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

Department of Cardiology, RWTH University Hospital Aachen, Germany; Division of Cardiology, The University of Texas Medical Branch, Galveston, Texas

Philipp H. Kersting, MD

Thorsten Reffelmann, MD

Dennis A. Meven, MD

Raja Al-Dashti, MD

Erik C. Skobel, MD

Department of Cardiology, RWTH University Hospital Aachen, Germany

Bernd Klosterhalfen, MD

Department of Pathology, RWTH University Hospital Aachen, Germany

Peter Hanrath, MD, FESC, FACC

Department of Cardiology, RWTH University Hospital Aachen, Germany

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

Key Words: apoptosis • carvedilol • ischemia • myocardial infarction • rats

Journal of Cardiovascular Pharmacology and Therapeutics, Vol. 8, No. 3, 207-215 (2003)
DOI: 10.1177/107424840300800306


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