced by catecholamines. In the acutely ischemic

B

eta-adrenergic blocking agents are effective antiarrhythmic drugs. Several /3blockers have been shown in well-designed clinical trials to prevent sudden cardiac death and reinfarction in patients after infarction.1-4 In addition, this class of drugs has been shown to reduce the frequency of spontaneous ventricular arrhythmias in patients with high grade ventricular ectopic activity.5-1* They have also been shown to prevent the initiation of ventricular tachycardia in a small subset of patients studied by invasive electrophysiologic techniques, 12-14In patients with recurrent ventricular tachycardia induced by exercise, p blockers are the mainstay of therapy.l5J6 With the exception of patients demonstrating exercise- and catecholamine-induced ventricular tachycardia, the mechanism of antiarrhythmic action of /3 blockers in most patients with ventricular arrhythmias

MD,

ventricle, some p blockers selectively depress conduction within the ischemic zone. The long-term administration of some p blockers has, in contrast to their short-term effects, been shown to prolong action potential duration and effective refractory period in the ventricle. Which of these observed electrophysiologic effects, either alone or in combination, contributes to the ventricular antiarrhythmic effects of B-blocking drugs in man is at present unknown. (Am J Cardiol

1987;80:3D-91))

is not clear. In the former group of patients, ,6-adrenergic blockade probably explains the antiarrhythmic action of this class of drugs. However, this may not be the antiarrhythmic mechanism of action in the vast majority of patients receiving P-blocking drugs, This article reviews the basic and clinical electrophysiologic properties of ,6 blockers and discusses some of the potential mechanisms of their antiarrhythmic actions.

Electrophysiologic Effects of Beta-Adrenergic Stimulation

The electrophysiologic effects of fl-adrenergic stimulation on ventricular tissue are well known and will be summarized only briefly here. The effects of catecholamines on ventricular tissue are dependent on the concentration of the catecholamine used, the degree of a-adrenergic stimulation produced by the catecholamine administered and whether the fibers are norFrom the Cardiac Unit and Arrhythmia Service, Massachusetts mal or abnormal. General Hospital, Boston, Massachusetts. This study was supCellular effects: In normal Purkinje fibers, @-adreported in part by Grant HL26215 from the National Heart, Lung, nergic stimulation causes no change in the resting and Blood Institute and the National Institutes of Health, Be- transmembrane potential, the initial portions of the thesda, Maryland. Dr. Garan is the recipient of Established Inaction potential, phase 0 and phase 1,17 or conduction vestigatorship 84-209 from the American Heart Association, velocity.18 However, repolarization is altered with Dallas, Texas. pure fl-adrenergic stimulation resulting in shortening Address for reprints: Jeremy N. Ruskin, MD, and Ferdinand of the action potential duration. Conversely, or-adreJ. Venditti Jr,, MD, Cardiac Unit, Massachusetts General Hospi- nergic stimulation results in lengthening of the action tal, Boston, Massachusetts 02114. potential duration. lgs20The most dramatic and consis-

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tent effect of ,B-adrenergic stimulation in normal Purkinje fibers is an increased rate of rise of phase 4 depolarization, thus increasing automaticity.lQ* In normal ventricular fibers, /3-adrenergic stimulation has very little effect on resting transmembrane potential, phase 0 of the action potential, action potential duration or conduction velocity.21 Additionally, diastolic depolarization is not altered and therefore automatic@ is not enhanced. Repolarization is not consistently altered, and has been reported to be slightly prolonged as well as shortened.2zJ3 In fibers with abnormal resting transmembrane potentials from many causes, catecholamines restore excitability to cells with membrane potentials less negative than -50 mV without altering the resting membrane potential by increasing the slow inward current. This augmented slow inward current generated by catecholamines may result in enhanced automaticity. In abnormal cells with resting potentials between -70 and -90 mV, both the amplitude and maximum upstroke velocity of the action potential are decreased. Catecholamines hyperpolarize these fibers, thereby restoring action potential amplitude and maximum upstroke velocity toward baseline.24 Automatic@ is decreased in these fibers by catecholamines as a result of depressed diastolic depolarization. Intact heart: /3-adrenergic stimulation in intact animal hearts results in modest effects. No effect is observed in conduction velocity in the main bundlesz5; however, a shortened effective refractory period of the His-Purkinj e system,z6 a shortened ventricular monophasic action potential durationz7 and a transient decrease in the ventricular fibrillation thresholdz8 are observed.

