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Antiarrhythmic and hemodynamic effects of calcium channel blocking agents during coronary arterial reperfusion
Antiarrhythmic and Hemodynamic Effects of Calcium Channel Blocking Agents During Coronary Arterial Reperfusion Comparative Effects of Verapamil and Nifdipine
LAIR
G. T. RIBEIRO,
TEDD
A. BRANDON
THOMAS PETER
MD’
L. DEBAUCHE, R. MAROKO,
RICHARD
R. MILLER,
MD, MD,
MD FACC FACC
Houston, Texas
From the Section of Cardiology, Department of Medicine, Baylor College of Medicine, Houston, Texas, and the Deborah Heart and Lung Center, Browns Mills, New Jersey. This study was supported in part by the National Heart, Lung, and Blood Vessel Research and Demonstration Center, Baylor College of Medicine, Houston, Texas: Grant l-k-17269 from the National Heart, Lung, and Blood Institute, Bethesda, Maryland. Manuscript received November 25, 1980; revised manuscript received February 9, 1981, accepted February 13, 1981. Present address: Deborah Heart and Lung Center, Browns Mills, New Jersey. Address for reprints: Section of Cardiology. Baylor College of Medicine, 6535 Fannin. MS F905, Houston, Texas 77030. l
To determine the comparative actions of the calcium channel blocking agents verapamil and nifedipine on coronary flow and ventricular arrhythmias during myocardial reperfusion, 24 open chest dogs underwent proximal occlusion of the left anterlor descending coronary artery. Regional myocardial blood flow (ml/mln per 100 g) was quantitated by microspheres (strontium [%r] and cerium [141Ce]) 20 minutes after coronary occluston and 10 minutes after reperfusion. Dogs were randomty as@gned to one of three groups 20 minutes after coronary occlusion: (1) control group (n = 8); (2) dogs given intravenous verapamil (n = 8), 0.2 mg/kg body weight in 5 minutes followed by an infusion of 0.01 mg/kg per min; or (3) dogs given nifedlpine (n = 8), 100 pg/kg in 5 minutes followed by an infusion of 3 pg/kg per min. Ten minutes after reperfusion, transmural regional myocardial blood flow in the ischemlc zone was unchanged by verapamil and nlfedipine (p = not signlflcant [NS] versus control value). The endocardial/epicardial ratio in the hyperemic zone tended to be lowered by the calcium blocking agents compared with that observed in control animals. Coronary resistance during reperfusion was similar (p = NS) in animals treated with verapamil and ntfedlplne. Ventricular tachycardia or fibrillation occurred in six dogs In the control group (tachycardia In three and fibrlllatlon In three). Among dogs given verapamll, none had ventricular tachycardla and one of elght had ventricular fibrillation (p <0.05 versus control value). Four of the eight dogs given nifedipine, had ventricular tachycardia (two dogs) or flbrtllation (two dogs) (p = NS versus control and verapamll values). Thus, verapamil and nifedlpine had similar effects on central and coronary hemodynamlcs during myocardial reperfusion. However, verapamil, in contrast to nifedipfne, decreased reperfusion ventricular arrhythmlas. These data suggest that despite similar calcium channel blocklng actlons, verapamll and nifediplne possess different antiarrhythmlc effects.
Since the initial observations of Jennings et a1.l that reperfusion of the ischemic myocardium is not always beneficial, a large body of datal-l5 on the biochemical, electrophysiologic and structural alterations associated with reperfusion has been amassed. Growing awareness of the potential importance of coronary arterial spasm in the production of reperfusion arrhythmias has led to increased interest in the clinical sequelae of reperfusion. The observations that the majority of deaths consequent to coronary artery disease are sudden in onset and result from ventricular fibrillatiorW7 and that most victims as well as survivors of primary ventricular fibrillation demonstrate no definitive evidence of myocardial infarction17 has further heightened interest in spasm and reperfusion as precursors of sudden death. Recently, the calcium antagonist drugs have been found effective in the therapy of angina pectoris and coronary spasm. The papavarine derivative verapamil has been found effective in treating supraven-
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tricular tachyarrhythmias, an action attributed to partial blockage of the slow calcium channel conduction at the atria1 and junctional levels. The clinical efficacy of verapamil in the therapy of ventricular arrhythmias has not been documented. However, a recent studyI suggests that verapamil has a protective effect on vulnerability to ventricular fibrillation during myocardial ischemia and reperfusion. Nifedipine, a dihydropuridine derivative, also inhibits the slow calcium current and has been foundlg a more potent vasodilator than verapamil and, therefore, a potentially more useful antianginal agent. However, there are no data concerning either the antiarrhythmic actions of nifedipine on reperfusion arrhythmias or the comparative effects of these two calcium antagonists on distribution of myocardial blood flow including endocardial-epicardial distribution during reperfusion. We therefore performed this investigation in a standardized model of myocardial ischemia and reperfusion to evaluate the comparative actions of verapamil and nifedipine on (1) reperfusion ventricular arrhythmias, and (2) distribution of myocardial blood flow during myocardial ischemia and reperfusion.
