卡维地洛的心脏保护作用：抗凋亡作用独立于大鼠心脏中的β-肾上腺素能受体阻滞。

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

作者信息

Schwarz Ernst R, Kersting Philipp H, Reffelmann Thorsten, Meven Dennis A, Al-Dashti Raja, Skobel Erik C, Klosterhalfen Bernd, Hanrath Peter

机构信息

Department of Cardiology, RWTH University Hospital Aachen, Germany.

出版信息

J Cardiovasc Pharmacol Ther. 2003 Sep;8(3):207-15. doi: 10.1177/107424840300800306.

DOI:10.1177/107424840300800306

PMID:14506546

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.

摘要

背景

卡维地洛是一种具有β受体阻滞特性的β受体阻滞剂，目前广泛用于治疗充血性心力衰竭。除了其β肾上腺素能受体阻滞作用外，在实验动物中还证实了其抗凋亡作用。

目的

在大鼠心脏实验性梗死模型中，测试卡维地洛及其羟基化类似物BM - 91.0228在梗死限制和抗凋亡特性方面的心脏保护作用。

方法

将麻醉的大鼠冠状动脉阻断30分钟（第1至3组）或60分钟（第4至6组），随后再灌注30分钟。第1组和第4组作为对照；第2组和第5组在冠状动脉阻断前5分钟静脉注射卡维地洛（1mg/kg），第3组和第6组分别静脉注射BM - 91.0228（1mg/kg）。通过氯化三苯基四氮唑染色测量梗死面积。通过缺口末端标记法原位观察凋亡情况。

结果

与对照组相比，冠状动脉阻断30分钟后卡维地洛减小了梗死面积（8.7%±2.7%对27.3%±3.4%，P<.001），而BM - 91.0228未显示出梗死面积的显著减小（23.7%±5.9%，无显著性差异）。与对照组相比，冠状动脉阻断60分钟后，卡维地洛（36.9%±3.9%）和BM - 91.0228（42.4%±3.6%）均未减小梗死面积（47.7%±3.9%，无显著性差异）。与对照组相比，冠状动脉阻断30分钟后卡维地洛减少了凋亡（4.9%±1.3%对16.7%±3.2%，P<.01），60分钟后也减少了凋亡（11.7%±1.8%对25.5%±0.5%，P<.001）。与对照组相比，冠状动脉阻断30分钟后BM - 91.0228减少了凋亡（7.3%±1.4%对16.7%±3.2%，P<.01），60分钟后也减少了凋亡（13.4%±1.8%对25.5%±0.5%，P<.001）。