Electrophysiologic Effects of Beta Blockade Animal studies: &adrenergic blocking agents have been evaluated extensively in numerous experimental

TABLE Agents

I Electrophysiologic Effects in Experimental Preparations

of /%tieceptor

Ventricular

Purkinje

Propranolol Nadolol Pindolol Labetalol Atenolol Timolol Metoprolol Oxprenolol

*

APD

Amp

RMP

4

1

1 1

! t

I --

V,,

APD

Amp

1

1

1

RMP 1 t,

JZ:: 1

J+

r:

r:

v,,,

VFT

1

t

c,

t t t i

Propranolol+ Metoprolol+

1:

Atenolol+ Acebutololt Propranololt

i

* = high dose; + = long-term: 1: = intact Amp = amplitude; APD = action potential brane potential; VFT = ventricular fibrillation decreased:

Blocking

-

= no change.

heart. duration: threshold;

RMP = resting t = increased;

mem$ =

models both in vitro and in the intact heart. Each preparation is slightly different because of the species or techniques used by the individual investigators. All of the in vitro preparations are devoid of neuronal influences and circulating catecholamines and therefore differ significantly from intact animals, In addition, the local catecholamine levels in both in vitro and in vivo preparations may vary over time. Even the type of anesthesia used may influence importantly the sympathetic input to the heart. Thus, the data to follow should be interpreted in light of the confounding factors just noted. Cellular effects (Table I): One of the first ,6 blockers to be studied in the laboratory was propranolol.29 Papillary muscle preparations isolated from canine ventricles were studied with varying concentrations of propranolol in the perfusate. At low concentrations of propranolol(O.l pg/ml), there was no effect on any of the parameters measured in either Purkinje fibers or ventricular tissue. However, in Purkinje fibers, high concentrations of propranolol(10.0 ,ug/ml) resulted in a small (4%) decrease in the resting transmembrane potential, a 12% decrease in the amplitude of the action potential, a shortening of the duration of the action potential by 5%, a shortening of the plateau or phase 2 by 30% and a 30% decrease in the maximum rate of increase of phase 0. In ventricular fibers there were qualitatively similar changes, but of lesser magnitude in response to the higher concentration of propranolol. The resting transmembrane potential decreased by 270, the action potential amplitude decreased by 770, phase 2 was shortened by 8%, the action potential duration shortened by 5% and the maximum rate of increase decreased by 35%. The concentrations of propranolol required in these studies to produce the observed changes were much higher than concentrations achieved with the doses used clinically. Nadolol, a long-acting /3 blocker, has also been investigated in in vitro preparations.30s31 Unlike propranolol, nadolol decreases the resting transmembrane potential and the amplitude of the action potential in Purkinje fibers without such’an effect on ventricular tissue. The duration of the action potential is decreased in Purkinje fibers, with a slight increase in the duration of ventricular cells. The maximum rate of increase of the action potential in Purkinje fibers is slightly decreased, without any change in ventricular tissue, Nadolol has no effect on diastolic depolarization in normal Purkinje fibers or in an ouabain-treated preparation.31 Pindolol, a 0 blocker with intrinsic sympathomimetic activity, has also been studied in vitro.3Z Like propranolol, pindolol caused a significant decrease in the action potential amplitude and duration, the maximum rate of depolarization and the functional refractory period of Purkinje fibers at a concentration of 5.0 mg/liter. As with nadolol, no significant effects were observed in ventricular tissue. Labetalol is an agent with both ,& and or-adrenergic blocking properties. 33 The cellular electrophysiologic effects of this agent have been studied in rabbit tissue preparations.34 Resting transmembrane potentials and

