Effects of timolol and propranolol on inducible sustained ventricular tachyarrhythmias in dogs with subacute myocardial infarction

Effects of Timolol and Propranololon Inducible Sustained Ventricular Tachyarrhythmias in Dogs with Subacute Myocardial Infarction ELI S. GANG, MD, J. THOMAS BIGGER, Jr., MD, and ELIZABETH VV. UHL

Timolol and propranolol reduce the incidence of cardiac death after myocardial infarction (Ml). To explore possible mechanisms of this reduction in mortality, the antiarrhythmic effects of these 2 @ blockers were compared in a dog model of inducible sustained ventricular tachycardia (VT) or fibrillation (VF) 4 to 6 days after experimental closed-chest Ml. Dogs with inducible VT or VF underwent drug studies with timolol and propranolol; the sequence of drug administration was randomized. Timolol doses were 0.1, 0.3, and 1.0 mg/kg; propranolol doses were 1.0, 3.0 and 10.0 mg/kg. Timolol and propranolol were equally effective in abolishing inducible VT or VF: 77 % of instances of inducible VT or VF responded to 1 or both p blockers. The VF threshold was significantly elevated by both timolol and propranolol; the elevation in the VF threshold was significantly greater in “res onders,” i.e., dogs in whom VT was prevented by B blockade (15 f 9 vs 6 f 9 mA, p <0.05). The ventricular effective refractory period was prolonged by both drugs; again, more so in the

responders than in the nonresponders (16 f 9 vs 6 f 14 mA, p <0.05). The QTc interval was not significantly affected by either p blocker. Among the responders, no difference was detected between timolol and propranolol in the extent to which the effective refractory period was prolonged or the VF threshold elevated. However, the highest dose of propranolol decreased the mean blood pressure significantly more than the comparable dose of timolol. In conclusion, timolol and propranolol are equally effective in abolishing inducible VT or VF in the dog after subacute MI. Both drugs tend to elevate the VF threshold and to prolong the ventricular effective refractory period without significantly altering the QTc interval, suggesting a possible direct membrane depressant effect for both drugs. At a high dose, propranolol tends to lower mean blood pressure more than the comparable dose of timolol.

Recent large clinical trials have demonstrated significant reductions in the death rate after myocardial infarction (MI) in patients treated with /3-adrenergic blocking agents. The sudden death rate was reduced by 45% with timololl and by 28%= and 50%3 with propranolol. How /3 blockers exert their protective effect after MI is not known. Sudden cardiac death in ischemic

heart disease is usually caused by ventricular tachycardia (VT) or ventricular fibrillation (VF).4 Recent clinical electrophysiologic studies have demonstrated a strong association between VT or VF induced by programmed ventricular stimulation and the spontaneous occurrence of these arrhythmias.5-7 When pharmacologic therapy prevents the induction of VT or VF, recurrence is much less likely during long-term followUP.~-~ To test the hypothesis that timolol and propranolol exert at least part of their protective effect by acting as potent antiarrhythmic drugs, we used a subacute, post-MI, closed-chest dog model of inducible VTl” to examine and compare the effects of timolol and propranolol on inducible VT, on the VF threshold and on the ventricular effective refractory period. To simulate clinical multiday drug-testing stimulation protocols7-g each dog was tested with each ,!3blocker on

(Am J Cardiol 1964;53:275-261)

From the Department of Medicine, Columbia University, and the Arrhythmia Control Unit, Columbia-Presbyterian Medical Center, New York, New York. This study was supported in part by grants-in-aid from the Winthrop Foundation, New York, New York; Merck Sharp and Dohme, West Point, Pennsylvania; and by grant HL-07406 from the National Heart, Lung, and Blood Institute, Bethesda, Maryland. Manuscript received April 18, 1983; revised manuscript received September 22, 1983, accepted September 26, 1983. Address for reprints: J. Thomas Bigger, Jr., MD, Department of Medicine, Columbia University, 630 West 168th Street, New York, New York 10032. 275

276

BETA BLOCKERS AND INDUCIBLE VENTRICULAR

separate days and the sequence was randomized.

