POTENT VASODILATORY WITH MINOR CARDIODEPRESSANT ACTIONS OF MIBEFRADILIN HUMAN CARDIAC TISSUE

1 The present study compared the cardiovascular effects of mibefradil (MIB), a novel Ca2+-channel antagonist with high selectivity for T-typ e Ca2+-channels to the effect of the L-type Ca2+-channel-antagonists n ifedipine (NIF) and diltiazem (DIL) in left ventricular myocardium and coronary arteries of hearts obtained from patients suffering from dil ated cardiomyopathy (NYHA IV). Right atrial myocardium from patients u ndergoing aortocoronary bypass surgery without signs of cardiac failur e was studied as well. 2 NIF and DIL (100 mu mol l(-1)) completely dep ressed force of contraction (FOC) in electrically driven left ventricu lar myocardium (NIF 6.5 +/- 1.4% and DIL 7.1 +/- 1.2% of control), whe reas a similar concentration of MIB only reduced force of contraction to 55.1 +/- 4.0% of the basal FOG. The negative inotropic potency as m easured by the concentration needed to reduce basal FOC for 25% was NI F (0.0095 mu mol l(-1)) > DIL (0.041 mu mol l(-1)) > MIB (9.47 mu mol l(-1)). 3 All three Ca2+-channel antagonists were more potent in human atrial compared to human left ventricular myocardium to reduce FOG. 4 The rank order of Ca2+-antagonistic moiety as measured by the decreas e of the intracellular Ca2+-transient (fura-2 ratio method) was NIF>DI L>MIB. 5 All Ca2+-channel antagonists completely relaxed human coronar y arteries (% of papaverine effect: MIB 81.7 +/- 5.5%, DIL 91.3 +/- 0. 9%, NIF 96.4 +/- 3.7%) precontracted with PGF(2 alpha) (0.3 mu mol l(- 1)). The rank order of vasodilatory potency was NIF (EC50; 0.02 mu mol l(-1)) >DIL (0.13 mu mol l(-1)) > MIB (2.05 mu mol I-L). 6 The vasose lectivity measured by the ratio of the concentration needed to achieve a 25% decrease in force and the concentration needed for 25% vasodila tation was 316 for MIB, 1.5 for NIF and 1.0 for DIL. 7 The present stu dy provides evidence that blockade of T-type Ca2+-channels (e.g. mibef radil) results in potent vasodilatory properties with only minor cardi odepressant effects.