EFFECTS OF THE CALCIUM-CHANNEL ANTAGONIST MIBEFRADIL ON HEMODYNAMIC AND MORPHOLOGICAL PARAMETERS IN MYOCARDIAL INFARCTION-INDUCED CARDIAC-FAILURE IN RATS

Objective: Calcium channel antagonists (CCA) have been proposed for th e prevention of cardiac events after myocardial infarction (MI). Mibef radil is a CCA featuring a selective blockade of T-type Ca2+-channels. The aim of the study was to characterize the effects of mibefradil on haemodynamic and morphological parameters in a model of postMI chroni c heart failure and to establish the ''therapeutic window'' for the st art of therapy. Methods: MI was induced by permanent ligation of the l eft coronary artery in male normotensive Wistar rats. Animals were ass igned to placebo- or mibefradil-treated (10 mg/kg/day p.o.) groups as follows: (1) sham operation; (2) MI placebo treatment; (3) 7 days preM I start of treatment; (4) 3 h postMI start of treatment; (5) 24 h post MI start of treatment; (6) 3 days postMI start of treatment; (7) 7 day s postMI start of treatment. Treatment was continued for 6 weeks postM I. At this time point, mean arterial blood pressure (MAP), heart rate, left ventricular enddiastolic pressure (LVEDP) and contraction force (dP/dt(max)) were measured in conscious rats at baseline and after met hoxamine (MEX; 0.5-1.0 mg/h i.v.) stimulation to increase afterload. T he hearts were subjected to histological determination of infarct size (IS), infarct length (IL), noninfarcted length (NL), left ventricular circumference (LVC), inner LV-diameter (LVD) and septal thickness (ST ). Results: Six weeks after MI, MAP was lowered, LVEDP increased and d P/dt(max) reduced. Mibefradil treatment increased basal MAP in groups 3-5 compared to the placebo-treated MI group. Under mibefradil, LVEDP was reduced at baseline in groups 3-6 and, after MEX, in all groups. d P/dt(max) was increased in groups 3-4 at baseline and after MEX. In th e placebo-treated MI group, the infarcted area was 39% of the LV and h eart weight, LVD and LVC were increased. Heart weights of mibefradil-t reated rats (groups 3-6) did not differ from those of the placebo-trea ted group. Early onset of treatment with mibefradil reduced IS and IL and increased NL in groups 3-4, LVD and LVC were decreased in group 3 only, ST was increased in groups 3-5. Conclusion: Chronic treatment wi th mibefradil exerts beneficial actions on cardiac structure and perfo rmance in postMI cardiac failure in rats, especially when the onset of treatment is either prior to or within hours after the acute ischemic event. (C) 1998 Published by Elsevier Science B.V. All rights reserve d.