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action potential amplitude were unaffected in either Purkinj e fibers or papillary muscle. With high doses of labetalol, the maximum rate of depolarization was decreased in Purkinj e fibers, although the papillary muscle preparations demonstrated no change. Conduction velocity was significantly reduced in both types of fibers. All phases of repolarization were significantly lengthened in both ventricular muscle and Purkinje fibers, resulting in prolongation of the action potential duration. This finding contrasts with the effects observed with other p blockers that do not possess (Yadrenergic blocking properties. The effects on repolarization were observed at relatively low concentrations of labetalol, comparable to those attained clinically. Atenolol in low as well as high concentrations has very little effect on the action potential recorded in vitro from ventricular fibers.35,36 Action potential duration increases slightly or does not change at all, while other parameters are unchanged. Atenolol and acebutolol have been studied in intact dogs using a suction catheter to record monophasic action potentials. Both agents prolonged monophasic action potential duration minimally by 4% to 8% at all the pacing cycle lengths tested and prolonged right ventricular effective refractory periods by 10% to 20% at multiple sites. 37 In addition, a small but significant prolongation of the monophasic action potential duration was demonstrated in animals treated with propranolol, which differs from the in vitro findings.zg Ischemic tissue: During acute ischemia, action potential durations are shortened and conduction is prolonged. When /3-adrenergic blockers are administered, conduction times in the ischemic zone are prolonged further and action potential durations are increased.38 Initially within the first 2 to 3 minutes after coronary artery ligation, there is less prolongation of conduction times in the ischemic zone in preparations treated with propranolol, nadolol or alprenolol compared with ischemia in the absence of fl-adrenergic blockade.38 After 15 minutes, the prolongation of conduction observed in the ischemic zone was greater after propranolol than with ischemia at baseline.38 In addition, propranolol increased the monophasic action potential duration and lengthened the effective refractory period in the ischemic zone. The net results of these changes are reduced disparity in monophasic action potential duration between ischemic and normal tissues, prolonged refractoriness and slowed conduction in the ischemic zone, all potentially antiarrhythmic effects, Ventricular fibrillation threshold: Initial work on the effect of p blockers on ventricular fibrillation (VF) thresholds in animal models yielded mixed results. In a comparative study with propranolol and pronethalol, propranolol did not consistently increase the VF threshold while pronethalol, a p blocker with quinidine-like properties, did .3g This study used relatively small doses of propranolol in only 7 animals. More recent animal studies have revealed that propranolol and timolol increase the VF threshold by 60% to 67% and 60% to 96%, respectively.40-43 These studies evaluated P-adrenergic blockade in both open- and closed-

