TY - JOUR T1 - Differential Effects of Mibefradil, Verapamil, and Amlodipine on Myocardial Function and Intracellular Ca<sup>2+</sup> Handling in Rats with Chronic Myocardial Infarction JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 1038 LP - 1044 VL - 291 IS - 3 AU - Jiang-Yong Min AU - Steffen Sandmann AU - Achim Meissner AU - Thomas Unger AU - Ruediger Simon Y1 - 1999/12/01 UR - http://jpet.aspetjournals.org/content/291/3/1038.abstract N2 - 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. The American Society for Pharmacology and Experimental Therapeutics ER -