Effects of the calcium channel antagonist mibefradil on haemodynamic parameters and myocardial Ca2+-handling in infarct-induced heart failure in rats

Objective: Abnormal intracellular Ca2+-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 tha t the blockade of T-type Ca2+-channels induced a heart rate reduction witho ut negative inotropic effects. We investigated the effects of the preferent ially T-channel blocking CCA, mibefradil, on haemodynamic parameters and in tramyocardial Ca2+-handling and contractility in the early and late period after MI. Methods: MI was induced by permanent ligation of the left coronar y artery in male normotensive Wistar rats. Animals were divided in sham-ope rated and placebo- or mibefradil-treated MI rats. Placebo or Mibefradil tre atment(10 mg/kg/d via gastric gavage) was started 7 days prior to MI-induct ion. Haemodynamic and intramyocardial Ca2+ measurements were performed 1, 3 , 7 and 42 days after surgery. At these time points, mean arterial blood pr essure (MAP), heart rate (HR) left ventricular enddiastolic pressure (LVEDP ) and cardiac contractility (dP/dt(max)) were measured in conscious rats. A fter haemodynamic measurements, the left ventricular papillary muscle was s eparated to determine developed tension (DT), time to peak tension (TPT) an d systolic and diastolic free intracellular Ca2+ concentrations ([Ca2+](i)) using the Ca2+ indicator aequorin. Dose response curves after extracellula r isoproterenol- or Ca2+-stimulation were recorded. Results: In the early ( 1-3 days) period after MI, MAP and dP/dt(max) were decreased and LVEDP and HR were increased in placebo-treated MI rats. Mibefradil treatment increase d MAP and dP/dt(max) and decreased LVEDP and HR in infarcted rats. In the p apillary 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-tre ated MI rats showed a reduced reactivity after isoproterenol- or Ca2+-stimu lation. 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 respo nse to beta-adrenergic or extracellular Ca2+-stimulation was markedly impro ved by mibefradil 7 and 42 days after MI. Conclusion: We conclude, that mib efradil improves cardiac function, protects the myocardium against ischemia -induced Ca2+-overload and increases beta-adrenergic responsiveness in chro nically failing rat hearts. (C) 1999 Elsevier Science B.V. All rights reser ved.