Mibefradil Improves β-drenergic Responsiveness and Intracellular Ca2+ Handling in Hypertrophied Rat Myocardium

Abstract

The present study investigated the effects of mibefradil, a novel T-type channel blocker, on ventricular function and intracellular Ca2+ handling in normal and hypertrophied rat myocardium. Ca2+ transient was measured with the biolumlnescent protein, aequorin. Mibefradil (2 μM) produced nonsignificant changes in isometric contraction and peak systolic intracellular Ca2+ concentration ([Ca2+],) in normal rat myocardium. Hypertrophied papillary muscles isolated from aortic-banded rats 10 weeks after operation demonstrated a prolonged duration of isometric contraction, as well as decreased amplitudes of developed tension and peak Ca2+ transient compared with the sham-operated group. Additionally, diastolic [Ca2+], Increased In hypertrophied rat myocardium. The positive inotropic effect of isoproterenol stimulation was blunted in hypertrophied muscles despite a large increase in Ca2+ transient amplitude. Afterglimmers and corresponding aftercontractions were provoked with isoproterenol (10-5 and 10-4 M) stimulation in 4 out of 16 hypertrophied muscles, but were eliminated in the presence of mibefradil (2 μM). In addition, hypertrophied muscles in the presence of mibefradil had a significant improvement of contractile response to isoproterenol stimulation and a reduced diastolic [Ca2+], although a mild decrease of peak Ca2+-transient was also shown. However, verapamil (2 μM) did not restore the inotropic and Ca2+ modulating effects of isoproterenol in hypertrophied myocardium. Mibefradil partly restores the positive Inotropic response to β-adrenergic stimulation in hypertrophied myocardium from aortic-banded rats, an effect that might be useful in hypertrophied myocardium with impaired [Ca2+], homeostasis.