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chest experiments with similar results. Metoprolol has also been shown to increase the VF threshold when given in doses of 0.1 to 10.0 mg/kg.44 Recent work on the effects of P-adrenergic blockade in both ischemic and nonischemic dog hearts has demonstrated a striking increase in the VF threshold during both states. 45All of the p blockers tested (pindo101, propranolol, labetalol, metoprolol and timolol) demonstrated marked (5- to 7-fold) increases in VF thresholds under both ischemic and nonischemic conditions. Pindolol produced the largest change under nonischemic conditions. VF thresholds increased from a mean of 11.8 mA to a mean of 80.8 mA after treatment. The largest change during ischemia occurred with labetalol, resulting in an increase in VF thresholds from a mean of 7.2 mA to a mean of 52.4 mA after treatment. Left ventricular effective refractory periods increased an average of 15% in the nonischemic hearts and 10% in the ischemic ones treated with P blockers. The drugs were given in 5 different doses including a clinically relevant dose (i.e., propranolol 0.03 to 0.10 mg/kg intravenously and metoprololO.1 to 0.3 mg/kg intravenously. The mechanism of this increase in VF threshold with P-blocker therapy is unknown, but probably reflects a direct effect of /3-adrenergic blockade. When animals were given propranolol, pindolol and oxpren0101, increases in VF threshold of 42%,25%, and 5670, respectively, were observed.46 The effective refractory period of the left ventricle increased by 8% and lo%, respectively, with oxprenolol and propranolol while pindolol, a p blocker with intrinsic sympathomimetic activity, produced a decrease of 470, an effect consistent with /3-adrenergic stimulation.z6 When the same animals were pretreated with reserpine to deplete catecholamine stores, pindolol actually decreased the VF threshold. This effect was then reversed with propran0101, a p blocker without intrinsic sympathomimetic activity. ’ Spontaneous arrhythmias: The effect of P-adrenergic blockade on spontaneous ventricular arrhythmias has also been evaluated. In a large group of animals who underwent coronary artery occlusion in the conscious state, there was a significant difference between the animals pretreated with fl blockers compared with those not pretreated.47 The control group of animals demonstrated a 72% incidence of VF after sudden coronary artery occlusion compared with a 20% incidence in dogs pretreated with propranolol (p
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found that all 3 p blockers were effective in suppressing ventricular ectopy resulting from ischemia and catecholamines. However, nadolol was ineffective in ouabain-induced arrhythmias even at very high doses, Labetalol has been evaluated in the chloraloseanesthetized cat at a clinically relevant concentration, as well as at higher concentrations.50 The drug produced no effect on spontaneous ventricular ectopy or VF occurring after acute coronary artery occlusion or reperfusion when used in a dose of 1.0 mg/kg. However, when labetalol was used in higher doses of 2.0 and 5.0 mg/kg, a significant decrease in both the frequency of spontaneous ventricular ectopy and VF was observed. Inducible arrhythmias: The response to programmed electrical stimulation after ,8-adrenergic blockade has been studied in dogs 4 to 6 days after experimental myocardial infarction.42 At baseline, only 6 of 22 dogs had sustained monomorphic ventricular tachycardia, while the other 16 animals (73%) had polymorphic ventricular tachycardia or VF. Timolol treatment resulted in suppression of the programmed electrical stimulation-induced ventricular tachycardia or VF in 13 of the 22 dogs treated (59%) and proprano101suppressed ventricular tachycardia or VF in 9 of 15 dogs treated (60%). In the subgroup of animals with monomorphic ventricular tachycardia the response to ,&adrenergic blockade was not specified.4z Ventricular effective refractory periods were increased in the timolol-treated dogs by approximately lo%, while propranolol increased effective refractory periods by 9%. There was no effect on the QTc measured in these animals. Metoprolol has been investigated in a late infarction model of ventricular tachycardia in dogs51 The preliminary report indicated that after an intravenous loading dose of metoprolol (0.2 mg/kg), 2 of 9 dogs (22%) no longer had inducible arrhythmias compared with baseline. No effect on ventricular refractory period was observed in these animals. Long-term administration: The response of cardiac fibers to long-term therapy with /3-adrenergic blocking agents seems to differ from that of short-term adminisTABLE II /I Blockers

Acute Electrophysiologic in Man

Effects

of Currently

FRP

Propranolol Metoprolol Atenolol Acebutolol Pindolol Labetalol Timolol Nadolol Esmolol

AH

HV

QTc

7

-

4

/zyf

ERP

SNRT

-

AVN

HP

f

--

;y

1

-1:

j++‘;

i

AVN t

‘; -

Available

HP -

A -,t

V

HumanStudies (Table II)

-

t-

-

I:-

,”

7x7

c,

-,t-

~~:

1 ++“,-

tration. In studies by Raine and Vaughan Williams, 52-55in vitro action potential duration was prolonged by as much as 25% (35 to 40 ms) in atria1 as well as ventricular fibers after 6 weeks of therapy with doses of ,8 blockers equivalent to those used clinically (4 mg/ kg of propranolol and 6 mg/kg of metoprolol). Initially, the action potential duration in muscle fibers shortened in animals studied after 3 days of ,&blocker therapy compared with controls (p X0.01). However, by 6 days there was a prolongation of action potential duration, which reached statistical significance by 24 days compared to control animals (p
-

t = increased; 1 = decreased; ++ = no change. A = atrial; AVN = atrioventricular node; ERP = effective refractory period; FRP = functional refractory period; SNRT = sinus node recovery time; V = ventricular.