ARRHYTHMIAS

of drug administration

Methods Experimental protocol: Mongrel dogs that weighed 15 to 28 kg were anesthetized with a-chloralose (100 mg/kg), intubated and ventilated with a volume-cycled respirator. Arterial blood gases and body temperature were maintained within physiologic range. The ECG and arterial blood pressure were displayed on an Electronics for Medicine VR12@recorder and stored on FM magnetic tape (Honeywell, model 101). Experimental MI was created as previously described.lO In closed-chest dogs, a balloon catheter was positioned in the left anterior descending coronary artery under fluoroscopic control and inflated. Coronary artery occlusion was confirmed by characteristic electrocardiographic changes. The occlusion was terminated after 2 hours, the catheters were removed and the dogs were returned to their kennel. Four to 6 days after MI the dogs were returned to the laboratory and anesthetized. A quadripolar No. 6Fr catheter (USCI) was placed in the right ventricular apex under fluoroscopic control. Programmed electrical stimulation was then performed (see below) with 2 ms, twice-threshold current pulses from a digital stimulator (Bloom Associates). The distal 2 electrodes of the catheter were used for bipolar stimulation; the distal electrode was always the cathode. The proximal 2 electrodes were used to record a right ventricular electrogram. We first assessed the antiarrhythmic efficacy of timolol in a pilot study using 7 dogs with inducible VT or VF (Group I). After control measurements of induction and termination of ventricular tachyarrhythmia, several doses of timolol were infused and stimulation repeated 15 to 20 minutes after each dose until VT or VF was no longer inducible or the highest dose of the drug administered. We next compared timolol with propranolol in 15 dogs with inducible VT or VF 4 to 6 days after MI (Group II). Each dog was randomized to either timolol or propranolol as initial treatment. After drug infusion and programmed stimulation, the dogs in Group II were allowed to awaken, returned to the kennel and brought back to the laboratory the next day for repeat electrophysiologic testing and infusion of the second P-blocking drug. Programmed ventricular stimulation: A train of 8 pulses at a paced cycle length of 350 ms was followed by a single premature stimulus (Sz). The S1-S2 interval was decreased by 10 ms until the Sz failed to elicit a ventricular response. The final lo-ms interval was then scanned in 2-ms intervals. The effective refractory period of the right ventricle was defined as the shortest SI-S2 interval that elicited a ventricular response. Diastole was scanned with dual (&-S&$ and triple (S1-S2-Ss-SJ premature stimuli as well as “burst” ventricular pacing, i.e., trains of 8 ventricular stimuli at decreasing cycle lengths until 1: 1 ventricular capture was no longer obtained. The end point for programmed stimulation was the induction of a sustained VT or VF. Sustained VT was defined as one that required pacing or DC countershock for its termination. At least 3 stimulation trials were performed in each dog and reproducibility of VT or VF induction was defined as induction of the tachyarrhythmia in at least 2 of 3 trials. Ventricular fibrillation threshold: After a train of 8 paced pulses (cycle length of 350 ms), diastole was scanned with an ST test pulse 5 ms in duration, starting approximately 15 ms after the inscription of the T wave; S1-S2 was shortened by 3 ms until ventricular refractoriness was reached. The initial current setting of the Sz stimulus was set at 1 mA and increased in 1-mA increments after each scan of diastole. The

VF threshold was defined as the lowest current strength of Sz required to produce VF. Defibrillation was then promptly performed. In this study, survival of each dog was a paramount consideration. Therefore, we subjected each dog to the fewest possible episodes of VT or VF and only measured VF threshold at the end of dose ranging. Drug infusion protocol: In Group I, 4 doses of timolol(O.1, 0.3, 1.0 and 3.0 mg/kg) were available for i.v. administration to each dog; each dose was given over 5 minutes. After 15 minutes, programmed ventricular stimulation was repeated. If VT or VF was still inducible, the next dose of timolol was infused. When VT or VF was no longer inducible, or when the highest dose of drug had been infused, the VF threshold was again measured. In Group II, each dog was randomized either to timolol or to propranolol treatment. The investigator was blinded with respect to the treatment sequence. Since timolol is approximately 10 times as potent as propranolol, both in its P-blocking effect as well as elevating the VF threshold,ll-l3 we gave propranolol and timolol in a 10: 1 dosing ratio: propranolol, 1.0,3.0 and 10.0 mg/kg and timolol, 0.1,0.3 and 1.0 mg/kg. As in Group I, when VT or VF was no longer inducible or when the highest dose had been given, the VF threshold was

