Mechanisms of relaxant activity of the nitric oxide-independent soluble guanylyl cyclase stimulator BAY 41-2272 in rat tracheal smooth muscle

Haroldo A. Toque, Fabíola Z.T. Mónica, Rafael P. Morganti, Gilberto De Nucci, Edson Antunes

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

The soluble guanylyl cyclase is expressed in airway smooth muscle, and agents that stimulate this enzyme activity cause airway smooth muscle relaxation and bronchodilation. The compound 5-Cyclopropyl-2-[1-(2-fluoro-benzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-pyrimidin-4-ylamine (BAY 41-2272) is a potent nitric oxide (NO)-independent soluble guanylyl cyclase stimulator, but little is known about its effects in airway smooth muscle. Therefore, this study aimed to investigate the mechanisms underlying the relaxations of rat tracheal smooth muscle induced by BAY 41-2272. Tracheal rings were mounted in 10-ml organ baths for isometric force recording. BAY 41-2272 concentration-dependently relaxed carbachol-precontracted tracheal rings (pEC50=6.68±0.14). Prior incubation with the NO synthesis inhibitor l-NAME (100μM) or the soluble guanylyl cyclase inhibitor ODQ (10μM) caused significant rightward shifts in the concentration-response curves to BAY 41-2272. Sodium nitroprusside caused concentration-dependent relaxations, which were greatly potentiated by BAY 41-2272 and completely inhibited by ODQ. In addition, BAY 41-2272 shifted to the right the tracheal contractile responses to either carbachol (0.01-1μM) or electrical field stimulation (EFS, 1-32Hz). BAY 41-2272 (1μM) also caused a marked rightward shift and decreased the maximal contractile responses to extracellular CaCl2, and such effect was not modified by pretreatment with ODQ. In addition, BAY 41-2272 (up to 1μM) significantly increased the cGMP levels, and that was abolished by ODQ. Our results indicate that BAY 41-2272 causes cGMP-dependent rat tracheal smooth muscle relaxations in a synergistic fashion with exogenous NO. BAY 41-2272 has also an additional mechanism independently of soluble guanylyl cyclase activation possibly involving Ca2+ entry blockade.

Original languageEnglish (US)
Pages (from-to)158-164
Number of pages7
JournalEuropean Journal of Pharmacology
Volume645
Issue number1-3
DOIs
StatePublished - Oct 1 2010

Fingerprint

Smooth Muscle
Nitric Oxide
Muscle Relaxation
Carbachol
3-(4-Amino-5-cyclopropylpyrimidine-2-yl)-1-(2-fluorobenzyl)-1H-pyrazolo(3,4-b)pyridine
Soluble Guanylyl Cyclase
Nitroprusside
Baths
Electric Stimulation
Enzymes

Keywords

  • Cyclic GMP
  • Nitric oxide
  • Soluble guanylyl cyclase
  • Tracheal smooth muscle

ASJC Scopus subject areas

  • Pharmacology

Cite this

Mechanisms of relaxant activity of the nitric oxide-independent soluble guanylyl cyclase stimulator BAY 41-2272 in rat tracheal smooth muscle. / Toque, Haroldo A.; Mónica, Fabíola Z.T.; Morganti, Rafael P.; De Nucci, Gilberto; Antunes, Edson.

In: European Journal of Pharmacology, Vol. 645, No. 1-3, 01.10.2010, p. 158-164.

Research output: Contribution to journalArticle

Toque, Haroldo A. ; Mónica, Fabíola Z.T. ; Morganti, Rafael P. ; De Nucci, Gilberto ; Antunes, Edson. / Mechanisms of relaxant activity of the nitric oxide-independent soluble guanylyl cyclase stimulator BAY 41-2272 in rat tracheal smooth muscle. In: European Journal of Pharmacology. 2010 ; Vol. 645, No. 1-3. pp. 158-164.
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AU - Morganti, Rafael P.

AU - De Nucci, Gilberto

AU - Antunes, Edson

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N2 - The soluble guanylyl cyclase is expressed in airway smooth muscle, and agents that stimulate this enzyme activity cause airway smooth muscle relaxation and bronchodilation. The compound 5-Cyclopropyl-2-[1-(2-fluoro-benzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-pyrimidin-4-ylamine (BAY 41-2272) is a potent nitric oxide (NO)-independent soluble guanylyl cyclase stimulator, but little is known about its effects in airway smooth muscle. Therefore, this study aimed to investigate the mechanisms underlying the relaxations of rat tracheal smooth muscle induced by BAY 41-2272. Tracheal rings were mounted in 10-ml organ baths for isometric force recording. BAY 41-2272 concentration-dependently relaxed carbachol-precontracted tracheal rings (pEC50=6.68±0.14). Prior incubation with the NO synthesis inhibitor l-NAME (100μM) or the soluble guanylyl cyclase inhibitor ODQ (10μM) caused significant rightward shifts in the concentration-response curves to BAY 41-2272. Sodium nitroprusside caused concentration-dependent relaxations, which were greatly potentiated by BAY 41-2272 and completely inhibited by ODQ. In addition, BAY 41-2272 shifted to the right the tracheal contractile responses to either carbachol (0.01-1μM) or electrical field stimulation (EFS, 1-32Hz). BAY 41-2272 (1μM) also caused a marked rightward shift and decreased the maximal contractile responses to extracellular CaCl2, and such effect was not modified by pretreatment with ODQ. In addition, BAY 41-2272 (up to 1μM) significantly increased the cGMP levels, and that was abolished by ODQ. Our results indicate that BAY 41-2272 causes cGMP-dependent rat tracheal smooth muscle relaxations in a synergistic fashion with exogenous NO. BAY 41-2272 has also an additional mechanism independently of soluble guanylyl cyclase activation possibly involving Ca2+ entry blockade.

AB - The soluble guanylyl cyclase is expressed in airway smooth muscle, and agents that stimulate this enzyme activity cause airway smooth muscle relaxation and bronchodilation. The compound 5-Cyclopropyl-2-[1-(2-fluoro-benzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-pyrimidin-4-ylamine (BAY 41-2272) is a potent nitric oxide (NO)-independent soluble guanylyl cyclase stimulator, but little is known about its effects in airway smooth muscle. Therefore, this study aimed to investigate the mechanisms underlying the relaxations of rat tracheal smooth muscle induced by BAY 41-2272. Tracheal rings were mounted in 10-ml organ baths for isometric force recording. BAY 41-2272 concentration-dependently relaxed carbachol-precontracted tracheal rings (pEC50=6.68±0.14). Prior incubation with the NO synthesis inhibitor l-NAME (100μM) or the soluble guanylyl cyclase inhibitor ODQ (10μM) caused significant rightward shifts in the concentration-response curves to BAY 41-2272. Sodium nitroprusside caused concentration-dependent relaxations, which were greatly potentiated by BAY 41-2272 and completely inhibited by ODQ. In addition, BAY 41-2272 shifted to the right the tracheal contractile responses to either carbachol (0.01-1μM) or electrical field stimulation (EFS, 1-32Hz). BAY 41-2272 (1μM) also caused a marked rightward shift and decreased the maximal contractile responses to extracellular CaCl2, and such effect was not modified by pretreatment with ODQ. In addition, BAY 41-2272 (up to 1μM) significantly increased the cGMP levels, and that was abolished by ODQ. Our results indicate that BAY 41-2272 causes cGMP-dependent rat tracheal smooth muscle relaxations in a synergistic fashion with exogenous NO. BAY 41-2272 has also an additional mechanism independently of soluble guanylyl cyclase activation possibly involving Ca2+ entry blockade.

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