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.
Footnotes
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Send reprint requests to: Achim Meissner, M.D., Department of Cardiology, University of Kiel, Schittenhelmstrasse 12, D-24105 Kiel, Germany. E-mail: meissner{at}cardio.uni-kiel.de
- Abbreviations:
- CCB
- calcium channel blocker
- MI
- myocardial infarction
- MAP
- mean arterial pressure
- LVEDP
- left ventricular end-diastolic pressure
- DT
- developed tension
- ISO
- isoproterenol
- Received May 12, 1999.
- Accepted August 12, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
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