Methods Experimental preparation: Studies were performed in 24 mongrel dogs of both sexes, weighing between 15 and 31 kg. They were anesthetized with sodium thiamylal (12.5 mg/kg intravenously) and succinyl choline chloride (1 mg/kg intravenously) and ventilated through a cuffed endotracheal tube by a volume respirator (Harvard Apparatus, Waltham, Massachusetts). A left thoracotomy was performed in the fifth intercostal space and the heart was suspended in a pericardial cradle. The left anterior descending coronary artery was dissected free from the adjacent tissue and occluded with a Schwartz intracranial arterial clamp, proximal to the first major diagonal branch. Electrocardiographic lead aVF and systemic arterial pressure, obtained through a catheter in the carotid artery (Statham P23Db pressure transducer), were recorded continuously for the duration of the study on a polygraph (Gould Brush system 200). A polyethylene catheter was placed in the left atrium through its appendage for the injection of radiolabeled microspheres (3M Company, Minneapolis, Minnesota) and measurement of left atria1 pressure, and another catheter was positioned in the femoral artery for the simultaneous withdrawal of reference blood samples according to methods previously described.20 Eighteen minutes after occlusion, 5 ml of solution containing 2 X lo6 microspheres 8 to 10 /J in diameter, labeled with either strontium-85 or cerium-141 were injected into the left atrium over a period of 15 seconds. The catheter was flushed with 6 ml of normal saline solution during the next 10 seconds. Commencing 5 seconds before injection, blood was withdrawn from the femoral artery at a constant rate of 15.3 ml/min for 90 seconds. The microspheres were suspended in a 53 percent sucrose solution and two drops of polyoxyethylene-80sorbitan mono-oleate (Tween 80@)were added to each bottle of 50 ml. Before injection, the microspheres were ultrasonicated for at least 15 minutes, then vigorously shaken by hand. Immediately after the injection of microspheres, the 24 dogs were randomly assigned to one of three groups: Group I, eight dogs that received no additional treatment and served as a control group; Group II, eight dogs
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that received verapamil, 209 kg/kg body weight, in 5 minutes as a loading dose followed by a constant infusion of 10 pug/kg per min; and Group III, eight dogs that received nifedipine, 100 pg/kg in 5 minutes as a loading dose followed by a constant infusion of 3 pg/kg per min. Reperfusion measurements: Twenty-five minutes after left anterior descending coronary arterial occlusion, the arterial clamp was removed and reperfusion of the ischemic myocardium was allowed to occur. The electrocardiogram was recorded continuously at a paper speed of 25 mm/s for 5 minutes in order to assess the appearance and type of arrhythmias. Ventricular tachycardia was defined as three or more successive extrasystoles with a heart rate of 150 beats/ min or more. Thirty-five minutes after occlusion (10 minutes after reperfusion), regional myocardial blood flow and cardiac output were again measured using microspheres labeled with an isotope different from that used during the previous injection. Myocardial biopsy and regional blood flow: Five animals in the control group survived to this point. All animals had returned to sinus rhythm during measurement of hemodynamic indexes, regional myocardial blood flow and cardiac output. Fifty-five minutes after occlusion and 30 minutes after reperfusion, the dogs were killed with an intravenous injection of potassium chloride, and the hearts excised. The distance from the aorta to the site of occlusion was measured; then the great vessels, atria, mitral valve anulus, right ventricle and epicardial fat were dissected from the left ventricle. Eight transmural specimens (3 to 4 g) were obtained from each heart. Four biopsy specimens were obtained from myocardium appearing cyanotic during coronary arterial occlusion and located adjacent to the mid left anterior descending coronary artery. Further confirmation that the specimens were obtained from ischemic myocardium was determined by the uniformly decreased blood flow in these samples. Four additional biopsy specimens were obtained from the nonischemic posterior basal myocardium. Each specimen was divided into endocardial and epicardial halves. The radioactivity of each specimen and that of the reference sample was measured in a gamma scintillation well counter (Searle, model 1186). The regional myocardial blood flow and cardiac output were calculated as previously described.20 Coronary resistance in dynesscm-5/100 g of mEcardium was calculated as follows: coronary resistance = (AP X 80)/regional myocardial blood flow, where AP = mean aortic pressure and RMBF = regional myocardial blood flow in the nonischemic myocardium. Statistical analyses: Values obtained in the same group of dogs were compared using Student’s paired t test. Values obtained in different groups of dogs were compared using Student’s t test for group observations. Mortality was evaluated by the Fisher exact text. All data were expressed as mean f standard error of the mean. Significance was established as a probability (p) value of less than 0.05.
Results Myocardial blood flow: Twenty minutes after coronary arterial occlusion, just before randomization, all measured and derived indexes were similar (p = not significant [NS]) in the three groups (Table I). In addition, the mean animal weight and measured distance from the aorta to the site of the left anterior descending coronary arterial occlusion were similar (p = NS) among the groups. The distance from the aorta to the site of the left anterior descending coronary arterial occlusion was
NIFEDIPINE AND VERAPAMIL IN CORONARY REPERFUSION-RIBEIRO ET AL.
TABLE I Hemodynamlc Effects of Verapamil and Nffedlplne During Coronary Arterial Occlusion and Reperfuslon 25 Minutes After Coronary Occlusion (5 minutes after drug infusion started)
20 Minutes After Coronary Occlusion (before drug administration) A7;
HR Control (n = 8) Verapamil (n = 8) Nifedipine (n = 8)
150 f
14
HR
HR
Ap
112f
10
3,018 f 284
159 f 21
99f
10
3,232 f 798
180 f
14
88 f
2,743 f 380
182 f
10
77 f 5
151 f 9 157 f 8
co
105 f 8
10 Minutes After Reperfusion
112f5 lot
5
co
115f7
3,488 f 488
142 f
12
154 f
15
71 f 8t
3,422 f 707
189 f
12
83 f 3+
4,428 f 831
l
p CO.05 versus 20 minutes. + p
2.6 f 0.2,2.7 f 0.1 and 2.5 f 0.2 cm, respectively, in the control group, and in the groups treated with verapamil and nifedipine. Control group: In the control group, all variables were unchanged (p = NS) throughout the investigation with the exception of regional myocardial blood flow in the ischemic myocardium (Tables I and II). As a result of reactive hyperemia during reperfusion, transmural regional myocardial blood flow increased from 24 f 5 to 223 f 60 ml/min per 100 g, +829 percent, from just before to 10 minutes after the onset of reperfusion (Fig. 1 and Table II). Verapamil group: Administration of verapamil, 200 pg/kg as a loading dose in 5 minutes, followed by 10 pg/kg per min, did not alter the heart rate (from 151 f 9 to 160 f 14 beats/min [NS]), but decreased the mean systemic arterial pressure (from 99 f 10 to 68 f 10 mm Hg [p.
values in both the predrug control period and the control group 10 minutes after reperfusion). Total systemic vascular resistance declined from 2,653 f 401 dyne* s.cm-5 to 1,788 f 390 (p <0.05). Calculated coronary resistance in the nonischemic myocardium decreased (from 6.9 f 1.5 X lo3 dynes-scm-5/100 g) 20 minutes after coronary arterial occlusion and before drug administration to 3.4 f 6.0 X lo3 dynes+cm-5/100 g of myocardimn (p <0.05). Transmural regional myocardial blood flow in the ischemic myocardium increased during reperfusion from 30 f 8 to 178 f 21 ml/min per 100 g (p
TABLE II Effects of Verapamll and Nlfedlplne on Reglonal Myocardlal Blood Flow During Coronary Arterial Occlusion and Reperfusion lschemic Myocardium 10 Minutes After Reperfusion
20 Minutes After Coronary Occlusion
Control Verapamil Nifedipine
Endccardial Flow
Epicardial Flow
Transmural Flow
Endocardial Flow
Epicardial Flow
Transmural Flow
22 f 8 19 f 5 21 f4
28 f 8 41 l 12 33 l 5
24 f 5 30 f 8 28 f 3
279 f 98’
189 f 32’ 172 f 28” 257 f 49+
223 f 80’ 178 f 21+ 215 f 37f
107 f 12 158 f 20 223 f 55’
115 f 11 150 f 18 189 f 42’
:;A$
;$
Nonischemic Myocardfum Control Verapamil Nifedipine
:::, 2 :: 99f
11
101 f 8 131 f 39 99f 11
108f 8 135 f 42 99f 11
121 f 12 143 f 17 154 f 31
p <0.05 versus 20 minutes. + p
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similar (p = NS) to that observed in the group treated with verapamil and in the control group. Evaluation of Arrhythmias Induced by Coronary Arterial Reperfusion lschemic Transmural FIOW ~mllmin/lOOg)
Verapamil
Nifedipine
FIGURE 1. Transmural myocardial blood flow in ischemic myocardium before and after reperfusion. Marked hyperemia occurs which is unaltered from control values (p >0.05) by either verapamil or nifedipine.
decline was not statistically significant (p = NS). Cardiac output increased from 2,743 f 380 before nifedipine infusion to 4,426 f 831 ml/min (p <0.05) 10 minutes after reperfusion during nifedipine infusion. Total peripheral vascular resistance was reduced from 3,454 f 448 20 minutes after coronary arterial occlusion to 1,857 f 476 dynes.s.cm-5 (p
IOOr
616
75
VTorVF
418
60-
(%I
“S 25
0
Verapamil
Control
Nifedipine
FIGURE 2. Comparative effects of verapamil and nifedipine on ventricular tachycardia (VT) or ventricular fibrillation (VF) during myocardial reperfusion.
