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


CONCLUSIONS
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.
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002227:Carbazoles / Q000494:pharmacology* / Q000627:therapeutic use; D000077261:Carvedilol; D005260:Female; D006321:Heart / Q000187:drug effects*; D006439:Hemodynamics / Q000187:drug effects; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D009203:Myocardial Infarction / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D015425:Myocardial Reperfusion / Q000009:adverse effects; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000473:pathology; D011412:Propanolamines / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley
D000319:Adrenergic beta-Antagonists; C103832:BM 910228; D002227:Carbazoles; D011412:Propanolamines; D000077261:Carvedilol