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Mechanisms underlying relaxation of rabbit aorta by BAY 41-2272, a nitric oxide-independent soluble guanylate cyclase activator.
Clin Exp Pharmacol Physiol. 2005 Sep; 32(9):728-34.CE

Abstract

1. 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. 2. 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 micromol/L). 3. The addition of BAY 41-2272 (0.01-10 micromol/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 micromol/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 micromol/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 micromol/L) significantly potentiated the relaxant effects of BAY 41-2272 in both endothelium-intact and -denuded rings. 4. At 1 micromol/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.

Authors+Show Affiliations

Department of Pharmacology, Faculty of Medical Sciences, State University of Campinas (UNICAMP), Campinas, Brazil.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

16173929

Citation

Priviero, Fernanda B M., et al. "Mechanisms Underlying Relaxation of Rabbit Aorta By BAY 41-2272, a Nitric Oxide-independent Soluble Guanylate Cyclase Activator." Clinical and Experimental Pharmacology & Physiology, vol. 32, no. 9, 2005, pp. 728-34.
Priviero FB, Baracat JS, Teixeira CE, et al. Mechanisms underlying relaxation of rabbit aorta by BAY 41-2272, a nitric oxide-independent soluble guanylate cyclase activator. Clin Exp Pharmacol Physiol. 2005;32(9):728-34.
Priviero, F. B., Baracat, J. S., Teixeira, C. E., Claudino, M. A., De Nucci, G., & Antunes, E. (2005). Mechanisms underlying relaxation of rabbit aorta by BAY 41-2272, a nitric oxide-independent soluble guanylate cyclase activator. Clinical and Experimental Pharmacology & Physiology, 32(9), 728-34.
Priviero FB, et al. Mechanisms Underlying Relaxation of Rabbit Aorta By BAY 41-2272, a Nitric Oxide-independent Soluble Guanylate Cyclase Activator. Clin Exp Pharmacol Physiol. 2005;32(9):728-34. PubMed PMID: 16173929.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Mechanisms underlying relaxation of rabbit aorta by BAY 41-2272, a nitric oxide-independent soluble guanylate cyclase activator. AU - Priviero,Fernanda B M, AU - Baracat,Juliana S, AU - Teixeira,Cleber E, AU - Claudino,Mário A, AU - De Nucci,Gilberto, AU - Antunes,Edson, PY - 2005/9/22/pubmed PY - 2005/10/20/medline PY - 2005/9/22/entrez SP - 728 EP - 34 JF - Clinical and experimental pharmacology & physiology JO - Clin Exp Pharmacol Physiol VL - 32 IS - 9 N2 - 1. 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. 2. 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 micromol/L). 3. The addition of BAY 41-2272 (0.01-10 micromol/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 micromol/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 micromol/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 micromol/L) significantly potentiated the relaxant effects of BAY 41-2272 in both endothelium-intact and -denuded rings. 4. At 1 micromol/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. SN - 0305-1870 UR - https://www.unboundmedicine.com/medline/citation/16173929/Mechanisms_underlying_relaxation_of_rabbit_aorta_by_BAY_41_2272_a_nitric_oxide_independent_soluble_guanylate_cyclase_activator_ L2 - https://doi.org/10.1111/j.1440-1681.2005.04262.x DB - PRIME DP - Unbound Medicine ER -