Abstract
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 [Nle4,d-Phe7]α-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.
Footnotes
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Send reprint requests to: Prof. Salvatore Guarini, Department of Biomedical Sciences, Section of Pharmacology, University of Modena and Reggio Emilia, via G. Campi 287, 41100 Modena, Italy. E-mail:guarini.salvatore{at}unimo.it
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This work was supported in part by grants from Ministero dell'Università e della Ricerca Scientifica e Tecnologica and Consiglio Nazionale delle Ricerche, Roma, Italy.
- Abbreviations:
- ACTH-(1-24)
- adrenocorticotropin
- NDP-MSH
- [Nle4,d-Phe7]α-melanocyte-stimulating hormone
- VT
- ventricular tachycardia
- VF
- ventricular fibrillation
- ESR
- electron spin resonance
- PBN
- α-phenyl-N-tert-butylnitrone
- a.u.
- arbitrary units
- Received December 27, 2000.
- Accepted February 27, 2001.
- The American Society for Pharmacology and Experimental Therapeutics