Anti-apoptotic effect of benidipine, a long-lasting vasodilating calcium antagonist, in ischaemic/reperfused myocardial cells

1 Ischaemia/reperfusion causes intracellular calcium overloading in cardiac cells. Administration of calcium antagonists reduces myocardial infarct si ze. Recent in vitro studies have demonstrated that calcium plays a critical role in the signal transduction pathway leading to apoptosis. However, whe ther or not calcium antagonists may reduce myocardial apoptosis induced by ischaemia-reperfusion, and thus decrease myocardial infarction, has not bee n directly investigated. 2 The present study investigated the effects of benidipine, an L-type calci um channel blocker, on myocardial infarct size, apoptosis, necrosis and car diac functional recovery in rabbits subjected to myocardial ischaemia/reper fusion (MI/R, 45min/240min). Ten minutes prior to coronary occlusion, rabbi ts were treated with vehicle or benidipine (10 mug kg(-1) or 3 mug kg(-1), i.v.). 3 In the vehicle-treated group, MI/R caused cardiomyocyte apoptosis as evid enced by DNA ladder Formation and TUNEL positive nuclear staining (12.2+/-1 .1%). Treatment with 10 mug kg(-1) benidipine lowered blood pressure, decre ased myocardial apoptosis (6.2+/-0.8%, P<0.01 vs vehicle) and necrosis, red uced infarct size (20+/-2.3% vs 49+/-2.6%, P<0.01), and improved cardiac fu nctional recovery after reperfusion. Administering benidipine at 3 mug kg(- 1), a dose at which no haemodynamic effect was observed, also exerted signi ficant anti-apoptosis effects, which were not significantly different from those observed with higher dose benidipine treatment. However, treatment wi th this low dose benidipine failed to reduce myocardial necrosis. 4 These results demonstrate that benidipine, a calcium antagonist. exerts s ignificant anti-apoptosis effects, which are independent of haemodynamic ch anges. Administration of benidipine at a higher dose produced favourable ha emodynamic effects and provided additional protection against myocardial ne crotic injury and further improved cardiac functional recovery.