Vol. 285, Issue 2, 746-752, May 1998

Short-Term Hemodynamic Effects of Mibefradil in Dogs With Chronic Heart Failure: Comparison With Diltiazem¹

Hisashi Shimoyama, Hani N. Sabbah, Mitsuhiro Tanimura, Steven Borzak and Sidney Goldstein

Department of Medicine, Division of Cardiovascular Medicine, Henry Ford Heart and Vascular Institute, Detroit, Michigan

Despite the marked vasodilator and antiischemic actions of existing calcium channel blockers, their use in the treatment of patients with chronic heart failure (HF) remains highly controversial. We compared the short-term hemodynamic effects of i.v. mibefradil, a predominant T-type calcium channel blocker with only partial L-type calcium channel antagonism, and diltiazem, a selective L-type calcium channel antagonist in dogs with chronic HF. Each of three drugs namely, mibefradil, diltiazem and normal saline (as placebo control), were studied in random order (6 days between each drug intervention), in each of 8 dogs with chronic HF produced by multiple intracoronary microembolizations. Intravenous mibefradil and diltiazem were administered as a 100 µg/kg bolus followed by a continuous infusion of 6 and 4 µg/kg/min, respectively, for 15 min. Equal volumes of normal saline were administered in an identical fashion. In all instances, hemodynamics were obtained at baseline and at 5, 10, 15, 30 and 60 min after bolus drug administration. Left ventriculograms were obtained at baseline, and at 15 and 60 min after bolus drug administration. Saline infusion had no effects on hemodynamic or angiographic indexes of left ventricular (LV) function. At 15 min, mibefradil caused significant increases of LV stroke volume and LV ejection fraction compared to baseline (40 ± 5 vs. 31 ± 3 ml, P < .05 and 41 ± 1 vs. 28 ± 1%, P < .05, respectively). In contrast, at 15 min, diltiazem produced no significant changes of LV stroke volume or ejection fraction compared to baseline despite reducing mean aortic pressure to the same extent as mibefradil. Short-term i.v. mibefradil improves LV function in dogs with chronic HF. The beneficial effects of mibefradil compared to diltiazem may be a consequence of T-type calcium channel selectivity resulting in a vasodilatory response that is free of negative inotropy.