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Type: Artigo de periódico
Title: Molecular mechanisms underlying rat mesenteric artery vasorelaxation induced by the nitric oxide-independent soluble guanylyl cyclase stimulators BAY 41-2272 [5-cyclopropyl-2-[1-(2-fluorobenzyl)-1H- pyrazolo[3,4-b]pyridin-3yl]pyrimidin-4-ylamine] and YC-1 [3-(5 '- hydroxymethyl-2 '-furyl)-1-benzyl indazole]
Author: Teixeira, CE
Priviero, FBM
Webb, RC
Abstract: The aim of this study was to investigate the mechanisms of relaxation to the nitric oxide (NO)-independent soluble guanylyl cyclase (sGC) stimulators 5-cyclopropyl-2-[1-(2fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-4-ylamine (BAY 41-2272) and 3-(5'-hydroxymethyl-2'-furyl)-1-benzyl indazole (YC-1) in the rat mesenteric artery. In endothelium-intact rings, BAY 41-2272 (0.0001-1 mu M) and YC-1 (0.001-30 mu M) caused concentration-dependent relaxations (pEC(50) values of 8.21 +/- 0.05 and 6.75 +/- 0.06, respectively), which were shifted to the right by 6-fold in denuded rings. The sGC inhibitor H-[1,2,4] oxadiazolo [4,3,-a] quinoxalin-1-one (ODQ) (10 mu M) partially attenuated the maximal responses to BAY 41-2272 and YC-1 and displaced their curves to the right by 9- to 10-fold in intact and 3-fold in denuded vessels. The NO synthesis inhibitor N-omega-nitro-L-arginine methyl ester (100 mu M) and the NO scavenger 2-(4-carboxyphenyl)4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (100 mu M) reduced BAY 41-2272 and YC-1 relaxations, whereas the phosphodiesterase type 5 inhibitor sildenafil (0.1 mu M) potentiated these responses. The phosphatase inhibitor calyculin A (50 nM) reduced the relaxant responses, and high concentrations of BAY 41-2272 (1 mu M) and YC-1 (10 mu M) inhibited Ca2+-induced contractions in K+-depolarized rings. BAY 41-2272 (0.1 mu M) and YC-1 (1 mu M) markedly elevated cGMP levels in an ODQ-sensitive manner. Coincubation of BAY 41-2272 or YC-1 with a NO donor resulted in a synergistic inhibition of phenylephrine-induced contractions paralleled by marked increases in cGMP levels. In conclusion, BAY 41-2272 and YC-1 relax the mesenteric artery through cGMP-dependent and - independent mechanisms, including blockade of Ca2+ influx. The synergistic responses probably reflect the direct effects of NO and NO-independent sGC stimulators on the enzyme, thus representing a potential therapeutic effect by permitting reductions of nitro-vasodilator dose.
Country: EUA
Editor: Amer Soc Pharmacology Experimental Therapeutics
Rights: fechado
Identifier DOI: 10.1124/jpet.105.095752
Date Issue: 2006
Appears in Collections:Unicamp - Artigos e Outros Documentos

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