Mechanisms underlying relaxation of rabbit aorta by BAY 41-2272, a nitric oxide-independent soluble guanylate cyclase activator

Fernanda B.M. Priviero, Juliana S. Baracat, Cleber E. Teixeira, Mário A. Claudino, Gilberto De Nucci, Edson Antunes

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Abstract

The compound BAY 41-2272 (5-cyclopropyl-2-[1-(2-fluoro-benzyl)-1H- pyrazolo[3,4-b]pyridin-3-yl]-pyrimidin-4-ylamine) has been described as a potent, nitric oxide (NO)-independent, stimulator of soluble guanylate cyclase. In the present study, the mechanisms underlying the relaxant effect of BAY 41-2272 in endothelium-intact and -denuded precontracted rabbit aortic rings were investigated. Male New Zealand white rabbits were anaesthetized with pentobarbital sodium. Aortic rings were transferred to 10 mL organ baths containing oxygenated and warmed Krebs' solution. Tissues were connected to force-displacement transducers and changes in isometric force were recorded. Aortic rings were precontracted submaximally with phenylephrine (1 μmol/L). The addition of BAY 41-2272 (0.01-10 μmol/L) to the organ bath produced concentration-dependent relaxations of the aortic rings with a higher potency in endothelium-intact (pEC50 6.59 ± 0.05) compared with endothelium-denuded (pEC50 6.19 ± 0.04; P < 0.05) preparations. No differences in maximal responses were observed in either preparation. The NO synthesis inhibitor NG-nitro-L-arginine methyl ester (100 μmol/L) produced a 2.1-fold rightward shift in endothelium-intact (P < 0.01) rings, but had no effect in endothelium-denuded rings. The soluble guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ; 1 μmol/L) caused significant rightward shifts of the concentration-response curves to BAY 41-2272 of 4.9- and 2.6-fold in endothelium-intact and -denuded rings, respectively. The phosphodiesterase-5 inhibitor sildenafil (0.1 μmol/L) significantly potentiated the relaxant effects of BAY 41-2272 in both endothelium-intact and -denuded rings. At 1 μmol/L, BAY 41-2272 significantly elevated the aortic cGMP content above basal levels in both endothelium-intact and -denuded rings. Furthermore, ODQ reduced BAY 41-2272-elicited increases in cGMP content by 17 and 90% in endothelium-intact and -denuded rings, respectively (P < 0.01). 5. In conclusion, BAY 41-2272 potently relaxes endothelium-intact and -denuded rabbit aortic rings. The basal release of endothelium-derived NO enhances BAY 41-2272-induced relaxations, suggesting a synergistic effect of BAY 41-2272 and NO on soluble guanylate cyclase. In addition, the endothelium-independent relaxation involves both GMP-dependent and -independent mechanisms.

Original languageEnglish (US)
Pages (from-to)728-734
Number of pages7
JournalClinical and Experimental Pharmacology and Physiology
Volume32
Issue number9
DOIs
Publication statusPublished - Sep 1 2005
Externally publishedYes

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Keywords

  • 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one
  • Aorta
  • BAY 41-2272
  • Nitric oxide
  • Sildenafil
  • Soluble guanylate cyclase

ASJC Scopus subject areas

  • Physiology
  • Pharmacology
  • Physiology (medical)

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