FIGURE 1. The types of sustained ventricular tachyarrhythmias induced with programmed ventricular stimulation in 3 dogs. A, a single premature stimulus (Sp) follows a train of 8 stimuli (S,) and induced a “slow” ventricular tachycardia (VT) (cycle length 300 ms). B, 2 premature stimuli (S&J induce a rapid, polymorphic VT (cycle length <200 ms). C, 3 premature stimuli (S2-SbS4) induce ventricular fibrillation. In each dog the characteristic response was reproducible. Limb leads of the surface ECG and stimulus artifact (S) are labeled.

January 15, 1984

Statistical analysis: McNemar’s chi-square test for matched pairs was used to compare the two treatments in Group 1I.l” We used the t test for paired samples to assess the effects of each drug on mean heart rate, blood pressure, VF threshold, ventricular effective refractory period and QTc. We used t tests for unpaired samples to compare timulol with propranolol with respect to the VF threshold, ventricular ef-

fective refractory period and QTc. The level of significance was fixed at a probability (p) value of less than 0.05. Results are expressed as mean f standard deviation. Rest& Types of ventricular tachycardia induced before treatment with &blocking drugs: Programmed stimulation of the right ventricle 4 to 6 days after MI reproducibly produced the following ventricular tachyarrhythmias (Fig. 1): In Group I, 2 dogs had a relatively slow VT (cycle length >200 ms) of a uniform morphology (A); 4 dogs had a rapid (cycle length <200 ms), polymorphic VT; and 1 dog had VF. In Group II, 15 dogs were randomized into treatment with timolol or propranolol and underwent multiday ventricular stimulation studies. Identical responses were obtained during the control period on both drug testing days in 12 of the 15 dogs (80%). Of 12 dogs with the identical tachycardias on both days, 4 had a “slow” VT, 3 had “fast” VT and 5 had VF. In the 3 dogs with discordant responses, VF was produced during the first

Results of Timolol Infusion in Group I and Group II Doss with Inducible Ventricular Tachyarrhvthmias VFT (ms)

VTIVF

Group 8 Dog No.

277

test, while the second test yielded slow VT in 1 dog and fast VT in 2 dogs. Programmed ventricular stimulation after &blocking drugs: In Group I, the induction of sustained VT or VF was abolished by timolol in 6 of the 7 dogs (86%). In Group II, one or both P-blocking drugs prevented the induction of VT in 11 of the 15 dogs (73%). Timolol was an effective drug in 7 of the 15 dogs (47%) in Group II; in 2 of these dogs timolol was the only effective fi blocker. Propranolol prevented the induction of VT in 9 of the 15 dogs in Group II (60%); it was the only effective p blocker in 4 dogs. Using McNemar’s chi-square test, no difference was found between the proportion of dogs responding to timolol and the proportion responding to propranolol (chi-square = 0.17). When either p blocker proved effective in preventing the induction of VT, the first dose of the administered drug was usually the effective dose. Specifically, in 4 of 6 dogs (67%) in Group I and in 5 of 7 dogs (71%) in Group II, the first dose of timolol (0.1 mg/kg) was effective. Likewise, the first dose of propranolol (1.0 mg/kg) was effective in 7 of the 9 dogs that responded (78%). Effect of timolol and propranolol on ventricular fibrillation threshold: Both drugs increased the VF threshold significantly (Tables 1 and II, Fig. 2). Timolol increased the VF threshold in Group I from 11 f 6 to 28 f 12 mA (p
measured. Group II dogs were tested with the other P-blocking drug the next day.

TABLE I

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THE AMERICAN JOURNAL OF CARDIOLOGY

Dose (mg/kg)

Abolished by Drug

Pre

Post

QTc (ms)

ERP (ms)

Pre

Post

BP (mm Hg)

HR (beats/min)

Pre

Post

Pre

Post

Pre

Post

282 312 263 275 288

312 296 297 304 265

$6

idd

95 %

98 tX

120 100 105 ::

100 92 108 95 47

306

293

“’

115

106

28:?25

29E18

Group1 : 3 4 5

0.1 3.0 5::

6 7

8::

Mean&

12 13 5:

!

