Viagra Research Today is a free monthly online journal that collates and summarizes the latest research about Viagra, including details on sildenafil, erectile dysfunction, impotence, side-effects, alternatives.

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-3-yl]pyrimidin-4-ylamine] and YC-1 [3-(5'-Hydroxymethyl-2'-furyl)-1-benzyl Indazole].

Teixeira CE, Priviero FB, Webb RC

Department of Physiology, Medical College of Georgia, 1120 Fifteenth Street, CA-3101, Augusta, GA 30912-3000. cteixeira@mail.mcg.edu.

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-(2-fluorobenzyl)-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 muM) and YC-1 (0.001-30 muM) 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 muM) 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 muM) and the NO scavenger 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (100 muM) reduced BAY 41-2272 and YC-1 relaxations, whereas the phosphodiesterase type 5 inhibitor sildenafil (0.1 muM) potentiated these responses. The phosphatase inhibitor calyculin A (50 nM) reduced the relaxant responses, and high concentrations of BAY 41-2272 (1 muM) and YC-1 (10 muM) inhibited Ca(2+)-induced contractions in K(+)-depolarized rings. BAY 41-2272 (0.1 muM) and YC-1 (1 muM) 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 Ca(2+) 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 nitrovasodilator dose.

Published 22 March 2006 in J Pharmacol Exp Ther, 317(1): 258-66.
Full-text of this article is available online (may require subscription).

© 2004-2008 Viagra Research Today. All Rights Reserved.