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]

Cleber E. Teixeira, Fernanda Priviero, R Clinton Webb

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Abstract

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 Nω-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.

Original languageEnglish (US)
Pages (from-to)258-266
Number of pages9
JournalJournal of Pharmacology and Experimental Therapeutics
Volume317
Issue number1
DOIs
StatePublished - Apr 1 2006

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Indazoles
Mesenteric Arteries
Vasodilation
Nitric Oxide
Phosphodiesterase 5 Inhibitors
Quinoxalines
Nitric Oxide Donors
Soluble Guanylyl Cyclase
3-(4-Amino-5-cyclopropylpyrimidine-2-yl)-1-(2-fluorobenzyl)-1H-pyrazolo(3,4-b)pyridine
Phenylephrine
Therapeutic Uses
Phosphoric Monoester Hydrolases
Endothelium

ASJC Scopus subject areas

  • Pharmacology

Cite this

@article{64259ee2bd034f0e88464fb1f922c1c7,
title = "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]",
abstract = "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 Nω-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.",
author = "Teixeira, {Cleber E.} and Fernanda Priviero and Webb, {R Clinton}",
year = "2006",
month = "4",
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doi = "10.1124/jpet.105.095752",
language = "English (US)",
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TY - JOUR

T1 - 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]

AU - Teixeira, Cleber E.

AU - Priviero, Fernanda

AU - Webb, R Clinton

PY - 2006/4/1

Y1 - 2006/4/1

N2 - 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 Nω-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.

AB - 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 Nω-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.

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