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Twenty-five minutes after the clamp was placed on the proximal left anterior descending coronary artery, the occlusion was released and arrhythmias induced by reperfusion were evaluated. All arrhythmias that occurred in the three groups occured during the first 30 seconds of reperfusion. In the control group, six of eight animals had either ventricular tachycardia (three dogs) or ventricular fibrillation (three dogs) (Fig. 2). In the dogs that had ventricular fibrillation, direct electrical defibrillation was attempted using progressive increments in energy with 10,20,30 and 40 watt-seconds. All attempts were unsuccessful. In the animals treated with verapamil, ventricular fibrillation occurred in only one of eight after coronary arterial release, and in this animal defibrillation with an electrical shock of 20 wattseconds resulted in sinus rhythm. No animal in the group treated with verapamil demonstrated ventricular tachycardia. The difference between the occurrence of ventricular tachycardia or fibrillation, or both, in the control group and in the group treated with verapamil was statistically significant (p <0.05). Four of the eight dogs given nifedipine had either ventricular tachycardia (two dogs) or ventricular fibrillation (two dogs). In the latter two dogs cardioversion to stable sinus rhythm occurred with administration of 10 and 20 watt-second shocks, respectively. The incidence of ventricular arrhythmias in the nifedipine-treated group did not differ from that in the control group (p = NS). Discussion Antiarrhythmic effects of verapamil versus nifedipine: The results of this investigation indicate that verapamil affords protection against ventricular fibrillation and tachycardia during myocardial reperfusion after a 25 minute period of ischemia. Nifedipine, while altering characteristics of ventricular fibrillation as evidenced by the ease of defibrillation and subsequent stability of sinus rhythm, did not prevent the occurrence of ventricular tachycardia or ventricular fibrillation to a significantly different extent compared with that observed in control animals. These findings are consistent with the previous observation that, despite similar antagonistic actions on the slow calcium channel, verapamil and nifedipine differ with regard to their antiarrhythmic effects in isolated animal cardiac tissue.21 Raschack2i has demonstrated in guinea pig left atrium that verapamil as well as nifedipine causes a dose-dependent prolongation of the functional refractory period and depresses atria1 excitability; however, verapamil is significantly more potent in its actions than nifedipine. Further, verapamil prolongs atrioventricular (AV) conduction in the conscious dog whereas nifedipine enhances conduction through the A-V node.21,22 Reperfusion of ischemic myocardium frequently produces malignant ventricular arrhythmiasll-l5 that
NIFEDIPINE AND VERAPAMIL IN CORONARY REPERFUSION-RISEIRO
have been shown to be consequent to enhanced ventricular automaticity in contrast to those arising as a result of ischemia, which are generally due to reentrant mechanisms.12 That different mechanisms produce the arrhythmias observed after ischemia and reperfusion may in part explain the failure of most traditional antiarrhythmic agents to suppress satisfactorily reperfusion arrhythmias. Perfusion gradients occurring in the hyperemic border zone surrounding the ischemic myocardium20 may further contribute to the electrical instability demonstrated in this setting. There is increasing evidence that reflex activation of the sympathetic nervous system is an important factor in ventricular fibrillation after coronary arterial occ1usion.14J5~23~24 In this regard, verapamil was found to exert an antagonistic action on adrenergic stimuli,18*25*26 and its protective effects against ventricular fibrillation may in part be through attenuation of the effects of alpha stimulation. The mechanism by which verapamil attenuates reperfusion arrhythmias is unclear. Recent data by
Sheridan et a1.13indicate that alpha adrenergic blockade, in contrast to beta adrenergic receptor blockade, attenuates reperfusion arrhythmias in cats. Thus, it is possible that the mild alpha receptor blocking effects of verapamil afford a protection beyond that provided by its calcium channel antagonism. The alternative mechanism that verapamil’s protective effect results from reduction in accumulation of washout products of ischemia such as potassium, calcium, lactate acid, cyclic nucleotides and hydrogen ion, seems unlikely because nifedipine has been shown to exert similar protective actions against ischemia and the effects of reperfusion at the cell leve1,27,28but has considerably less protective effect against reperfusion arrhythmias as reported herein. It is unknown if nifedipine is capable of antagonizing adrenergic stimuli. Comparative effects of verapamil and nifedipine on hemodynamic status and myocardial blood flow during ischemia and reperfusion: Both verapamil and nifedipine reduced mean aortic pressure and total systemic vascular resistance consistent with the vasodilating actions of each drug. However, nifedipine augmented cardiac output whereas this index was unchanged with verapamil. This disparity may be related to verapamil’s greater direct myocardial depressant effect,28 decreased impedance-reducing action or decreased myocardial protection against ischemia when compared with the effects of nifedipine.2Q Neither verapamil nor nifedipine significantly altered myocardial blood flow in the ischemic myocardium 20 minutes after coronary arterial ligation.
However, verapamil tended to increase epicardial flow, and the resultant calculated endocardial/epicardial ratio was significantly lower in the animals treated with verapamil than in the control animals. During reperfusion, nifedipine tended to cause a greater increase in epicardial flow compared with the value control whereas endocardial flow tended to be greater in the control animals. It may be postulated that endocardial ischemia
ET AL.
and accumulation of vasodilator metabolites were more pronounced in the control dogs or that nifedipine and verapamil caused relatively more coronary dilation of epicardial vessels with shunting from endocardium to epicardium, or both. Of interest in this regard is our recent finding20 that in the hyperemic border zone surrounding acute myocardial infarction, the magnitude of hyperemia in the epicardium is greater than that occurring in the endocardium. Additionally, it appears that vasodilator reserve after brief coronary arterial occlusion is greater in the subepicardium than in the subendocardium.30 This study suggests that with prolonged ischemia followed by release, vasodilator reserve differs relative to that seen with brief periods of coronary occlusion. Further, our data indicate that nifedipine, and to a lesser extent verapamil, reverses the differential in endocardial/epicardial flow ratio during reperfusion seen in control animals. These data raise an important question concerning the potential deleterious effects of exaggerated endocardial flow after prolonged ischemia and the possible arrhythmogenic effects of flow gradients with consequent gradients in washout of ischemic metabolic by-products across the myocardium. Verapamil, which appears to be most efficacious in preventing reperfusion arrhythmias, maintains the endocardial/epicardial flow ratio near unity during reperfusion. Clinical implications: Our results indicate that verapamil afforded substantial protection against ventricular arrhythmias during acute coronary arterial occlusion and reperfusion. In contrast, nifedipine failed to alter significantly susceptibility to ventricular arrhythmias during reperfusion. Verapamil’s antiarrhythmic actions in the reperfused ischemic heart differ from those in the normal canine heart, in which it does not alter vulnerability to ventricular fibrillation.ls The actions of verapamil and nifedipine on myocardial blood flow did not differ statistically; however, in ischemic myocardium nifedipine reversed the control endocardial/epicardial flow ratio during reperfusion, whereas verapamil maintained this ratio at approximate unity. Neither agent altered total transmural reperfusion hyperemia in ischemic myocardium compared with that in untreated animals. The differing actions of nifedipine and verapamil on reperfusion arrhythmias are related to effects other than their respective actions on calcium channels and protection of ischemic cells, which appear to be similar.27-2Q Thus, the possible alpha adrenergic blocking actions of verapamil, different direct membrane antiarrhythmic effects or differential actions on myocardial flow resulting in gradients in washout of ischemic metabolic by-products appear to be possible causes of the contrasting antiarrhythmic efficacy during reperfusion. Because of the important potential clinical implications of these findings, each of the possible explanations deserves further investigation. Acknowledgment We gratefully acknowledge Donna L. Chapman.
