Cardioprotection by Carvedilol: antiapoptosis is independent of beta-adrenoceptor blockage in the rat heart.

ABSTRACT

BACKGROUND: Carvedilol, a beta-blocking agent with beta-blocking properties is now widely used for the treatment of congestive heart failure. In addition to its beta-adrenergic receptor blockage, antiapoptotic effects have been demonstrated in experimental animals. OBJECTIVE: The cardioprotective effects of carvedilol and its hydroxylated analogue BM-91.0228 were tested with regard to their infarct-limiting and antiapoptotic properties in an experimental infarct model in the rat heart. METHODS: Anesthetized rats were subjected to either 30 (groups 1 to 3) or 60 minutes (groups 4 to 6) of coronary artery occlusion followed by 30 minutes of reperfusion. Groups 1 and 4 served as the control; groups 2 and 5 received intravenous Carvedilol (1 mg/kg) and groups 3 and 6 received intravenous administration of BM-91.0228 (1 mg/kg), respectively, 5 minutes prior to coronary occlusion. Infarct sizes were measured by triphenyltetrazolium chloride staining. In situ visualization of apoptosis was measured by nick end labeling. RESULTS: Carvedilol reduced infarct size after 30 minutes of coronary occlusion compared to controls (8.7% +/- 2.7% versus 27.3% +/- 3.4%, P <.001), while BM-91.0228 showed no significant infarct size reduction (23.7% +/- 5.9%, NS). Neither Carvedilol (36.9% +/- 3.9%) nor BM-91.0228 (42.4% +/- 3.6%) reduced infarct size after 60 minutes of coronary occlusion compared to controls (47.7% +/- 3.9%, NS). Carvedilol reduced apoptosis after 30 minutes (4.9% +/- 1.3% versus 16.7% +/- 3.2%, P <.01) and after 60 minutes (11.7% +/- 1.8% versus 25.5% +/- 0.5%, P <.001) of coronary occlusion compared to controls. BM-91.0228 reduced apoptosis after 30 minutes (7.3% +/- 1.4% versus 16.7% +/- 3.2%, P <.01) and after 60 minutes (13.4% +/- 1.8% versus 25.5% +/- 0.5%, P <.001) of coronary occlusion compared to controls. CONCLUSION: Carvedilol is cardioprotective by preventing ischemia-perfusion-induced necrosis and apoptosis of cardiomyocytes. The antiapoptotic effects of Carvedilol are independent of its beta-adrenoceptor blocking effects, but its effects might be caused by antioxidant properties and by modulation of the signalling pathway.