Differential Effects of Mibefradil, Verapamil, and Amlodipine on Myocardial Function and Intracellular Ca²⁺ Handling in Rats with Chronic Myocardial Infarction

Abstract

Mibefradil is a selective T-type Ca²⁺ channel blocker that exerts a potent vasodilating but weak inotropic action. The present study compared mibefradil with traditional L-type Ca²⁺ channel blockers in regard to the effects of chronic oral administration on hemodynamics, contractility, and intracellular Ca²⁺ handling in failing myocardium from postinfarction rats. Male Wistar rats with ligation-induced myocardial infarction were assigned to placebo or treatment with mibefradil (10 mg/kg/day), verapamil (8 mg/kg/day), or amlodipine (4 mg/kg/day) by oral gavage starting 7 days before the induction of myocardial infarction. Six weeks after myocardial infarction, hemodynamic measurements were performed in conscious animals. In addition, isometric force and free [Ca²⁺]_i were determined in isolated left ventricular papillary muscles. Placebo-treated rats exhibited a decreased mean atrial pressure, an increased left ventricular end-diastolic pressure, and a reduced rate of pressure rise compared with sham-operated animals. Mibefradil treatment significantly improved all of these parameters, whereas both amlodipine and verapamil exerted only minor effects. β-Adrenergic stimulation with isoproterenol (ISO) enhanced contractility and Ca²⁺ availability in papillary muscles from sham-operated rats, whereas the ISO-induced inotropic effect in muscles from placebo-treated rats was severely blunted. Chronic mibefradil treatment significantly improved the inotropic response to ISO stimulation, although the Ca²⁺_iavailability appeared to be less than in muscles from placebo-treated animals. In contrast, both verapamil and amlodipine did not restore the inotropic and Ca²⁺_i modulating effect of ISO in remodeled myocardium. Thus, T-type Ca²⁺ current appears to be of pathophysiological relevance in postischemic reperfused myocardium.