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References 1. JenMgs RB, S~mmaf% HM, Srnyth GA, Flack HA, Llnn H. Myocardial necrosis induced by temporary occlusion of a coronary artery in the dog. Arch Pathol 1980;70:68-78. 2. Danferth WA, Naegle S, Blng RJ. Effect of ischemia and reoxygenation on glycolytic reactions and adenosine triphosphate in heart muscle. Circ Res 1960;8:965-7 1. 3. Ganele CE, Seabra-Gemer R, Nayler WG, Jennings RB. Irreversible myocardial inju’y in anoxic perfwed rat hearts. Am J Pathol 1975;80:419-50. 4. Hearse RI, H-y SM, Chain EB. Abrupt reoxygenation of ths anoxic potassium arrested p&used rat heart: a study of myocardial enzyme release. J Mot Cell Cardiol 1973;5:395-407. 5. Hearse RI, Humphrey BM, Nayler WG, Stade A, Border 0. UItrastructural damage associated with reoxygenation of the anoxic myocardium. J Mel Cell Cardiol 1975;7:315-24. 6. JemMgs RB, G~MUGJ GE. Sbuctual changes in myocardium during acute ischemia. Circ Res 1974; 34, 35: Suppl lll:lll-156-72. 7. Kane JJ, Lkrphr ML, BBaet JK. Be Bqsa N, Deherly JE, Straub Kb. Mltochondrial function, oxygen extraction, epicardial S-T segment changes and trkiated dffxin distributionafter reperfuslon of ischemic myocardium. Am J Cardiol 1975;36:218-24. 8. Lang 1, Cardsy E. Geld H,etal. corisequences of reperfusion after coronary occlusion. Effects on hemodynamics and regional myocardiil metabolic function. Am J Cardiol 1974;33:69-61. 9. ReBefts R, Bobal BE. Coronary revascularization during evolving myocardial infarction-The need for caution. Circulation 1974; 501867-70. 10. Hearse DJ. Editorial: Reperfusion of the ischemic myocardium. J h4olCell Cardiol1977;9:605-18. 11. Cerbakm R, Verrler RL, Lown 9. Differing mechanisms for ventricular vulnerability during coronary artery occlusion and release. Am Heart J 1976;92:223-30. 12. Penkesko PA, Bebal BE, Con PB. Disparate electrophysiological alterations accompanying dysrhythmia due to coronary occlusion and reperfusion in the cat. Circulation 1978;58:1023-35. 13. BhaMfs~ RI, Pa&&e PA, Babel BE, Corr PB. Alpha adrenergic contributions to dysrhythmia during myocardial ischemia and reperfusion in cats. J Clin Invest 1980;65:161-71. 14. Ax&red PJ, Verrler AL, Lown 9. Vulnerability to ventricular fibrillatlon during acute coronary arterial occlusion and release. Am J Cardiol 1975;36:776-82. 15. Lown BL, Verrler RL. Neural activity and ventricular fibrillation. N Engl J f&d 1976;294:1165-70. 16. B&e WJ, Baba N, Keller MD, Geer JC, Anthony JR. Pathology of atherosclerotic hsart disease In sudden death. II. The significance
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of myocardial Infarction. Circulation 1975; 52: Suppl i1l:lll-63-9. 17. Schaffer WA Cobb LA. Recurrent ventricular fibrillation and modes of death in survivors of out-of-hospiil ventrka~larfibrillation. N Ergl J Med 1975;293:259-82. 18. Brodcs WW, Verrler RL, Lown B. Protective effect of verapamil on vulnerability to ventricular fibrillation during myocardial ischaemia and reperfusion. Cardiovasc Res 1980;14:295-302. 19. fleckensteln A, Fleckensteln 0. Further studies on the neutralization of glycoside-induced contractures of coronary smooth muscle by Ca-antagonistic compounds (verapamil, D-600, prenylamine, nifedlpine, fendiline or nitrites). Naunyn Schmledebergs Arch Pharmacol 1975;287:Suppl:R-38. 20. Rlbelro LOT, Hopkins Do, Brandon TA, Reduto LA, Miller RR. Quantification of hyperaemia bordering ischaemic myocardium in experimental myocardial Infarction. Cardiovasc Res 1980;14: 345-51. 21. Raschack M. Differences in the cardiac actions of the calcium antagonists verapamil and nifedipine. Arzneim Forsch 1976;26: 1330-3. 22. Amlb JP, Landmark K. The effect of nifedipine on the sinus and atrioventrkuiar node of the dog heart after be%adrenergic receptor blockade. Br J Clin Pratt: SUDPI 1980:9-13. 23. Cc&- PB, Gil68 RA. Autonomic neural influences on the dysrhythmias resulting from myocardial infarction. Circ Res 1978;43: l9. 24. Corr PB, Wltkowskl FX, sobel BE. Mechanisms contributing to malignant dysmythmi induced by ischsmii in the cat. J Clin Invest 1978;61:109-19. 25. Garvey HL, Melville KI. Effect of verapamil on cardiovascular responses to lateral hypothalamic stimulation in normal and coronary-ligated dogs. Can J Physiol Pharmacol 1969;47:675-84. 26. Melville KI, Barvey HL, Shlster HE. On the cardiac adrenergic blocking action of iproveratril in normal and coronary-ligated dogs. Can J Comp Med 1968;27:225-35. 27. Nayler WG, Grau A, Slade A. A protective effect of verapamil on hypoxic heart muscle. Cardiovasc Res 1976;10:650-62. 28. Plnsky WW, Lewls RM, McMlllln-Wood JB, et al. Myocardial protection from ischemic arrest: potassium and verapamil cardioplegia. Am J Physiol, in press. 29. Clark RE, Chrlstlleb IY, Henry PD, et al. Nifedipine: a myocardial protective agent. Am J Cardiol 1979;44:825-31. 30. Gallagher KP, Felts JD, Bhabuskl RJ, Rankln JHG, Rowe GG. Subepicardial vasodilator reserve in the presence of crltical coronary stenosis in dogs. Am J Cardiol 1980:46:67-73.
