Effects of the calcium channel antagonist mibefradil on haemodynamic parameters and myocardial Ca(2+)-handling in infarct-induced heart failure in rats.

Abstract

Abnormal intracellular Ca(2+)-handling has been implicated in the pathogenesis of contractile dysfunction and arrhythmias in failing hearts. Calcium channel antagonists (CCA) have been proposed for the prevention of cardiac events after myocardial infarction (MI). Recent studies suggest that the blockade of T-type Ca(2+)-channels induced a heart rate reduction without negative inotropic effects. We investigated the effects of the preferentially T-channel blocking CCA, mibefradil, on haemodynamic parameters and intramyocardial Ca(2+)-handling and contractility in the early and late period after MI. MI was induced by permanent ligation of the left coronary artery in male normotensive Wistar rats. Animals were divided in sham-operated and placebo- or mibefradil-treated MI rats. Placebo or Mibefradil treatment (10 mg/kg/d via gastric gavage) was started 7 days prior to MI-induction. Haemodynamic and intramyocardial Ca2+ measurements were performed 1, 3, 7 and 42 days after surgery. At these time points, mean arterial blood pressure (MAP), heart rate (HR), left ventricular enddiastolic pressure (LVEDP) and cardiac contractility (dP/dtmax) were measured in conscious rats. After haemodynamic measurements, the left ventricular papillary muscle was separated to determine developed tension (DT), time to peak tension (TPT) and systolic and diastolic free intracellular Ca2+ concentrations ([Ca2+]i) using the Ca2+ indicator aequorin. Dose-response curves after extracellular isoproterenol- or Ca(2+)-stimulation were recorded. In the early (1-3 days) period after MI, MAP and dP/dtmax were decreased and LVEDP and HR were increased in placebo-treated MI rats. Mibefradil treatment increased MAP and dP/dtmax and decreased LVEDP and HR in infarcted rats. In the papillary muscle of placebo-treated rats, MI induced a decrease in DT and an increase in TPT and in diastolic and systolic [Ca2+]i. DT of placebo-treated MI rats showed a reduced reactivity after isoproterenol- or Ca(2+)-stimulation. After mibefradil treatment DT was increased and TPT was reduced in the late period (7-42 days) after MI, and diastolic and systolic [Ca2+]i were decreased in the early period after MI (1-3 days). The inotropic response to beta-adrenergic or extracellular Ca(2+)-stimulation was markedly improved by mibefradil 7 and 42 days after MI. We conclude, that mibefradil improves cardiac function, protects the myocardium against ischemia-induced Ca(2+)-overload and increases beta-adrenergic responsiveness in chronically failing rat hearts.