5 1; 1:

44

155 148 160 160 200

:

12

IS

:;:

+

:

0.1

SD

1::6

28fl2

185 182 173 195 210

183 163 184f15

165fl7

i& 92fll

91ylO

106 99f21

92?21

Group II 166 167 155 148 154 143 788 163 125 193 163 192 180 165 170 165f 19

177 153 175 163 154 158 792 185 140 203 173 183 203 158 178 173f 19

Grams

Mean f SD

17f9

29f14

165fl8

306 253 267 274 270 244 296 256

310 293 284 313 268 244 329 304 294 268 221 242 247 312 322 283 f 33

274 247 224 304 229 286 306 26$i 27

:20 97flO

283f30

276f26

95flO

120 107 134 145

iiS 98:

:: 172

1:; 110 100 105

1% 90 i:

117 1:: 112 110 ;; 66 114 92

92flO

1:: 108 102f25

;z 54 110 83 95fl8

92flO

lOlf23

94fl9

:;

I and II

177fl8

-I = responders (ventricular tachyarrhythmia abolished); 0 = nonresponders; BP = mean blood pressure; ERP = ventricular effective refractory period; HR = mean heart rate: SD = standard deviation; VFT = ventricular fibrillation threshold; VT/VF = ventricular tachycardia or ventricular fibrillation.

278

BETA BLOCKERS AND INDUCIBLE VENTRICULAR

ARRHYTHMIAS

(14 f 16 vs 4 f 6 mm Hg, p <0.05). In only 1 of the 29 drug trials did the lowest dose (dog 16, propranolol treatment) decrease mean blood pressure more than 10 mm Hg. Timolol decreased the heart rate modestly in the 22 dogs, from 101 f 23 to 93 f 18 beats/min (p <0.05). The 15 propranolol-treated dogs, however, did not show a significant change (from 99 f 22 to 100 f 18 beats/min).

We compared the changes in VF threshold in responders, i.e., dogs that responded to either /3 blocker, and nonresponders, i.e., dogs in which VT or VF was not abolished by either fi blocker. The increase in VF threshold was significantly greater in the 22 responders than in the 13 nonresponders (15 f 9 vs 8 f 9 mA, p <0.05). Moreover, among the responders, there was no difference between the elevation of the VF threshold produced by timolol and by propranolol(l5 f 10 vs 15 f 7 mA). Effect of timolol and propranolol on the ventricular effective refractory period: Both drugs prolonged the right ventricular effective refractory period significantly (Tables I and II, Fig. 3). Timolol prolonged the effective refractory period in Group I (from 167 f 17 to 184 f 15 ms, p <0.05) and in Group II (from 165 f 19 to 173 f 19 ms, p <0.05). Propranolol also prolonged the ventricular effective refractory period (from 161 f 16 to 176 f 15 ms, p
TABLE II

Recent clinical trials in postinfarction patients have demonstrated significant reductions in mortality in patients treated with the fi-adrenergic blocking drugs timolol and propranolol.1-3 The mechanism of this drug-related reduction in postinfarction sudden death has not been established. One possible mechanism might be related to the potential antiarrhythmic effects exerted by timolol and propranolol in the survivors of an acute infarction. Both timolol and propranolol were effective in preventing VT or VF induced by programmed ventricular stimulation and significantly increased the electrical VF threshold. Beta-adrenergic blocking drugs have potent antiarrhythmic action on certain experimental arrhythmias: (1) immediately after acute occlusion of a coronary arventricular tery in dogs 15J6; (2) epinephrine-induced arrhythmias in dogsl7; and (3) experimental VT due to digitalis toxicity. l7 Also, the ventricular arrhythmias that occur in the dog 1 or 2 days after permanent coronary artery occlusion are reduced by propranolol and alprenolol (i.e., with both 0 blockers with membranestabilizing action), but not by timolo1.17J8 Our study extends the knowledge about the antiarrhythmic action of P-blocking drugs. Both timolol, thought to be devoid of effects on depolarization of ventricular cells,13 and propranolol, which possesses direct effects on depolarization at high perfusate concentrations,lg are comparable in their antiarrhythmic effect on the VT and

Results of Propranolol Infusion in Group II Dogs VFT

Dog

Discussion

Dose (m!$W

VTNF Abolished by Drug

(beatsimin) Pre

Post

Pre

ERP

QTc

(ms)

(ms) Post

BP

(mmHg)

HR (beatsjmin)

Pre

Post

Pre

Post

Pre

Post

316

‘.. .

