Bazzani C, Guarini S, Botticelli A R, Zaffe D, Tomasi A, Bini A, Cainazzo M M, Ferrazza G, Mioni C, Bertolini A
Department of Biomedical Sciences, Section of Pharmacology, University of Modena and Reggio Emilia, Modena, Italy.
J Pharmacol Exp Ther. 2001 Jun;297(3):1082-7.
The influence of the melanocortin peptide ACTH-(1-24) (adrenocorticotropin) on the consequences of short-term coronary ischemia (5 min) followed by reperfusion, and the effect of the long-acting melanocortin [Nle(4),D-Phe(7)]alpha-melanocyte-stimulating hormone (NDP-MSH) on the damage induced by a permanent coronary occlusion, were investigated in anesthetized rats. Ischemia was produced by ligature of the left anterior descending coronary artery. Reperfusion-induced arrhythmias [ventricular tachycardia (VT), ventricular fibrillation (VF)] and survival rate within the 5 min following reperfusion, blood levels of free radicals detected 2 min after reperfusion by electron spin resonance spectrometry, and amount of healthy myocardial tissue, measured 72 h after permanent coronary occlusion on immunohistologically stained serial sections, were evaluated. Postischemic reperfusion induced VT in all saline-treated rats, and VF and death in a high percentage of animals (87%). In rats treated i.v. (2.5 min after coronary occlusion) with ACTH-(1-24) (0.16-0.48 mg/kg) there was a significantly dose-dependent reduction in the incidence of arrhythmias and lethality. Ischemia/reperfusion caused a large increase in free radical blood levels; treatment with ACTH-(1-24) (0.48 mg/kg i.v.) almost completely prevented this increase. In rats subjected to permanent coronary occlusion, the amount of healthy myocardial tissue was much reduced in saline-treated rats, while in rats treated s.c. with NDP-MSH (0.27 mg/kg every 12 h) it was significantly higher. The present data demonstrate, for the first time, an unforeseen property of melanocortin peptides, i.e., their ability to significantly reduce both heart ischemia/reperfusion injury and size of the ischemic area induced by permanent coronary occlusion.
在麻醉大鼠中，研究了促黑素肽促肾上腺皮质激素（1-24）[促肾上腺皮质激素（ACTH）-（1-24）]对短期冠状动脉缺血（5分钟）后再灌注后果的影响，以及长效促黑素[Nle（4），D-Phe（7）]α-黑素细胞刺激素（NDP-MSH）对永久性冠状动脉闭塞所致损伤的作用。通过结扎左冠状动脉前降支产生缺血。评估再灌注后5分钟内再灌注诱导的心律失常[室性心动过速（VT）、室颤（VF）]和存活率，通过电子自旋共振光谱法在再灌注后2分钟检测的自由基血水平，以及在永久性冠状动脉闭塞72小时后在免疫组织化学染色的连续切片上测量的健康心肌组织量。缺血后再灌注在所有生理盐水处理的大鼠中诱发VT，在高比例动物（87%）中诱发VF和死亡。在冠状动脉闭塞后2.5分钟静脉注射ACTH-（1-24）（0.16 - 0.48毫克/千克）的大鼠中，心律失常和致死率的发生率呈显著剂量依赖性降低。缺血/再灌注导致自由基血水平大幅升高；静脉注射ACTH-（1-24）（0.48毫克/千克）治疗几乎完全阻止了这种升高。在接受永久性冠状动脉闭塞的大鼠中，生理盐水处理的大鼠健康心肌组织量大幅减少，而皮下注射NDP-MSH（每12小时0.27毫克/千克）的大鼠健康心肌组织量显著更高。本数据首次证明了促黑素肽的一种意外特性，即它们能够显著降低心脏缺血/再灌注损伤以及永久性冠状动脉闭塞所致缺血区域的大小。
