Pharmacological characterisation of the mechanisms underlying the relaxant effect of adrenomedullin in the rat carotid artery

Autor(es)

Passaglia, Patricia ^[1] ; Gonzaga, Natalia A. ^{[2, 3]} ; Tirapelli, Daniela P. C. ^[4] ; Tirapelli, Luis F. ^[4] ; Tirapelli, Carlos R. ^[2]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Programa Posgrad Toxicol, BR-14040902 Ribeirao Preto, SP - Brazil

^[2] Univ Sao Paulo, Escola Enfermagem Ribeirao Preto, Lab Farmacol, Dept Enfermagem Psiquiatr & Ciencias Humanas, BR-14040902 Ribeirao Preto, SP - Brazil

^[3] Univ Sao Paulo, Programa Posgrad Farmacol, BR-14040902 Ribeirao Preto, SP - Brazil

^[4] Univ Sao Paulo, Fac Med Ribeirao Preto, Dept Cirurgia & Anat, BR-14040902 Ribeirao Preto, SP - Brazil

• Tipo de documento: Artigo Científico
• Fonte: Journal of Pharmacy and Pharmacology; v. 66, n. 12, p. 1734-1746, DEC 2014.
• Citações Web of Science: 6

Resumo

ObjectivesWe investigated the mechanisms underlying the relaxant effect of adrenomedullin (AM) in the rat carotid artery and verified the expression of AM system components in this tissue. MethodsThe carotid artery was isolated from male Wistar rats and immunohistochemical, Western immunoblotting, real-time polymerase chain reaction and functional assays were conducted. Key findingsProtein and mRNA expression of AM, calcitonin receptor-like receptor (CRLR) and receptor activity-modifying proteins (RAMP)1, 2, 3 were detected in carotid segments from male Wistar rats. Immunohistochemical assays showed that AM and CRLR receptors are expressed in the endothelium and smooth muscle cells. Functional assays showed that AM concentration dependently relaxed carotid rings with intact endothelium. Endothelial removal reduced, but not abolished, the relaxation induced by AM. AM(22-52) (selective antagonist for AM receptors) and calcitonin gene-related peptide (CGRP)(8-37) (selective CGRP receptor antagonist) reduced AM-induced relaxation in endothelium-intact rings. Pre-incubation of endothelium-intact rings with N-nitro-L-arginine methyl ester, 1H-{[}1,2,4]oxadiazolo{[}4,3-a]quinoxalin-1-one or Rp-8-Bromo-?-phenyl-1,N2-ethenoguanosine 3,5cyclic monophosphorothioate reduced AM-induced relaxation. Inhibition of cyclooxygenase-1 and protein kinase A (PKA) reduced AM-induced relaxation. The relaxation induced by AM was attenuated by the K+ channel blockers apamin and glibenclamide. AM increased nitrate levels and 6-keto-prostaglandin F-1 (stable product of prostacyclin) in the rat carotid. In endothelium-denuded rings, AM(22-52), glibenclamide and PKA inhibition by H89 reduced AM-induced relaxation. ConclusionsThe novelty of this work is that it first demonstrated functionally that AM-induced relaxation is mediated by AM and CGRP receptors located on the endothelium and AM receptors located on smooth muscle of rat carotid arteries. AM-induced relaxation involves the nitric oxide-cGMP pathway, a vasodilator prostanoid, the opening of K+ channels and the activation of PKA. (AU)

• Processo FAPESP: 11/12911-2 - Consequências do consumo crônico de etanol sobre a reatividade e expressão dos componentes do sistema endotelinérgico em corpo cavernoso de rato
• Beneficiário: Carlos Renato Tirapelli
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 06/60076-7 - Efeito do consumo crônico de etanol sobre o sistema adrenomedulina em aorta e leito mesentérico de ratos e avaliação do papel protetor desse peptídeo nas alterações vasculares induzidas pelo etanol
• Beneficiário: Carlos Renato Tirapelli
• Modalidade de apoio: Auxílio à Pesquisa - Jovens Pesquisadores