Effect of sulfinpyrazone on ventricular fibrillation during acute myocardial ischemia.

Abstract

SUMMARY In patients treated with sulfinpyrazone, an apparent reduction in the incidence of sudden death and presumed ventricular fibrillation has been reported. Using an intact animal model without microcirculatory thrombosis, we studied the effects of sulfinpyrazone on ischemic myocardium in 58 anesthetized dogs divided into three groups: control untreated (n = 24), group 1 (n = 16), treated daily with 300 mg of sulfinpyrazone for 7 days, and group 2 (n = 18), treated daily with 300 mg of sulfinpyrazone for 7 days but omitting treatment on day 8. Although consistent hemodynamic differences were not apparent, the degree of injury determined by ECG mapping was significantly lower in group 1. The incidence of fibrillation was 54% for control and 0% in group 1. Group 2 had a 44% incidence, suggesting a limited duration of action. The apparent absence of microcirculatory thrombosis in this model suggests other mechanisms of action. A significantly smaller increase in tissue water and Na+ and smaller loss of K+ in group 1 may have contributed to the lower incidence of fibrillation, perhaps through selective prostaglandin inhibition.THE USE of drugs in coronary artery disease that interfere with platelet function' has been prompted by the presumed role of the latter in the pathogenesis of ischemic heart disease.2-' Recent developments on the effects of platelet-active agents on prostaglandin metabolism have suggested several mechanisms that might affect the course of coronary artery disease.5'6 Our studies with aspirin in a canine model have indicated that aspirin did not significantly inhibit formation of experimentally induced platelet thrombus in the epicardial coronary vessels but survival rate was significantly increased.7 In patients treated with sulfinpyrazone in the postinfarction period, there was an apparent reduction in the incidence of sudden death,8 and presumably ventricular fibrillation, an effect that may be independent of antiplatelet activity.9' 10 These considerations prompted us to study the effects of sulfinpyrazone on ischemic myocardium using an animal model with nonthrombotic coronary occlusion, which permitted the study of sulfinpyrazone in the absence of evident platelet microaggregates.Methods Fifty-eight apparently healthy male mongrel dogs that weighed 22-32 kg were used for the study. After an 18-hour period of fasting, all dogs on the day of the experiment were anesthetized with morphine sulfate (3 mg/kg i.m.) and sodium pentobarbital (20 mg/kg i.v.) and were placed on a respiratory pump to maintain adequate ventilation. Through vessels exposed by small skin incisions, catheters were placed under From

A protective effect of sulphinpyrazone against coronary occlusion‐induced shortening of myocardial refractory periods in the rat

“…Sulphinpyrazone has also been shown to protect animal hearts against some but not all of the biochemical and histological consequences of coronary artery occlusion (Kelliher et al, 1980;Povalski et al, 1980;Bolli et al, 1981;Innes & Wiseman, 1981;Moschos et al, 1981;Karmazyn, 1984). It was of interest, therefore, to examine the effects of sulphinpyrazone on the electrical changes that occur within ischaemic myocardium.…”

Electrophysiologic and Antiarrhythmic Actions of Sulphinpyrazone and Its Sulfide Metabolite G25671

“…In the Anturane Rcinfarction Trial, sul phinpyrazone administration was associated with a reduced incidence of sudden cardiac death, an event primarily due to ventricular tachyarrhythmia degenerating into ventricu lar fibrillation [Pratt ct al., 1983;Panidis and Morganroth, 1983], during the initial 6 months after acute myocardial infarc tion [Anturane Reinfarction Trial Research Group, 1980], Initial experimental evalua tions in animal preparations of myocardial ischemic injury produced by acute coronary artery occlusion [Kelliher et al, 1980;Brun ner et al, 1980;Lepran et al, 1981;Moschos et al, 1982, Dix et al, 1982 or temporary coronary artery occlusion followed by reperfusion [Povalski et al, 1980] confirmed the efficacy of sulphinpyrazone in suppressing ischemic ventricular arrhythmias. There is considerable uncertainty, however, whether sulphinpyrazone possesses 'direct' electrophysiologic and antiarrhythmic properties, or whether the suppression of ischemic ven tricular arrhythmias by this agent is a reflec tion of antiischemic and/or cytoprotective actions [Browning, 1982], In vitro evaluations using canine cardiac Purkinje fibers [Bcnditt et al, 1980] and rat atria [Kristiansen et al, 1982] have failed to demonstrate marked electrophysiologic al terations in these isolated preparations with sulphinpyrazone.…”

“…These findings do not preclude an 'indirect' antiarrhythmic potential during acute myocardial ischemic injury, particu larly for sulphinpyrazone, based upon antiischemic or cytoprotective actions. In this regard, previous investigators have sug gested that an enhancement in coronary col lateral blood flow [Davenport et al, 1981], limitation in the severity and extent of isch emic injury' [Moschos et al, 1981;Innes and Weismann, 1981], direct cardioprotective actions with preservation of histological in tegrity and enzyme content [Innes and Wcisman, 1981;Karmazyn, 1984], and/or the in hibition of prostaglandin synthesis, with consequent effects on platelet function, he modynamics and neurotransmitter release [Moschos et al, 1982;Dix et al, 1982] con stitute pharmacologic actions of sulphinpyrazonc which might 'indirectly' suppress the development and severity of ventricular ar rhythmias.…”

“…The results of the trial indi cated an apparent reduction in cardiac mor tality over the 24-month trial duration, with a reduction in the incidence of sudden car diac death particularly evident in the first 6 months after infarction [Anturane Reinfarc tion Trial Research Group, 1980]. The re sults of several experimental evaluations of sulphinpyrazone in animal models of myo cardial ischemia and infarction have sug gested that the salutary actions of the agent on postinfarction mortality may be due to a suppression of ischemic ventricular arrhyth mias [Kellihcr et al, 1980;Povalski et al, 1980;Brunner et al, 1980;Lepran et al, 1981;Moschos et al, 1982). It is unclear from the preceding studies however, whether the antiarrhythmic actions of sulphinpyra zone in the setting of myocardial ischemic injury are due to primary electrophysiological effects, or secondary to alterations in hemodynamics, coronary circulation and/or platelet function which may attenuate the severity of ischemia [Browning, 1982].…”

Reduction of mortality by sulphinpyrazone after experimental myocardial infarction in the rat

“…In their initial studies, Kelliher et al and Povalski et al (in press) and Moschos et al (1979) found that the early arrhythmias (ventricular fibrillation, ventricular tachycardia and ventricular extrasystoles) occurring subsequent to coronary occlusions in cats and dogs were less frequent if the animals had been pretreated with sulphinpyrazone. reinfarctions and, expecially, sudden cardiac deaths were less frequent among patients treated with sulphinpyrazone than among those receiving placebo medication.…”