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CARDIOVASCULAR

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]

Department of Physiology, Medical College of Georgia, Augusta, Georgia (C.E.T., R.C.W.); and Department of Pharmacology, Faculty of Medical Sciences, State University of Campinas, Campinas, Brazil (F.B.M.P.)

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 µM) and YC-1 (0.001–30 µM) caused concentration-dependent relaxations (pEC₅₀ 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 µM) 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-nitro-L-arginine methyl ester (100 µM) and the NO scavenger 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (100 µM) reduced BAY 41-2272 and YC-1 relaxations, whereas the phosphodiesterase type 5 inhibitor sildenafil (0.1 µM) potentiated these responses. The phosphatase inhibitor calyculin A (50 nM) reduced the relaxant responses, and high concentrations of BAY 41-2272 (1 µM) and YC-1 (10 µM) inhibited Ca²⁺-induced contractions in K⁺-depolarized rings. BAY 41-2272 (0.1 µM) and YC-1 (1 µM) 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 nitrovasodilator dose.

Address correspondence to: Dr. Cleber E. Teixeira, Department of Physiology, Medical College of Georgia, 1120 Fifteenth Street, CA-3101, Augusta, GA 30912-3000. E-mail: cteixeira{at}mail.mcg.edu

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