Mibefradil, a T-type and L-type calcium channel blocker, limits infarct size through a glibenclamide-sensitive mechanism

Mibefradil is a novel calcium channel blocker with activity at both L-type and T-type calcium channels. There are data suggesting that this compound c an protect the ischemic/reperfused myocardium in spite of the fact that the re is a very low abundance of T-type calcium channels within ventricular ti ssue. The aims of this study were twofold. First, we wished to study the pr otective effect of mibefradil on ischemia/reperfusion injury in the isolate d rat heart using infarct size as the endpoint of injury. In this respect, we compared mibefradil with amlodipine, a well-known and potent L-type calc ium channel blocker, and with ischemic preconditioning, an intervention kno wn to reduce infarct size consistently. Secondly, we investigated the possi ble mechanisms through which protection was achieved. For this second purpo se, we examined the effects on protection of glibenclamide (an ATP-dependen t K+ channel blocker) and chelerythrine (a protein kinase C inhibitor). Iso lated rat hearts were perfused in the Langendorff mode at constant pressure . Control, mibefradil-treated (0.3 mu M), mibefradil plus glibenclamide (50 mu M), and mibefradil plus chelerythrine (10 mu M) treated hearts underwen t 35 minutes regional ischemia followed by 120 minutes reperfusion. At the end of the experiments, infarct size was determined with triphenyltetrazoli um chloride and was expressed as a percentage of the ischemic risk zone (I/ R %). A significant reduction in infarct size with mibefradil treatment was observed (I/R 11.1 +/- 2.1% vs. 35.5 +/- 3.1% in controls). This was compa rable with the infarct reduction seen with two 5-minute cycles of ischemic preconditioning (17.7 +/- 2.5%). Amlodipine 0.1 mu M, a concentration that caused equivalent coronary vasodilatation as that produced by mibefradil tr eatment, had no significant effect on infarct size (I/R 29.7 +/- 3.5%). The protective effect of mibefradil was not significantly modified by the pres ence of the PKC inhibitor chelerythrine 10 mu M (I/R 19.1 +/- 4.9%) but was abolished when glibenclamide 50 mu M was coadministered with mibefradil pr ior to ischemia (I/R 28.1 +/- 4.7%). Neither chlelerythrine nor glibenclami de alone had any influence on infarct size. We conclude from these data tha t mibefradil, unlike amlodipine, markedly reduces infarct size in the rat i solated heart. This protection is sensitive to inhibition by glibenclamide, suggesting that K-ATP channel opening may be an important additional and n ovel mechanism of mibefradil's action.