Effects of the calcium channel antagonist mibefradil on haemodynamic

21 Objective: Abnormal intracellular Ca -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 21 (MI). Recent studies suggest that the blockade of T-type Ca -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 21 Ca -handling and contractility in the early and late period after MI. Methods: MI was induced by permanent ligation of the left coronary artery in male normotensive Wistar rats. Animals were divided in sham-operated and placeboor mibefradil-treated MI rats. Placebo or 21 Mibefradil treatment (10 mg/kg/d via gastric gavage) was started 7 days prior to MI-induction. Haemodynamic and intramyocardial Ca 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/dt ) were measured in conscious rats. After max haemodynamic measurements, the left ventricular papillary muscle was separated to determine developed tension (DT), time to peak 21 21 21 tension (TPT) and systolic and diastolic free intracellular Ca concentrations ([Ca ] ) using the Ca indicator aequorin. Dosei 21 response curves after extracellular isoproterenolor Ca -stimulation were recorded. Results: In the early (1–3 days) period after MI, MAP and dP/dt were decreased and LVEDP and HR were increased in placebo-treated MI rats. Mibefradil treatment increased MAP max and dP/dt and decreased LVEDP and HR in infarcted rats. In the papillary muscle of placebo-treated rats, MI induced a decrease in max 21 DT and an increase in TPT and in diastolic and systolic [Ca ] . DT of placebo-treated MI rats showed a reduced reactivity after i 21 isoproterenolor Ca -stimulation. After mibefradil treatment DT was increased and TPT was reduced in the late period (7–42 days) after 21 MI, and diastolic and systolic [Ca ] were decreased in the early period after MI (1–3 days). The inotropic response to b-adrenergic or i 21 extracellular Ca -stimulation was markedly improved by mibefradil 7 and 42 days after MI. Conclusion: We conclude, that mibefradil 21 improves cardiac function, protects the myocardium against ischemia-induced Ca -overload and increases b-adrenergic responsiveness in chronically failing rat hearts.  1999 Elsevier Science B.V. All rights reserved. 21 21