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EXPERIMENTAL STUDIES

Effects of mibefradil, a novel calcium channel blocking agent with T-type activity, in acute experimental myocardial ischemia

maintenance of ventricular fibrillation threshold without inotropic compromise

^a Medical Research Council Heart Research Group, Cape Heart Centre, University of Cape Town, Cape Town, South Africa
^* National Accelerator Centre, Cape Town, South Africa

Manuscript received October 14, 1997; revised manuscript received March 5, 1998, accepted March 16, 1998.

Address for correspondence: Dr. Cecilia A. Muller, Heart Research Unit, University of Cape Town Medical School, Observatory 7925, Cape Town, South Africa
cecile{at}samiot.uct.ac.za

Objectives. We tested whether mibefradil, a selective T-type calcium channel blocking agent, could differentially inhibit experimental ventricular arrhythmogenesis more than contractility during acute regional ischemia and reperfusion compared with that during L-channel blockade by verapamil.

Background. T-type calcium channels are found in nodal and conduction tissue and in vascular smooth muscle, but in much lower density in contractile myocardium. The potential role of mibefradil in ventricular arrhythmogenesis remains unclear.

Methods. Mibefradil (Ro 40-5967, 1 mg/kg body weight intravenously [IV]) was given as a bolus 30 min before anterior descending coronary artery ligation, followed by 2 mg/kg per h IV during 20 min of ischemia and 25 min of reperfusion in open chest pigs. In a second group, mibefradil was given in a dose twice as high. A third group received verapamil (0.3 mg/kg IV), followed by an infusion of 0.6 mg/kg per h.

Results. During the ischemic period, the low (clinically relevant) dose of mibefradil prevented the fall of the ventricular fibrillation threshold, without depressing the maximal rate of pressure development of the left ventricle (LV_max dP/dt). This low dose increased left ventricular blood flow, whereas peripheral arterial pressure remained unchanged. The higher dose of both mibefradil and verapamil was antiarrhythmic during ischemia, at the cost of depressed contractile activity. During reperfusion, only the higher dose of mibefradil and verapamil was antiarrhythmic but both depressed contractile activity.

Conclusions. Mibefradil is antiarrhythmic, without inotropic compromise. Speculatively, both T-type and L-type calcium channel blockade are involved in these effects.

Abbreviations and Acronyms   CAL = coronary artery ligation   IV = intravenously   LVmax dP/dt = maximal rate of pressure development of the left ventricle   LVSP = left ventricular systolic pressure   MAP = mean arterial pressure   VF = ventricular fibrillation   VFT = ventricular fibrillation threshold   VT = ventricular tachycardia