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(Hypertension. 2006;47:596.)
© 2006 American Heart Association, Inc.

Part 2 Original Articles

Vasorelaxing Effect of BAY 41-2272 in Rat Basilar Artery

Involvement of cGMP-Dependent and Independent Mechanisms

Cleber E. Teixeira; Fernanda B.M. Priviero; Joseph Todd, Jr; R. Clinton Webb

From the Department of Physiology (C.E.T., J.T., R.C.W.), Medical College of Georgia, Augusta, and Department of Pharmacology (F.B.M.P.), Faculty of Medical Sciences, UNICAMP, Campinas, São Paulo, Brazil.

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

Decreases in intrinsic NO cause cerebral vasospasms because of the dysregulation of cGMP formation by NO-mediated pathways. Because 5-cyclopropyl-2-{1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl}pyrimidin-4-ylamine (BAY 41-2272) is a potent soluble guanylyl cyclase (sGC) stimulator in an NO-independent manner, this study aimed to investigate the mechanisms underlying the relaxant effects of BAY 41-2272 in the rat basilar artery. BAY 41-2272 (0.0001 to 1 µmol/L) induced relaxations in a concentration-dependent manner, with pEC₅₀ values of 8.13±0.03 and 7.63±0.05 in intact and denuded rings, respectively. The sGC inhibitor 1H-[1,2,4] oxadiazolo [4,3,-a]quinoxalin-1-one (ODQ) markedly displaced the curve for BAY 41-2272 to the right in intact or denuded rings (&10-fold). The NO synthesis inhibitor N^G-nitro-L-arginine methyl ester caused a rightward shift in the curve for BAY 41-2272 (4-fold), whereas the phosphodiesterase type 5 inhibitor sildenafil enhanced BAY 41-2272–induced relaxations (3- to 4-fold). The Na⁺-K⁺-ATPase inhibitor ouabain caused 3-fold rightward shifts in the curves for BAY 41-2272. Ca²⁺-induced contractions in K⁺ depolarized rings were significantly attenuated by BAY 41-2272 in an ODQ-insensitive manner. The NO donor glyceryl trinitrate and BAY 41-2272 caused rightward shifts in the contractile responses to serotonin. Their coincubation caused a synergistic inhibition of serotonin-induced contractions. BAY 41-2272 and glyceryl trinitrate increased cGMP levels (but not cAMP) by 10-fold and 4-fold above baseline, respectively, in an ODQ-sensitive manner. cGMP levels increased by 50-fold after coincubation. BAY 41-2272 potently relaxes the rat basilar artery in a synergistic fashion with NO. Targeting the sGC with selective activators, such as BAY 41-2272, may represent a new therapy to treat cerebrovascular disease.

Key Words: nitric oxide • cyclic GMP • nitric oxide synthase

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