.” .

1;:

125 105

'j;

Group II :

10.0

0

;"6

t:

155 185

173 187

304 290

;:

10.0 i::

+ :

:2"

28 22

133 165

156 174

290 268

247 %

iii

158 90

1::

:; 100

108 ::

1:: 120

112 105 125

:: 108 90

:: 130

:: :z

3.0 1.0 1.0

:

0

:: ;:

'.' 42 ;:

148 133 169 175

168 158 188 183

262 278 282 394

301 258 ::;

16 ::

1.0 10.0

: :

zo" 40

2; 50

145 180 160

153 155 193

272 256 324

268 323 299

1% ::

:: 68 70

19 fY

10.0 1.0

!

2:

4:

173 167 168

182 198 187

268 354

333 310 364

::

:z

'%

:

z; 21f9

163 16lfl6

190 176fl5

:z 299f39

281 298f35

z 92flO

:: 80fl5

Mear%SD

Abbreviationsand symbols as inTable I.

5'; 34fl3

9': E 99f23

:"8 100 85 70 lOOfl8

January 15, 1984

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JOURNAL OF CARDIOLOGY

Volume 53

279

effects of /3-adrenergic blockade on the VF threshold of normal dogs have been extensively studied. In an early report, propranolol(4.0 mg/kg) had no effect on the VF threshold of dogs, while pronethanol produced an increase.23 Subsequently, d- and l-isomers of propranolol, pronethalol, acebutolol and timolol all were shown to elevate the VF threshold. 11~24m2e The VF threshold is markedly reduced in postinfarction dogs that have inducible sustained VT, but not in dogs in which VT cannot be induced.lO In the present study, using the same dog model of inducible sustained ventricular tachyarrhythmias, we demonstrated that both timolol and propranolol significantly elevate the VF threshold. Furthermore, this elevation in VF threshold is significantly higher in the group of responders (dogs in which VT or VF was abolished by a p blocker) than in the nonresponders. The observation that both timolol and propranolol significantly elevate the VF threshold only in the group of responders again suggests a strong association between VF threshold and inducible VT or VF in animals with MI.1°

VF that can be induced in this dog model 4 to 6 days after MI. In our study, either timolol or propranolol was effective in abolishing inducible tachyarrhythmias in 73% of the drug trials performed in the Group II dogs. There was no difference in efficacy between the 2 drugs. Clinical studies have shown that /3-adrenergic blocking drugs can be effective in preventing VT or VF induced by ventricular stimulation.gJO A recent large clinical study found that among the 15 drugs tested in a clinical electrophysiology laboratory, propranolol had a success rate in abolishing inducible ventricular tachyarrhythmias as high as any other drug.21 Furthermore, high doses of propranolol suppressed chronic ventricular arrhythmias (including VT) in a group of 32 patients with heart disease.22 The doses of propranolol used by Woosley et al are equivalent to the effective doses of the timolol and propranolol used in this study. These data indicate the timolol and propranolol have antiarrhythmic effects and that they exert a significant portion of their protective effect in post-MI patients by their antiarrhythmic action.

Changes in ventricular effective refractory period: The ventricular effective refractory period was

Elevation of the ventricular fibrillation threshold: The responders had a large increase in the VF

increased comparably after the infusion of either timolol or propranolol and the prolongation was significantly greater in responders than in nonresponders (Fig. 3). In

threshold after the infusion of P-blocking drugs, while nonresponders showed little or no change (Fig. 2). The

FIGURE 2. Changes in the ventricular fibrillation (VF) threshold after the administration of timolol or propran0101.Sustained VT or VF was readily inducible in all dogs before the administration of timolol or propranolol. Solid circles represent the group of responders, i.e., dogs in which timolol or propranolol abolished inducible VT or VF. Open circles represent the nonresponders. The VF threshold was elevated both in timolol- and propranolol-treated dogs. The responders had significantly greater increases in VF threshold than nonresponders.

t I

P
1 ,

CONTROL

CONTROL

TIMOLOL

200

200 FIGURE 3. Ventricular effective refractory period before and after timolol or propranolol. As in Figure 2, all dogs had inducible sustained ventricular tachycardia (VT) or ventricular fibrillation (VF) before drug administration; the solid circles represent the responders and the open circles the nonresponders. The ventricular effective refractory period is prolonged by both timolol and propranolol, significantly more so in the responders than in the nonresponders.