LAIR
G. T. RIBEIRO,
TEDD
A. BRANDON
THOMAS PETER
MD’
L. DEBAUCHE, R. MAROKO,
RICHARD
R. MILLER,
MD, MD,
MD FACC FACC
Houston, Texas
From the Section of Cardiology, Department of Medicine, Baylor College of Medicine, Houston, Texas, and the Deborah Heart and Lung Center, Browns Mills, New Jersey. This study was supported in part by the National Heart, Lung, and Blood Vessel Research and Demonstration Center, Baylor College of Medicine, Houston, Texas: Grant l-k-17269 from the National Heart, Lung, and Blood Institute, Bethesda, Maryland. Manuscript received November 25, 1980; revised manuscript received February 9, 1981, accepted February 13, 1981. Present address: Deborah Heart and Lung Center, Browns Mills, New Jersey. Address for reprints: Section of Cardiology. Baylor College of Medicine, 6535 Fannin. MS F905, Houston, Texas 77030. l
To determine the comparative actions of the calcium channel blocking agents verapamil and nifedipine on coronary flow and ventricular arrhythmias during myocardial reperfusion, 24 open chest dogs underwent proximal occlusion of the left anterlor descending coronary artery. Regional myocardial blood flow (ml/mln per 100 g) was quantitated by microspheres (strontium [%r] and cerium [141Ce]) 20 minutes after coronary occluston and 10 minutes after reperfusion. Dogs were randomty as@gned to one of three groups 20 minutes after coronary occlusion: (1) control group (n = 8); (2) dogs given intravenous verapamil (n = 8), 0.2 mg/kg body weight in 5 minutes followed by an infusion of 0.01 mg/kg per min; or (3) dogs given nifedlpine (n = 8), 100 pg/kg in 5 minutes followed by an infusion of 3 pg/kg per min. Ten minutes after reperfusion, transmural regional myocardial blood flow in the ischemlc zone was unchanged by verapamil and nlfedipine (p = not signlflcant [NS] versus control value). The endocardial/epicardial ratio in the hyperemic zone tended to be lowered by the calcium blocking agents compared with that observed in control animals. Coronary resistance during reperfusion was similar (p = NS) in animals treated with verapamil and ntfedlplne. Ventricular tachycardia or fibrillation occurred in six dogs In the control group (tachycardia In three and fibrlllatlon In three). Among dogs given verapamll, none had ventricular tachycardla and one of elght had ventricular fibrillation (p <0.05 versus control value). Four of the eight dogs given nifedipine, had ventricular tachycardia (two dogs) or flbrtllation (two dogs) (p = NS versus control and verapamll values). Thus, verapamil and nifedlpine had similar effects on central and coronary hemodynamlcs during myocardial reperfusion. However, verapamil, in contrast to nifedipfne, decreased reperfusion ventricular arrhythmlas. These data suggest that despite similar calcium channel blocklng actlons, verapamll and nifediplne possess different antiarrhythmlc effects.
Since the initial observations of Jennings et a1.l that reperfusion of the ischemic myocardium is not always beneficial, a large body of datal-l5 on the biochemical, electrophysiologic and structural alterations associated with reperfusion has been amassed. Growing awareness of the potential importance of coronary arterial spasm in the production of reperfusion arrhythmias has led to increased interest in the clinical sequelae of reperfusion. The observations that the majority of deaths consequent to coronary artery disease are sudden in onset and result from ventricular fibrillatiorW7 and that most victims as well as survivors of primary ventricular fibrillation demonstrate no definitive evidence of myocardial infarction17 has further heightened interest in spasm and reperfusion as precursors of sudden death. Recently, the calcium antagonist drugs have been found effective in the therapy of angina pectoris and coronary spasm. The papavarine derivative verapamil has been found effective in treating supraven-
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tricular tachyarrhythmias, an action attributed to partial blockage of the slow calcium channel conduction at the atria1 and junctional levels. The clinical efficacy of verapamil in the therapy of ventricular arrhythmias has not been documented. However, a recent studyI suggests that verapamil has a protective effect on vulnerability to ventricular fibrillation during myocardial ischemia and reperfusion. Nifedipine, a dihydropuridine derivative, also inhibits the slow calcium current and has been foundlg a more potent vasodilator than verapamil and, therefore, a potentially more useful antianginal agent. However, there are no data concerning either the antiarrhythmic actions of nifedipine on reperfusion arrhythmias or the comparative effects of these two calcium antagonists on distribution of myocardial blood flow including endocardial-epicardial distribution during reperfusion. We therefore performed this investigation in a standardized model of myocardial ischemia and reperfusion to evaluate the comparative actions of verapamil and nifedipine on (1) reperfusion ventricular arrhythmias, and (2) distribution of myocardial blood flow during myocardial ischemia and reperfusion.
Methods Experimental preparation: Studies were performed in 24 mongrel dogs of both sexes, weighing between 15 and 31 kg. They were anesthetized with sodium thiamylal (12.5 mg/kg intravenously) and succinyl choline chloride (1 mg/kg intravenously) and ventilated through a cuffed endotracheal tube by a volume respirator (Harvard Apparatus, Waltham, Massachusetts). A left thoracotomy was performed in the fifth intercostal space and the heart was suspended in a pericardial cradle. The left anterior descending coronary artery was dissected free from the adjacent tissue and occluded with a Schwartz intracranial arterial clamp, proximal to the first major diagonal branch. Electrocardiographic lead aVF and systemic arterial pressure, obtained through a catheter in the carotid artery (Statham P23Db pressure transducer), were recorded continuously for the duration of the study on a polygraph (Gould Brush system 200). A polyethylene catheter was placed in the left atrium through its appendage for the injection of radiolabeled microspheres (3M Company, Minneapolis, Minnesota) and measurement of left atria1 pressure, and another catheter was positioned in the femoral artery for the simultaneous withdrawal of reference blood samples according to methods previously described.20 Eighteen minutes after occlusion, 5 ml of solution containing 2 X lo6 microspheres 8 to 10 /J in diameter, labeled with either strontium-85 or cerium-141 were injected into the left atrium over a period of 15 seconds. The catheter was flushed with 6 ml of normal saline solution during the next 10 seconds. Commencing 5 seconds before injection, blood was withdrawn from the femoral artery at a constant rate of 15.3 ml/min for 90 seconds. The microspheres were suspended in a 53 percent sucrose solution and two drops of polyoxyethylene-80sorbitan mono-oleate (Tween 80@)were added to each bottle of 50 ml. Before injection, the microspheres were ultrasonicated for at least 15 minutes, then vigorously shaken by hand. Immediately after the injection of microspheres, the 24 dogs were randomly assigned to one of three groups: Group I, eight dogs that received no additional treatment and served as a control group; Group II, eight dogs