Short-term effects: The short-term electrophysiologic effects of many of the currently approved and investigational /Sadrenergic blockers have been assessed in man.56-71 The major electrophysiologic effects of p blockers are found not in the ventricle, but in the sinoatrial and atrioventricular nodes. The first p blocker to be studied was propranolol.5658 The effect of this agent on atrioventricular conduction as well as intraventricular conduction was as-

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sessed by standard intracardiac recording techniques. The investigators found a prolongation of atrioventricular nodal effective refractory periods, prolongation of A-H intervals and no effect on H-V intervals. A later study found significant prolongation of A-H intervals and atrioventricular nodal functional and effective refractory periods, minimal (5%) shortening of the QTc interval and no effect on atrial, His-Purkinje or ventricular effective refractory periods.57 In addition to having no effect on the ventricular effective refractory period, intravenous propranolol given acutely to 4 patients did not terminate ventricular tachycardia once initiated in the electrophysiologic laboratory. The tachycardia zone (the intervals at which premature extrastimuli initiated ventricular tachycardia during programmed stimulation] was also unaffected by propranolol. Metoprolol has been shown to have no effect on the H-V interval and refractory periods of the His-Purkinje system when given in a dose of 0.10 mg/kg intravenously.5g However, metoprolol prolonged the effective refractory period of the right ventricle to a small degree [8%] 4 to 6 hours after a loading dose of 0.15 mg/ kg intravenously. 6o The QTc interval was unchanged in this study. Atenolol, pindolol and timolol have also been studied acutely in man .61-63These drugs have been shown to have no effect on the right ventricular effective refractory periods, H-V intervals or intraventricular conduction. Atenolol shortened the QTc interval by 570, similar to the effect of propranolol. Acebutolol, when administered acutely in a dose of 0.3 to 0.5 mg/kg, has effects similar to those of other @ blockers.64-66 When given in a higher dose (1.0 mg/kg), acebutolol prolonged the H-V interval especially when serum concentrations achieved exceeded 1,000 ng/ml.@j Labetalol has also been studied acutely in man.67,68 There was no significant effect on H-V intervals, right ventricular effective refractory period or the QTc interval when the drug was given intravenously in a dose of 1 mg/kg over several minutes. Several investigational p blockers have also been evaluated acutely. 6g-71Esmolol, oxprenolol and penbutolol have been given intravenously with electrophysiologic effects similar to those observed with currently approved p blockers. Esmolol has a very short half-life; therefore, the sinus rate returns to baseline within 5 minutes after drug administration.69 Long-term effects: The acute electrophysiologic effects of p blockers differ from the long-term effects in humans as they do in animals. In 1 study,7Z a group of 16 normal volunteers underwent a comprehensive electrophysiologic study that included monophasic action potentials recorded from the right ventricle. They received 15 mg of metoprolol intravenously over 5 minutes. The same parameters were remeasured 10 minutes after the drug was given, The investigators found that intravenous metoprolol had no effect on HV intervals, right ventricular effective refractory periods or right ventricular monophasic action potentials. In a subgroup of 8 patients, these parameters were remeasured after 5 weeks of oral metoprolol therapy,

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200 mg twice daily.

This group was studied 36 hours after the last dose of metoprolol to avoid any acute effects of the drug. There was no change in the H-V interval. However, there was an 8% to 10% increase in the ventricular effective refractory period measured both at the right ventricular apex and outflow tract (15 to 24 ms increase). In addition, there was a 6% increase in the duration of the monophasic action potential recorded from the right ventricle. In a follow-up study the same investigators found that the QTc interval was significantly prolonged after 3 weeks of therapy with 200 mg of metoprolol daily in a population of patients with indications for fl blockers.73 Recent work by another investigator with propranolol was shown no significant change in the QTc interval during constant-rate pacing in a group of 8 patients after 2 weeks of therapy with modest doses of propranolol.74

