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ORIGINAL ARTICLE

Mibefradil Improves ß-Adrenergic Responsiveness and Intracellular Ca²⁺ Handling in Hypertrophied Rat Myocardium

Jiang-Yong Min^*, Achim Meissner, Jianan Wang^* and James P. Morgan^*,1

^* Cardiovascular Division, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts; and
Cardiovascular Division, Soest City Hospital of Munster University Medical School, Soest, Germany

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 bioluminescent protein, aequorin. Mibefradil (2 µM) produced nonsignificant changes in isometric contraction and peak systolic intracellular Ca²⁺ concentration ([Ca²⁺]_i) 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⁺]_i 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⁺]_I, 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 ß-adrenergic stimulation in hypertrophied myocardium from aortic-banded rats, an effect that might be useful in hypertrophied myocardium with impaired [Ca²⁺]_i homeostasis.

Key Words: hypertrophied myocardium • intracellular Ca²⁺ • mibefradil