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that received verapamil, 209 kg/kg body weight, in 5 minutes as a loading dose followed by a constant infusion of 10 pug/kg per min; and Group III, eight dogs that received nifedipine, 100 pg/kg in 5 minutes as a loading dose followed by a constant infusion of 3 pg/kg per min. Reperfusion measurements: Twenty-five minutes after left anterior descending coronary arterial occlusion, the arterial clamp was removed and reperfusion of the ischemic myocardium was allowed to occur. The electrocardiogram was recorded continuously at a paper speed of 25 mm/s for 5 minutes in order to assess the appearance and type of arrhythmias. Ventricular tachycardia was defined as three or more successive extrasystoles with a heart rate of 150 beats/ min or more. Thirty-five minutes after occlusion (10 minutes after reperfusion), regional myocardial blood flow and cardiac output were again measured using microspheres labeled with an isotope different from that used during the previous injection. Myocardial biopsy and regional blood flow: Five animals in the control group survived to this point. All animals had returned to sinus rhythm during measurement of hemodynamic indexes, regional myocardial blood flow and cardiac output. Fifty-five minutes after occlusion and 30 minutes after reperfusion, the dogs were killed with an intravenous injection of potassium chloride, and the hearts excised. The distance from the aorta to the site of occlusion was measured; then the great vessels, atria, mitral valve anulus, right ventricle and epicardial fat were dissected from the left ventricle. Eight transmural specimens (3 to 4 g) were obtained from each heart. Four biopsy specimens were obtained from myocardium appearing cyanotic during coronary arterial occlusion and located adjacent to the mid left anterior descending coronary artery. Further confirmation that the specimens were obtained from ischemic myocardium was determined by the uniformly decreased blood flow in these samples. Four additional biopsy specimens were obtained from the nonischemic posterior basal myocardium. Each specimen was divided into endocardial and epicardial halves. The radioactivity of each specimen and that of the reference sample was measured in a gamma scintillation well counter (Searle, model 1186). The regional myocardial blood flow and cardiac output were calculated as previously described.20 Coronary resistance in dynesscm-5/100 g of mEcardium was calculated as follows: coronary resistance = (AP X 80)/regional myocardial blood flow, where AP = mean aortic pressure and RMBF = regional myocardial blood flow in the nonischemic myocardium. Statistical analyses: Values obtained in the same group of dogs were compared using Student’s paired t test. Values obtained in different groups of dogs were compared using Student’s t test for group observations. Mortality was evaluated by the Fisher exact text. All data were expressed as mean f standard error of the mean. Significance was established as a probability (p) value of less than 0.05.
Results Myocardial blood flow: Twenty minutes after coronary arterial occlusion, just before randomization, all measured and derived indexes were similar (p = not significant [NS]) in the three groups (Table I). In addition, the mean animal weight and measured distance from the aorta to the site of the left anterior descending coronary arterial occlusion were similar (p = NS) among the groups. The distance from the aorta to the site of the left anterior descending coronary arterial occlusion was
NIFEDIPINE AND VERAPAMIL IN CORONARY REPERFUSION-RIBEIRO ET AL.
TABLE I Hemodynamlc Effects of Verapamil and Nffedlplne During Coronary Arterial Occlusion and Reperfuslon 25 Minutes After Coronary Occlusion (5 minutes after drug infusion started)
20 Minutes After Coronary Occlusion (before drug administration) A7;
HR Control (n = 8) Verapamil (n = 8) Nifedipine (n = 8)
150 f
14
HR
HR
Ap
112f
10
3,018 f 284
159 f 21
99f
10
3,232 f 798
180 f
14
88 f
2,743 f 380
182 f
10
77 f 5
151 f 9 157 f 8
co
105 f 8
10 Minutes After Reperfusion
112f5 lot
5
co
115f7
3,488 f 488
142 f
12
154 f
15
71 f 8t
3,422 f 707
189 f
12
83 f 3+
4,428 f 831
l
p CO.05 versus 20 minutes. + p
2.6 f 0.2,2.7 f 0.1 and 2.5 f 0.2 cm, respectively, in the control group, and in the groups treated with verapamil and nifedipine. Control group: In the control group, all variables were unchanged (p = NS) throughout the investigation with the exception of regional myocardial blood flow in the ischemic myocardium (Tables I and II). As a result of reactive hyperemia during reperfusion, transmural regional myocardial blood flow increased from 24 f 5 to 223 f 60 ml/min per 100 g, +829 percent, from just before to 10 minutes after the onset of reperfusion (Fig. 1 and Table II). Verapamil group: Administration of verapamil, 200 pg/kg as a loading dose in 5 minutes, followed by 10 pg/kg per min, did not alter the heart rate (from 151 f 9 to 160 f 14 beats/min [NS]), but decreased the mean systemic arterial pressure (from 99 f 10 to 68 f 10 mm Hg [p.
values in both the predrug control period and the control group 10 minutes after reperfusion). Total systemic vascular resistance declined from 2,653 f 401 dyne* s.cm-5 to 1,788 f 390 (p <0.05). Calculated coronary resistance in the nonischemic myocardium decreased (from 6.9 f 1.5 X lo3 dynes-scm-5/100 g) 20 minutes after coronary arterial occlusion and before drug administration to 3.4 f 6.0 X lo3 dynes+cm-5/100 g of myocardimn (p <0.05). Transmural regional myocardial blood flow in the ischemic myocardium increased during reperfusion from 30 f 8 to 178 f 21 ml/min per 100 g (p
TABLE II Effects of Verapamll and Nlfedlplne on Reglonal Myocardlal Blood Flow During Coronary Arterial Occlusion and Reperfusion lschemic Myocardium 10 Minutes After Reperfusion
20 Minutes After Coronary Occlusion
Control Verapamil Nifedipine
Endccardial Flow
Epicardial Flow
Transmural Flow
Endocardial Flow
Epicardial Flow
Transmural Flow
22 f 8 19 f 5 21 f4
28 f 8 41 l 12 33 l 5
24 f 5 30 f 8 28 f 3
279 f 98’
189 f 32’ 172 f 28” 257 f 49+
223 f 80’ 178 f 21+ 215 f 37f
107 f 12 158 f 20 223 f 55’
115 f 11 150 f 18 189 f 42’
:;A$
;$
Nonischemic Myocardfum Control Verapamil Nifedipine
:::, 2 :: 99f
11
101 f 8 131 f 39 99f 11
108f 8 135 f 42 99f 11
121 f 12 143 f 17 154 f 31
p <0.05 versus 20 minutes. + p
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similar (p = NS) to that observed in the group treated with verapamil and in the control group. Evaluation of Arrhythmias Induced by Coronary Arterial Reperfusion lschemic Transmural FIOW ~mllmin/lOOg)
Verapamil
Nifedipine
FIGURE 1. Transmural myocardial blood flow in ischemic myocardium before and after reperfusion. Marked hyperemia occurs which is unaltered from control values (p >0.05) by either verapamil or nifedipine.
decline was not statistically significant (p = NS). Cardiac output increased from 2,743 f 380 before nifedipine infusion to 4,426 f 831 ml/min (p <0.05) 10 minutes after reperfusion during nifedipine infusion. Total peripheral vascular resistance was reduced from 3,454 f 448 20 minutes after coronary arterial occlusion to 1,857 f 476 dynes.s.cm-5 (p
IOOr
616
75
VTorVF
418
60-
(%I
“S 25
0
Verapamil
Control
Nifedipine
FIGURE 2. Comparative effects of verapamil and nifedipine on ventricular tachycardia (VT) or ventricular fibrillation (VF) during myocardial reperfusion.