Discussion The mechanisms by which P-receptor blocking drugs exert their antiarrhythmic effects are not clearly defined by the experimental and clinical data available to date. Numerous in vitro studies performed in several animal models using fi blockers with different profiles (intrinsic sympathomimetic activity and membrane stabilizing properties) demonstrate that acute administration of these drugs results in a decrease in action potential duration and maximum upstroke velocity. Importantly, however, acute effects differ from long-term effects. In microelectrode studies, long-term P-adrenergic blockade prolongs the action potential duration, an effect opposite to that seen with acute administration. In addition, effective refractory periods in ventricular fibers are also prolonged during long-term administration of some fl blockers. Both of these effects represent potentially important antiarrhythmic properties. Moreover, all of the /3 blockers studied increase the ventricular fibrillation threshold at baseline and during experimental ischemia while decreasing the incidence of spontaneous ventricular arrhythmias during acute ischemia. In human studies, the acute administration of @ blockers has very little effect on the His-Purkinje system or ventricular myocardium, including effective refractory periods, monophasic action potentials and intraventricular conduction. However, long-term administration results in a small degree of prolongation of the ventricular effective refractory period, monophasic action potential and QTc interval. These longterm electrophysiologic effects represent important manifestations of the antiarrhythmic actions of other classes of drugs. Their relative significance in explaining the antiarrhythmic effects of P-receptor blocking drugs remains to be defined. In patients with catecholamine-sensitive ventricular arrhythmias, ,&adrenergic blockade results in the suppression of spontaneous arrhythmias in the majority of patients. However, a direct effect on /3 receptors resulting in the suppression of catecholamineand exercise-induced arrhythmias explains the efficacy of /3 blockers in only a small group of patients.

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P-receptor blocking agents are the only antiarrhythmic drugs that have demonstrated a decrease in cardiac mortality when studied in prospective, randomized, placebo-controlled trials. These trials in postinfarction patients revealed a significant decrease in mortality primarily based on a decrease in sudden cardiac death among patients receiving /3 blockers.l-4 Because the majority of sudden cardiac deaths are the result of ventricular tachyarrhythmias, these trials affirm the efficacy of P-receptor blocking drugs as antiarrhythmic agents in patients with ischemic heart disease. Nevertheless, the mechanism of their antiarrhythmic action in this and other clinical settings remains largely unknown. In animal models, ,6 blockers decrease conduction velocity in ischemic tissue and significantly increase ventricular fibrillation thresholds, both under control conditions and during acute ischemia. The clinical significance, if any, of the marked increases in experimentally determined ventricular fibrillation thresholds caused by /3-adrenergic blocking drugs, particularly during acute ischemia, is unknown at the present time. It is possible, however, that selective prolongation of conduction time in ischemically depressed fibers may, under some conditions, prevent the emergence of reentrant ventricular arrhythmias. In addition to the aforementioned effects on conduction velocity and ventricular fibrillation thresholds, several studies have reported prolongation of action potential duration in ventricular fibers and prolongation of ventricular effective refractory periods in experimental animals after long-term therapy with ,&adrenergic blocking drugs. Also, clinical studies in small populations have reported slight prolongation of monophasic action potential duration and right ventricular effective refractory periods after 3 to 6 weeks of P-blocker therapy. Some investigators have interpreted these electrophysiologic changes as evidence of a class III-like effect of long-term P-blocker therapy and a potential basis for their antiarrhythmic effect.75 However, more data will be required to define the magnitude, mechanism and clinical significance of these changes in patients with ischemic heart disease or recurrent ventricular arrhythmias. In summary, ,&adrenergic receptor blocking drugs exert little or no measurable electrophysiologic effect on normal Purkinje and ventricular muscle fibers when administered acutely. They prevent catecholamine-induced increases in Purkinje fiber automaticity and may interfere with catecholamine-dependent slow responses. /3-adrenergic blocking drugs also prevent the decrease in ventricular fibrillation threshold induced by catecholamines. In the acutely ischemic ventricle, some /3blockers selectively depress conduction within the ischemic zone. The long-term administration of some @blockers has, in contrast to their acute effects, been shown to prolong action potential duration and effective refractory period in the ventricle. Which of these observed electrophysiologic effects, either alone or in combination, contributes to the ventricular antiarrhythmic effects of P-blocking drugs in man is at present unknown.

