Cardioprotection by Carvedilol: Antiapoptosis is Independent of β-Adrenoceptor Blockage in the Rat Heart

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Abstract
Background: Carvedilol, a β-blocking agent with α-blocking properties is now widely used for the treatment of congestive heart failure. In addition to its β-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 I 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 β-adrenoceptor blocking effects, but its effects might be caused by antioxidant properties and by modulation of the signalling pathway.