2 160z

PROPRANOLOL

fii v) 160

*

E I

I

I

P < 0.01 1

CONTROL

I

1

TIMOLOL

I

P< 0.01

I

I

CONTROL

1 I

PAOPRANOLOL

I

280

BETA BLOCKERS AND INDUCIBLE VENTRICULAR

ARRHYTHMIAS

tential duration. High doses of some fl blockers prolong the ventricular effective refractory period by a direct membrane effect.33 Additional evidence that high doses of timolol also possesses direct membrane effects is the increase in the H-V interval seen in pentobarbitalanesthetized dogs treated with 0.08 mg/kg of timolo1.34 Lower doses of timolol did not significantly prolong the H-V interval. Further in vitro tissues studies are required to explore the direct membrane effects suggested in our study. The observation that timolol and propranolol prolong refractoriness suggests that the observed antiarrhythmic effect of these 2 drugs in this dog model may be due to block in the reentrant circuit.35 Detailed mapping experiments are required to test this hypothesis. Blood pressure changes: In vitro experiments performed in cat papillary muscle have demonstrated a negative inotropic effect both for timolol and for the racemic (dl) form of propranolol.i2 However, propran0101has at least 5 times the negative inotropic effect of timolol.12 Several studies have demonstrated a significant reduction in cardiac output by propranolol.36-38 A direct comparison of timolol and propranolol in hypertensive patients showed that propranolol reduced cardiac output significantly (23%), whereas timolol did not.38 In the recent Norwegian postinfarction propranolol study, withdrawal from the study because of heart failure during the first 2 weeks of therapy was significantly more common among the propranololtreated patients than among the placebo-treated group.3 In this study propranolol reduced mean arterial blood pressure more than timolol(14 vs 4 mm Hg) despite a 10: 1 dosing ratio between propranolol and timolol. Since the antiarrhythmic effect occurs at high doses, the differences in hemodynamic response to these 2 drugs may be clinically relevant.

human studies, the ventricular effective refractory period did not change after the infusion of 0.1-0.2 mg/kg of propranolol.27m2g The infusion of 0.02 mg/kg of timolol did not change ventricular effective refractory period in 12 patients.30 In vitro studies in canine Purkinje and ventricular fibers demonstrated acceleration of repolarization and a shortening of the effective refractory period of Purkinje fibers with high concentrations of propranolol(>3 mg/liter), but neither effect was seen in ventricular muscle.lg More recent in vivo animal studies have yielded entirely different results. Moderate and high doses (0.3 and 2.0 mg/kg) of racemic propranolol significantly prolonged the ventricular effective refractory period of pentobarbital-anesthetized dogs.31 In another study of pentobarbital-anesthetized dogs, i.v. propranolol(O.04 mg/kg) prolonged the ventricular effective refractory period in both ischemic and normal ventricular muscle.32 At least 2 possible explanations can account for the prolongation in the ventricular effective refractory period. First, it can be argued that prior to drug administration the sympathetic tone in our dogs was high; hence, ventricular repolarization might have been accelerated and refractoriness shortened.33 Administration of either a ,B-adrenergic antagonist to animals with a high adrenergic state would increase refractoriness and prolong repolarization. This explanation appears unlikely because our dogs did not manifest a rapid heart rate in the control state (101 f 23 beats/min before timolol and 99 f 23 beats/min before propranolol); furthermore, the mean QTc interval, a reasonable measure of ventricular repolarization,27 was not affected by either drug. A more likely explanation is that timolol and propranolol prolonged ventricular refractoriness without altering ventricular repolarization, i.e., these drugs may have slowed reactivation of the inward sodium current without significantly altering action po-

TIMOLOL N=l7

PROPRANOLOL N=l2

N=IO N=9 1-

N=6

N=5

l-

FIGURE 4. Response of mean blood pressure (BP) to the administration of 3 doses of timoloi or propranolol. All dogs in the control state (C) have inducible ventricular tachycardia or ventricular fibrillation. Numbers above each bar represent the number of dogs that received each dose of the drug. There is a steep decline in mean BP after the third propranolol dose (10.0 mg/kg) and no such decrease after the equivalent dose of timolol(1 .O mgikg).

