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Characterization of the calcitonin gene-related peptide receptor antagonist telcagepant (MK-0974) in human isolated coronary arteries.
Chan, K Y; Edvinsson, L; Eftekhari, S; Kimblad, P O; Kane, S A; Lynch, J; Hargreaves, R J; de Vries, R; Garrelds, I M; van den Bogaerdt, A J; Danser, A H J; Maassenvandenbrink, A.
Afiliação
  • Chan KY; Division of Pharmacology, Vascular, and Metabolic Diseases, Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.
J Pharmacol Exp Ther ; 334(3): 746-52, 2010 Sep 01.
Article em En | MEDLINE | ID: mdl-20573757
ABSTRACT
The sensory neuropeptide calcitonin gene-related peptide (CGRP) plays a role in primary headaches, and CGRP receptor antagonists are effective in migraine treatment. CGRP is a potent vasodilator, raising the possibility that antagonism of its receptor could have cardiovascular effects. We therefore investigated the effects of the antimigraine CGRP receptor antagonist telcagepant (MK-0974) [N-[(3R,6S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-1-yl)piperidine-1-carboxamide] on human isolated coronary arteries. Arteries with different internal diameters were studied to assess the potential for differential effects across the coronary vascular bed. The concentration-dependent relaxation responses to human alphaCGRP were greater in distal coronary arteries (i.d. 600-1000 microm; E(max) = 83 +/- 7%) than proximal coronary arteries (i.d. 2-3 mm; E(max) = 23 +/- 9%), coronary arteries from explanted hearts (i.d. 3-5 mm; E(max) = 11 +/- 3%), and coronary arterioles (i.d. 200-300 microm; E(max) = 15 +/- 7%). Telcagepant alone did not induce contraction or relaxation of these coronary blood vessels. Pretreatment with telcagepant (10 nM to 1 microM) antagonized alphaCGRP-induced relaxation competitively in distal coronary arteries (pA(2) = 8.43 +/- 0.24) and proximal coronary arteries and coronary arterioles (1 microM telcagepant, giving pK(B) = 7.89 +/- 0.13 and 7.78 +/- 0.16, respectively). alphaCGRP significantly increased cAMP levels in distal, but not proximal, coronary arteries, and this was abolished by pretreatment with telcagepant. Immunohistochemistry revealed the expression and colocalization of the CGRP receptor elements calcitonin-like receptor and receptor activity-modifying protein 1 in the smooth muscle cells in the media layer of human coronary arteries. These findings in vitro support the cardiovascular safety of CGRP receptor antagonists and suggest that telcagepant is unlikely to induce coronary side effects under normal cardiovascular conditions.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Azepinas / Vasos Coronários / Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina / Imidazóis Limite: Adult / Aged / Female / Humans / Male / Middle aged Idioma: En Revista: J Pharmacol Exp Ther Ano de publicação: 2010 Tipo de documento: Article País de afiliação: Holanda

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Azepinas / Vasos Coronários / Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina / Imidazóis Limite: Adult / Aged / Female / Humans / Male / Middle aged Idioma: En Revista: J Pharmacol Exp Ther Ano de publicação: 2010 Tipo de documento: Article País de afiliação: Holanda