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Twenty-five minutes after the clamp was placed on the proximal left anterior descending coronary artery, the occlusion was released and arrhythmias induced by reperfusion were evaluated. All arrhythmias that occurred in the three groups occured during the first 30 seconds of reperfusion. In the control group, six of eight animals had either ventricular tachycardia (three dogs) or ventricular fibrillation (three dogs) (Fig. 2). In the dogs that had ventricular fibrillation, direct electrical defibrillation was attempted using progressive increments in energy with 10,20,30 and 40 watt-seconds. All attempts were unsuccessful. In the animals treated with verapamil, ventricular fibrillation occurred in only one of eight after coronary arterial release, and in this animal defibrillation with an electrical shock of 20 wattseconds resulted in sinus rhythm. No animal in the group treated with verapamil demonstrated ventricular tachycardia. The difference between the occurrence of ventricular tachycardia or fibrillation, or both, in the control group and in the group treated with verapamil was statistically significant (p <0.05). Four of the eight dogs given nifedipine had either ventricular tachycardia (two dogs) or ventricular fibrillation (two dogs). In the latter two dogs cardioversion to stable sinus rhythm occurred with administration of 10 and 20 watt-second shocks, respectively. The incidence of ventricular arrhythmias in the nifedipine-treated group did not differ from that in the control group (p = NS). Discussion Antiarrhythmic effects of verapamil versus nifedipine: The results of this investigation indicate that verapamil affords protection against ventricular fibrillation and tachycardia during myocardial reperfusion after a 25 minute period of ischemia. Nifedipine, while altering characteristics of ventricular fibrillation as evidenced by the ease of defibrillation and subsequent stability of sinus rhythm, did not prevent the occurrence of ventricular tachycardia or ventricular fibrillation to a significantly different extent compared with that observed in control animals. These findings are consistent with the previous observation that, despite similar antagonistic actions on the slow calcium channel, verapamil and nifedipine differ with regard to their antiarrhythmic effects in isolated animal cardiac tissue.21 Raschack2i has demonstrated in guinea pig left atrium that verapamil as well as nifedipine causes a dose-dependent prolongation of the functional refractory period and depresses atria1 excitability; however, verapamil is significantly more potent in its actions than nifedipine. Further, verapamil prolongs atrioventricular (AV) conduction in the conscious dog whereas nifedipine enhances conduction through the A-V node.21,22 Reperfusion of ischemic myocardium frequently produces malignant ventricular arrhythmiasll-l5 that
NIFEDIPINE AND VERAPAMIL IN CORONARY REPERFUSION-RISEIRO
have been shown to be consequent to enhanced ventricular automaticity in contrast to those arising as a result of ischemia, which are generally due to reentrant mechanisms.12 That different mechanisms produce the arrhythmias observed after ischemia and reperfusion may in part explain the failure of most traditional antiarrhythmic agents to suppress satisfactorily reperfusion arrhythmias. Perfusion gradients occurring in the hyperemic border zone surrounding the ischemic myocardium20 may further contribute to the electrical instability demonstrated in this setting. There is increasing evidence that reflex activation of the sympathetic nervous system is an important factor in ventricular fibrillation after coronary arterial occ1usion.14J5~23~24 In this regard, verapamil was found to exert an antagonistic action on adrenergic stimuli,18*25*26 and its protective effects against ventricular fibrillation may in part be through attenuation of the effects of alpha stimulation. The mechanism by which verapamil attenuates reperfusion arrhythmias is unclear. Recent data by
Sheridan et a1.13indicate that alpha adrenergic blockade, in contrast to beta adrenergic receptor blockade, attenuates reperfusion arrhythmias in cats. Thus, it is possible that the mild alpha receptor blocking effects of verapamil afford a protection beyond that provided by its calcium channel antagonism. The alternative mechanism that verapamil’s protective effect results from reduction in accumulation of washout products of ischemia such as potassium, calcium, lactate acid, cyclic nucleotides and hydrogen ion, seems unlikely because nifedipine has been shown to exert similar protective actions against ischemia and the effects of reperfusion at the cell leve1,27,28but has considerably less protective effect against reperfusion arrhythmias as reported herein. It is unknown if nifedipine is capable of antagonizing adrenergic stimuli. Comparative effects of verapamil and nifedipine on hemodynamic status and myocardial blood flow during ischemia and reperfusion: Both verapamil and nifedipine reduced mean aortic pressure and total systemic vascular resistance consistent with the vasodilating actions of each drug. However, nifedipine augmented cardiac output whereas this index was unchanged with verapamil. This disparity may be related to verapamil’s greater direct myocardial depressant effect,28 decreased impedance-reducing action or decreased myocardial protection against ischemia when compared with the effects of nifedipine.2Q Neither verapamil nor nifedipine significantly altered myocardial blood flow in the ischemic myocardium 20 minutes after coronary arterial ligation.
However, verapamil tended to increase epicardial flow, and the resultant calculated endocardial/epicardial ratio was significantly lower in the animals treated with verapamil than in the control animals. During reperfusion, nifedipine tended to cause a greater increase in epicardial flow compared with the value control whereas endocardial flow tended to be greater in the control animals. It may be postulated that endocardial ischemia
ET AL.
and accumulation of vasodilator metabolites were more pronounced in the control dogs or that nifedipine and verapamil caused relatively more coronary dilation of epicardial vessels with shunting from endocardium to epicardium, or both. Of interest in this regard is our recent finding20 that in the hyperemic border zone surrounding acute myocardial infarction, the magnitude of hyperemia in the epicardium is greater than that occurring in the endocardium. Additionally, it appears that vasodilator reserve after brief coronary arterial occlusion is greater in the subepicardium than in the subendocardium.30 This study suggests that with prolonged ischemia followed by release, vasodilator reserve differs relative to that seen with brief periods of coronary occlusion. Further, our data indicate that nifedipine, and to a lesser extent verapamil, reverses the differential in endocardial/epicardial flow ratio during reperfusion seen in control animals. These data raise an important question concerning the potential deleterious effects of exaggerated endocardial flow after prolonged ischemia and the possible arrhythmogenic effects of flow gradients with consequent gradients in washout of ischemic metabolic by-products across the myocardium. Verapamil, which appears to be most efficacious in preventing reperfusion arrhythmias, maintains the endocardial/epicardial flow ratio near unity during reperfusion. Clinical implications: Our results indicate that verapamil afforded substantial protection against ventricular arrhythmias during acute coronary arterial occlusion and reperfusion. In contrast, nifedipine failed to alter significantly susceptibility to ventricular arrhythmias during reperfusion. Verapamil’s antiarrhythmic actions in the reperfused ischemic heart differ from those in the normal canine heart, in which it does not alter vulnerability to ventricular fibrillation.ls The actions of verapamil and nifedipine on myocardial blood flow did not differ statistically; however, in ischemic myocardium nifedipine reversed the control endocardial/epicardial flow ratio during reperfusion, whereas verapamil maintained this ratio at approximate unity. Neither agent altered total transmural reperfusion hyperemia in ischemic myocardium compared with that in untreated animals. The differing actions of nifedipine and verapamil on reperfusion arrhythmias are related to effects other than their respective actions on calcium channels and protection of ischemic cells, which appear to be similar.27-2Q Thus, the possible alpha adrenergic blocking actions of verapamil, different direct membrane antiarrhythmic effects or differential actions on myocardial flow resulting in gradients in washout of ischemic metabolic by-products appear to be possible causes of the contrasting antiarrhythmic efficacy during reperfusion. Because of the important potential clinical implications of these findings, each of the possible explanations deserves further investigation. Acknowledgment We gratefully acknowledge Donna L. Chapman.