C

0.1 OOSE

0.3 (mg/kg)

1.0

C

1.0

3.0

DOSE tmg/kgI

10.0

January 15, 1984

Acknowledgment:

preparation

We thank Zena Toran of the illustrative material.

for expert

References I. 2. 3.

4. 5.

8. 7. 8.

9. IO.

Il. 12. 13. 14. 15. 18. 17.

Norwegian Multicenter Study Group. Timolol-induced reduction in mortality in patients surviving acute myocardial infarction. N Engl J Med 1981;304: 801-807. Beta-Blocker Heart Attack Trial Research Grouo. A randomized trial of propranolol in patients with acute myocardial infaiction. Mortality results. JAMA 1982:247:1707-1714. Hansteen V; Moinichen E, Lore&en E, Andersen A, Strom 0, Soiland K, Dyrbekk D, Refsum AM, Tromsdal A, Knudsen K, Eika C, Bakken J, Smith P, Hoff PI. One year’s treatment with propranolol after myocardial infarction preliminary report of Norwegian multicentre trial. Br Med J 1982;284: 155-160. Lown B. Sudden cardiac death: the major challenge confronting cardiology. Am J Cardiol 1979;43:313-328. Livelli FD Jr, Bigger JT Jr, Reiffel JA, Gang ES, Patton JN, Noethling PM, Rolnitzky LM, Gliklich JI. Response to programmed ventricular stimulation: sensitivity, specificity and relation to heart disease. Am J Cardiol 1982; 50:452-458. Vandepol CJ, Farshidi A, Spielman SR, Greenspan AM, Horowitz LN, Josephson ME. Incidence and clinical significance of induced ventricular tachycardia. Am J Cardiol 1980;45:725-731. Ruskin JN, DiMarco JP, Garan H. Out-of-hospital cardiac arrest. Electrophysiologic observations and selection of Ion&term antiarrhythmic therapy. N Enql J Med 1980:303:607-813. Horowitz LN, Josephson ME, Farshidi A, Spielman SR,, Michelson EL, Greenspan AM. Recurrent sustained ventricular tachycardla 3. Role of the electrophysiologic study in selection of antiarrhythmic regimens. Circulation 1978;58:986-997. Mason JW. Winkle AA. Accuracv of the ventricular tachvcardia-induction study for predicting long-term effi&cy and inefficacy of antiarrhythmic drugs. N Enal J Med 1980:303:1073-1077. Gang ES, Bigger jT Jr, Llvelli FD Jr. A model of chronic ischemic arrhythmias: the relation between electrically inducible ventricular tachycardia, ventricular fibrillation threshold and myocardial infarct size. Am J Cardiol 1982;50:469-477. Hodess AB, Spear JF, Moore EN. Effects of timolol on the ventricular fibrillation threshold (abstr). Clin Res 1979;27:175A. Scriabine A, Torchiana ML, Stavorski JM, Ludden CT, Minsker DH, Stone CA. Some cardiovascular effects of timolol a new beta-adrenergic blocking agent. Arch Intern Pharmacodyn 1973;205:76-93. Hall RA, Robson RD, Share NN. Timolol maleate, a new beta-adrenergic receptor blocking agent. Arch Int Pharmacodyn 1975;213:251-283. Fleiss JL. Statistical Methods for Rates and Proportions. New York: John Wiley 8 Sons, 1973:74. Pentecost BL. Austen WG. Beta-adreneraic blockade in exoerimental myocardial infarction. Am Heart J 1988;72:790-798. Khan MI. Hamilton JT. hlannina GW. Earlv arrhvthmias followino coronarv occlusion in conscioui dogs an; their modificatl’on bibeta-adrecoF&ep blocking drugs. Am Heart J 1973;88:347-358. Mouille P, Schmitt H, Cheymol G, Gautier E. Cardiovascular and betaadrenergic blocking effects of timolol. Eur J Pharmacol 1976;35:235243.

