THE EFFECTS OF MIBEFRADIL, A NOVEL CALCIUM-CHANNEL ANTAGONIST ON VENTRICULAR ARRHYTHMIAS INDUCED BY MYOCARDIAL-ISCHEMIA AND PROGRAMMED ELECTRICAL-STIMULATION

Calcium channel antagonists can reduce calcium overload induced by myo cardial ischemia and thereby protect against malignant arrhythmias. Ho wever these drugs may also adversely affect cardiac contractile functi on. Mibefradil is a new calcium antagonist that can inhibit cardiac ca lcium current without reducing myocardial force development. The effec ts of mibefradil on the inducibility of arrhythmias both before and du ring ischemia were therefore evaluated in animals with healed infarcti ons. First, a 2-min coronary occlusion was made during the last minute of exercise (n = 48): 25 animals had ventricular fibrillation (suscep tible), whereas 23 did not (resistant). On a subsequent day, programme d electrical stimulation (PES, 8 paced beats followed by two extrastim uli) induced ventricular tachycardia in 19 of 25 susceptible animals b ut in none of the resistant animals (chi square = 24.6, P < .001). Ver apamil (n = 14), diltiazem (n = 13) and mibefradil (n = 14) elicited s ignificant dose-dependent decreases in refractory period and in the Q- Tc interval (except mibefradil) yet failed to prevent PES-induced arrh ythmias. Diltiazem and verapamil also increased P-R interval and reduc ed the maximum rate of change of left ventricular pressure, whereas mi befradil did not. However, all three drugs abolished arrhythmias induc ed by PES during ischemia. In contrast, lidocaine suppressed PES-induc ed arrhythmias but failed to prevent ischemically induced arrhythmias. Thus mibefradil can prevent ischemically induced ventricular fibrilla tion without adverse actions on either A-V nodal conduction or contrac tile function. These data further suggest that calcium entry may play a critical role in the initiation of ventricular fibrillation during i schemia, whereas other factors must be responsible for the extrasystol es induced by PES.