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52. Vaughan Williams EM, Raine EG, Cabrera AA, Whyte JM. The effects of prolonged beta-adrenoceptor blockade on heart weight and intracellular potentiaJs in rabbits. Cardiovasc Res 1975;9:579-585. 53. Raine AEG, Vaughan Williams EM. Adaptational response to prolonged beta-adrenoceptor blockade in adult rabbits. Br J PharmacoJ1980;70:205-210. 54. Raine AEG, Vaughan Williams EM. Adaptation to prolonged beta-blockade of rabbit atrial, Purkinje, and ventricular potential, and of papillary muscle contraction. Circ Res 1981:48:804-811. 55. Raine AEG, Vaughan Williams EM. Electrophysiological basis for the contrasting prophylactic efficacy of acute and prolonged beta-blockade. Br Heart 1 1978;4O:suppJ:71-76. 56. Berkowitz WD, Wit AL, Lau SH, Steiner C, Damato AN. The effects of propranoIo1 on cardiac conduction. Circulation 1969;40:855-860. 57. Seides SF, Josephson ME, Batsford WP, Weisfogel GM, Lau SH, Damato AN. The electrophysiology of propranolol in man. Am Heart r 1974;88:733740. 58. Wellens HJJ, Bar FWH, Lie KI, Duren DR, Dohmen HJ. Effectsofprocainamide, propranoJoJ and verapamil on mechanism of tachycardia in patients with chronic recurrent ventricular tachycardia. Am r Cardiol 1977;58:579586. 59. Rizzon P, DiBiase M, Chiddo A, Mastrangelo D, Sorgente L. Electrophysiological properties of intravenous metoproIo1 in man. Br Heart J 1978;40:650656. 60. Marchlinski FE, Buxton AE, Waxman HL, Josephon ME. Electrophysiologic effects of intravenous metoproJoJ. Am Heart J 1984;107:1125-1131. 61. Robinson C, Birkhead J, Crook B, Jennings K, Jewitt D. Clinical electrophysiological effects of atenolol: a new cardioselective beta-blocking agent. Br Heart [ 1978;40:14-19. 62. DiBiase M, Brindicci G, Rizzon P. Effects of pindolol on impulse formation and conduction in man. 1 Electrocardiol 197?;10:45-52. 63. Ezri MD, Marchlinski FE, Buxton AE, Waxman HL, Josephon ME. Electrophysiofogic effects of intravenous timolol. Int r Cardiol 1983;3:329-334. 64. Singh BN, Thoden WR, Ward A. AcebutoJoJ: a review of its pharmacological properties and therapeutic efficacy in hypertension, angina pectoris and arrhythmias. Drugs 1985;29:531-550. 65. Marrott PK, Ruttley ST, Jenkins PM, Muir JR. The electrophysiological evaluation of intravenous acebutolol, a beta-blocking drug. Eur 1 Cardiol 1977;6:117-122. 66. Mason JW, Winkle RA, Meffin PJ. Electrophysiological effects of acebutofol. Br Heart 1 1978;40:35-42. 67. Harley A, Coverdale HA. The electrophysiological effects of intravenous JabetaJoJ in man. Eur J CIin Pharmacol 1981;20:241-246. 68. Upward JW, McLeod AA, Daly K, Jackson G. The electrophysiological effects of intravenous Jabetalol in man. Circulation 1983;68:suppJ III:III-274. 69. Greenspan AM, Spielman SR, Horwitz LN, Senior S, Steck J, Laddu A. Electrophysiology of esmolol. Am 1 Cardiol 1985;56:2OF-25F. 70. DiBiase M, Guglielmi R, Scarcia A, Chiddo A, Rizzon P. Electrophysiologic properties of intravenous oxprenolol in man. 1 EJectrocardioJ1977:10:267272. 71. Von Leitner ER, Biamino G. Clinical electrophysiological properties of penbutolol: a selective beta-blocking agent. Eur 1 Cardiol 1980;12:121-126. 72. Edvardsson N, Olsson SB. Effects of acute and chronic beta-receptor blockade on ventricular repolarization in man. Br Heart 1 1981;45:628-633. 73. Edvardsson N, Olsson SB. Induction of delayed repolarization during chronic beta-receptor blockade. Eur Heart J 1985;6:suppJ D:163-169. 74. Creamer JE, Nathan AW, Shennan A, Camm AJ. Acute and chronic effects of sotalol and propranolol on ventricular repolarization using constant-rate pacing. Am J Cardiol 1986;57:1092-1099. 75. Vaughan Williams EM. Delayed ventricular repolarization as an antiarrhythmic principle. Eur Heart r 1985;8:suppJ D:145-149.