title: Anti-apoptotic effect of benidipine, a long-lasting vasodilating calcium antagonist, in ischaemic/reperfused myocardial cells.
abstract: 1. Ischaemia/reperfusion causes intracellular calcium overloading in cardiac cells. Administration of calcium antagonists reduces myocardial infarct size. Recent in vitro studies have demonstrated that calcium plays a critical role in the signal transduction pathway leading to apoptosis. However, whether or not calcium antagonists may reduce myocardial apoptosis induced by ischaemia-reperfusion, and thus decrease myocardial infarction, has not been directly investigated. 2. The present study investigated the effects of benidipine, an L-type calcium channel blocker, on myocardial infarct size, apoptosis, necrosis and cardiac functional recovery in rabbits subjected to myocardial ischaemia/reperfusion (MI/R, 45 min/240 min). Ten minutes prior to coronary occlusion, rabbits were treated with vehicle or benidipine (10 microg x kg(-1) or 3 microg x kg(-1), i.v.). 3. In the vehicle-treated group, MI/R caused cardiomyocyte apoptosis as evidenced by DNA ladder formation and TUNEL positive nuclear staining (12.2+/-1.1%). Treatment with 10 microg x kg(-1) benidipine lowered blood pressure, decreased myocardial apoptosis (6.2+/-0.8%, P<0.01 vs vehicle) and necrosis, reduced infarct size (20+/-2.3% vs 49+/-2.6%, P<0.01), and improved cardiac functional recovery after reperfusion. Administering benidipine at 3 microg x kg(-1), a dose at which no haemodynamic effect was observed, also exerted significant anti-apoptosis effects, which were not significantly different from those observed with higher dose benidipine treatment. However, treatment with this low dose benidipine failed to reduce myocardial necrosis. 4. These results demonstrate that benidipine, a calcium antagonist, exerts significant anti-apoptosis effects, which are independent of haemodynamic changes. Administration of benidipine at a higher dose produced favourable haemodynamic effects and provided additional protection against myocardial necrotic injury and further improved cardiac functional recovery.
authors.affiliation: Division of Emergency Medicine, Thomas Jefferson University, 1020 Sansom Street, Philadelphia, Pennsylvania 19107, USA.
authors.forename: F
authors.initials: F
authors.lastname: Gao
authors.forename: B
authors.initials: B
authors.lastname: Gong
authors.forename: T A
authors.initials: TA
authors.lastname: Christopher
authors.forename: B L
authors.initials: BL
authors.lastname: Lopez
authors.forename: A
authors.initials: A
authors.lastname: Karasawa
authors.forename: X L
authors.initials: XL
authors.lastname: Ma
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001794:Blood Pressure / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D004095:Dihydropyridines / Q000494:pharmacology*; D006339:Heart Rate / Q000187:drug effects; D020287:In Situ Nick-End Labeling; D009203:Myocardial Infarction / Q000188:drug therapy; D017202:Myocardial Ischemia / Q000188:drug therapy* / Q000503:physiopathology; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D011817:Rabbits; D014665:Vasodilator Agents / Q000494:pharmacology*; D016277:Ventricular Function, Left / Q000187:drug effects
chemical_list: D002121:Calcium Channel Blockers; D004095:Dihydropyridines; D014665:Vasodilator Agents; C061004:benidipine; D002118:Calcium