The effects of diltiazem and reduced serum ionized calcium on ischemic ventricular fibrillation in the dog.

Abstract

SUMMARY. Calcium influx blockers reportedly suppress ventricular arrhythmias during acute ischemia. We therefore studied the effects of diltiazem and reduced serum ionized calcium on ventricular fibrillation (VF) in a reversible ligation model. VF was produced at 15-minute intervals by simultaneous occlusion of the left anterior descending and circumflex arteries of 31 dogs. Time from coronary occlusion to onset of VF showed no significant variation during 15 consecutive trials in six dogs that received saline alone. Intravenous infusion of diltiazem (0.02 mg/kg per min) markedly delayed the onset of VF in each of 10 dogs (P < 0.0001). Mean VF latency increased from 138 to 295 seconds during a 45-minute diltiazem infusion, declined exponentially when the infusion ceased, and was strongly correlated with serum diltiazem concentration (r = 0.96, P < 10~6). In five dogs, hemodynamic measurements, including coronary venous blood flow, were performed during each occlusion. The increase in VF latency by diltiazem was not due to increased coronary flow during occlusion or to reduction of left ventricular (LV) mechanical work. In six dogs, mean serum ionized calcium, [Ca ++ ], was reduced from 1.11 to 0.59 mM by infusion of sodium citrate. Citrate infusion increased mean VF latency from 155 to 243 seconds, and the increase observed in each dog was correlated (r = 0.84, P < 10~6) with the reduction in [Ca ++ ], VF latency was unaffected by lidocaine in nine dogs. The antifibrillatory effect of diltiazem during global LV ischemia may be an electrophysiological phenomenon related to reduction of cellular calcium influx. (Circ Res 50: 518-526, 1982) MORE than 10 years ago, Kaumann and Aramendia (1968) reported that the calcium influx blocker, verapamil, produces a dramatic reduction in the incidence of ventricular fibrillation following coronary artery ligation. This finding has been corroborated in several subsequent studies (Kaumann and Serur, 1975;Fondacaro et al., 1978, Brooks et al., 1980, but its physiological basis remains obscure. Calcium influx blockers are thought to improve myocardial metabolism during ischemia by alleviating intracellular calcium overload (Katz and Reuter, 1979), and they also suppress transmembrane currents that may mediate certain arrhythmias (Cranefield, 1975(Cranefield, , 1977. Furthermore, since calcium influx blockers are potent coronary vasodilators, they might prevent fibrillation by improving the distribution of coronary blood flow.The risk of VF following permanent coronary ligation is difficult to measure precisely in a manageable number of experimental animals. We have therefore developed a reversible ligation model in which the degree of ischemia is severe enough that VF occurs swiftly and predictably during successive trials (Clusin et al., 1979. The time between vessel occlusion and the development of VF-the VF latencycan be measured repeatedly before and after experimental interventions. Since the model involves the production of global left ventricular ischemia, changes...

Effect of verapamil and diltiazem on calcium‐dependent electrical activity in cardiac Purkinje fibres

“…The antifibrillatory effect of verapamil was first demonstrated by Kaumann & Aramendia in 1968, and subsequently confirmed by several other studies (Fondacaro et al, 1978;Brooks et al, 1980;Thandroyen, 1982). A similar effect has been suggested for other calcium antagonists including diltiazem (Clusin et al, 1982). However, the antifibrillatory efficacy of diltiazem has recently been denied (Sheehan & Epstein, 1982;Patterson et al, 1983).…”

Quasiperiodicity and chaos in cardiac fibrillation.

“…In particular, the deactivation kinetics of delayed rectifier potassium currents, recovery from inactivation of inward currents, and intracellular Ca 2ϩ cycling have been shown to be important determinants of restitution characteristics and alternans in APD, and offer realistic targets for modification by antiarrhythmic drugs. For example, previous studies have shown that Ca 2ϩ channel blockers inhibit both electrical (T wave) alternans and predisposition to ischemic VF (59,61). Pacing strategies based on chaos control theory have also been shown to be effective in a simpler cardiac arrhythmia (64), and may conceivably be adapted to fibrillation.…”

Mechanism by which metabolic inhibitors depolarize cultured cardiac cells.

“…Pretreatment of ventricular myocardium with Ca2+ channel blockers retards depolarization during ischemia, as judged by the reduction of extracellular "injury" current (23). Early ischemic arrhythmias, which may be initiated by injury current (24), are also suppressed by these agents (25). Therefore, reduction of intracellular Ca2+ stores may ameliorate the adverse electrophysiological effects of metabolic inhibition in vivo.…”