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References 1. JenMgs RB, S~mmaf% HM, Srnyth GA, Flack HA, Llnn H. Myocardial necrosis induced by temporary occlusion of a coronary artery in the dog. Arch Pathol 1980;70:68-78. 2. Danferth WA, Naegle S, Blng RJ. Effect of ischemia and reoxygenation on glycolytic reactions and adenosine triphosphate in heart muscle. Circ Res 1960;8:965-7 1. 3. Ganele CE, Seabra-Gemer R, Nayler WG, Jennings RB. Irreversible myocardial inju’y in anoxic perfwed rat hearts. Am J Pathol 1975;80:419-50. 4. Hearse RI, H-y SM, Chain EB. Abrupt reoxygenation of ths anoxic potassium arrested p&used rat heart: a study of myocardial enzyme release. J Mot Cell Cardiol 1973;5:395-407. 5. Hearse RI, Humphrey BM, Nayler WG, Stade A, Border 0. UItrastructural damage associated with reoxygenation of the anoxic myocardium. J Mel Cell Cardiol 1975;7:315-24. 6. JemMgs RB, G~MUGJ GE. Sbuctual changes in myocardium during acute ischemia. Circ Res 1974; 34, 35: Suppl lll:lll-156-72. 7. Kane JJ, Lkrphr ML, BBaet JK. Be Bqsa N, Deherly JE, Straub Kb. Mltochondrial function, oxygen extraction, epicardial S-T segment changes and trkiated dffxin distributionafter reperfuslon of ischemic myocardium. Am J Cardiol 1975;36:218-24. 8. Lang 1, Cardsy E. Geld H,etal. corisequences of reperfusion after coronary occlusion. Effects on hemodynamics and regional myocardiil metabolic function. Am J Cardiol 1974;33:69-61. 9. ReBefts R, Bobal BE. Coronary revascularization during evolving myocardial infarction-The need for caution. Circulation 1974; 501867-70. 10. Hearse DJ. Editorial: Reperfusion of the ischemic myocardium. J h4olCell Cardiol1977;9:605-18. 11. Cerbakm R, Verrler RL, Lown 9. Differing mechanisms for ventricular vulnerability during coronary artery occlusion and release. Am Heart J 1976;92:223-30. 12. Penkesko PA, Bebal BE, Con PB. Disparate electrophysiological alterations accompanying dysrhythmia due to coronary occlusion and reperfusion in the cat. Circulation 1978;58:1023-35. 13. BhaMfs~ RI, Pa&&e PA, Babel BE, Corr PB. Alpha adrenergic contributions to dysrhythmia during myocardial ischemia and reperfusion in cats. J Clin Invest 1980;65:161-71. 14. Ax&red PJ, Verrler AL, Lown 9. Vulnerability to ventricular fibrillatlon during acute coronary arterial occlusion and release. Am J Cardiol 1975;36:776-82. 15. Lown BL, Verrler RL. Neural activity and ventricular fibrillation. N Engl J f&d 1976;294:1165-70. 16. B&e WJ, Baba N, Keller MD, Geer JC, Anthony JR. Pathology of atherosclerotic hsart disease In sudden death. II. The significance
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of myocardial Infarction. Circulation 1975; 52: Suppl i1l:lll-63-9. 17. Schaffer WA Cobb LA. Recurrent ventricular fibrillation and modes of death in survivors of out-of-hospiil ventrka~larfibrillation. N Ergl J Med 1975;293:259-82. 18. Brodcs WW, Verrler RL, Lown B. Protective effect of verapamil on vulnerability to ventricular fibrillation during myocardial ischaemia and reperfusion. Cardiovasc Res 1980;14:295-302. 19. fleckensteln A, Fleckensteln 0. Further studies on the neutralization of glycoside-induced contractures of coronary smooth muscle by Ca-antagonistic compounds (verapamil, D-600, prenylamine, nifedlpine, fendiline or nitrites). Naunyn Schmledebergs Arch Pharmacol 1975;287:Suppl:R-38. 20. Rlbelro LOT, Hopkins Do, Brandon TA, Reduto LA, Miller RR. Quantification of hyperaemia bordering ischaemic myocardium in experimental myocardial Infarction. Cardiovasc Res 1980;14: 345-51. 21. Raschack M. Differences in the cardiac actions of the calcium antagonists verapamil and nifedipine. Arzneim Forsch 1976;26: 1330-3. 22. Amlb JP, Landmark K. The effect of nifedipine on the sinus and atrioventrkuiar node of the dog heart after be%adrenergic receptor blockade. Br J Clin Pratt: SUDPI 1980:9-13. 23. Cc&- PB, Gil68 RA. Autonomic neural influences on the dysrhythmias resulting from myocardial infarction. Circ Res 1978;43: l9. 24. Corr PB, Wltkowskl FX, sobel BE. Mechanisms contributing to malignant dysmythmi induced by ischsmii in the cat. J Clin Invest 1978;61:109-19. 25. Garvey HL, Melville KI. Effect of verapamil on cardiovascular responses to lateral hypothalamic stimulation in normal and coronary-ligated dogs. Can J Physiol Pharmacol 1969;47:675-84. 26. Melville KI, Barvey HL, Shlster HE. On the cardiac adrenergic blocking action of iproveratril in normal and coronary-ligated dogs. Can J Comp Med 1968;27:225-35. 27. Nayler WG, Grau A, Slade A. A protective effect of verapamil on hypoxic heart muscle. Cardiovasc Res 1976;10:650-62. 28. Plnsky WW, Lewls RM, McMlllln-Wood JB, et al. Myocardial protection from ischemic arrest: potassium and verapamil cardioplegia. Am J Physiol, in press. 29. Clark RE, Chrlstlleb IY, Henry PD, et al. Nifedipine: a myocardial protective agent. Am J Cardiol 1979;44:825-31. 30. Gallagher KP, Felts JD, Bhabuskl RJ, Rankln JHG, Rowe GG. Subepicardial vasodilator reserve in the presence of crltical coronary stenosis in dogs. Am J Cardiol 1980:46:67-73.