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18. Lucchesi BR, Whitsitt LS, Stickney JL. Antiarrhythmic effects of beta adrenergic blocking agents. Ann NY Acad Sci 1987;139:940-951. 19. Davis LD, Temte JV. Effects of propranolol on the transmembrane potentials of ventricular muscle and Purkinje fibers of the dog. Circ Res 1968;22: 661-677. 20. Josephson ME, Horowitz LN. Electrophysiologic approach to therapy of recurrent sustaned ventricular tachycardia. Am J Cardiol 1979;43:831642. 21. Swerdlow CD, Echt DS, Winkle RA, Griffin JC, Ross DL, Mason JW. Incidence of acute antiarrhythmic drug efficacy at electrophysiologic study (abstr). Circulation 1981;84:suppl IV:lV-137. 22. Woosley RL, Kornhauser D, Smith R, Reele S, Higgins SB, Nies AS, Shand DG, Oates JA. Suppression of chronic ventricular arrhythmias with propranolol. Circulation 1979;60:819-827. 23. Rosati RA. Alexander JA. Wallace AG. Sealv WC. Youna WC. Failure of beta-adrenergic blockade io alter ventri&lar fibrillation threshold in the dog, Circ Res 1968:19:721-725. 24. Spear JF, Moire EN, Riccintti M. The effects of d- and I- optical isomers of propranolol on the ventricular fibrillation threshold. Eur J Cardiol 1978; 7:117-123. 25. Wellens D, Wauters E. Modification of ventricular fibrillation threshold after sympatilytic drugs in the dog. Arch Int Phamxxc& 1972;198:355-371. 28. Jaillon P, Schnittger I, Griffin JC, Winkle RA. The relationship between the repeti!ive extrasystole threshold and the ventricular fibrillation threshold in the dog. Circ Res 1980;46:599-8.05. 27. Seides SF, Josephson ME, Batsford WP, Weisfogel GM, Lau SH, Damato AN. The electrophysiology of propranolol in man. Am Heart J 1974;88: 733-741, 28. Wellens HJJ, Bar FWHM, Lie KI, Duren DR, Dohmen HJ. Effects of procainamide, propranolol and verapamil on mechanism of tachycardia in patients with chronic recurrent ventricular tachycardia. Am J Cardiol 1977;40:579-585, 29. Echt DS, Berte LE, Clusin WT, Samuelssoq RG, Harrison DC, Mason JW. Monophasic action potential effects of sotalol compared to propranolol (abstr). Circulation 1981;64:suppl IV:136. 30. Ezrl MD, Marchlinski FE, Caln ME, Buxton AE, Gardner MJ, gadowskl LM, Waxman HL, Josephson ME. The electrophysiologic effects of timolol (abstr). Circulation 1981;84:suppl IV:138. 31. Giudicelli JF, Lhoste F, Boissier JR. Beta-adrenergic blockade and atrioventricular conduction impairment. Eur J Pharmacol 1975;31:216-225. 32. Kupersmith J, Shians H, Litwak RS. Herman MV. Electroohvsioloaical and aniiarrhythmic effec& of propranoldl in canine acute myobaidial &hernia. Circulation 1978;38:302-307. 33. Wit AL, Hoffman BF, Rosen MR. Electrophysiology and pharmacology of cardiac arrhythmias IX. Cardiac electrophysiologic effects of beta adrenergic receptor stimulation and blockade. Am Heart J 1975;90:521-533. 34. Jaillon P, Heckle J, Weissenburger J, Cheymol G. Comparative dromotropic activity of timolol and propranolol in anesthetized dogs. Eur J Pharmacol 1978;47:129-139. 35. Wit AL, Cranefield PF. Reentrant excitation as a cause of cardiac arrhvthmias. Am J Phvsiol 1978:235:Hl-H17. 38. Fifzgerald JD, Wale’JL, Austin’M. The hemcdynatiic effects of orooranolol. dexfropropranolol, oxprenolol, practolol, and.sotalol in ane$.th&iz&l dogs: Eur J Pharmacol 1972;17:123-134. 37. Tarazi RC, Dustan HP. Beta adrenergic blockade in hypertension. Am J Cardiol 1972:29:833-640, 38. Franciosa JA, Freis ED, Conway J. Antihypertensive and hemodynamic properties of the new beta adrenergic blocking agent timolol. Circulation 1973:48:118-124.