Mechanisms of relaxant activity of the nitric oxide-independent soluble guanylyl cyclase stimulator BAY 41-2272 in rat tracheal smooth muscle
| Autor: | Gilberto De Nucci, Edson Antunes, Fabíola Z. Mónica, Rafael P. Morganti, Haroldo A. Toque |
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| Rok vydání: | 2010 |
| Předmět: |
Male
Nitroprusside medicine.medical_specialty Carbachol Pyridines Muscle Relaxation Enzyme Activators Receptors Cytoplasmic and Nuclear Isometric exercise In Vitro Techniques Nitric Oxide Nitric oxide chemistry.chemical_compound Soluble Guanylyl Cyclase Quinoxalines Internal medicine Extracellular medicine Animals Nitric Oxide Donors Rats Wistar Cyclic GMP Pharmacology Oxadiazoles Dose-Response Relationship Drug Muscle Smooth Electric Stimulation Rats Enzyme Activation Trachea NG-Nitroarginine Methyl Ester Endocrinology Mechanism of action chemistry Guanylate Cyclase Pyrazoles Sodium nitroprusside Nitric Oxide Synthase medicine.symptom Soluble guanylyl cyclase Bay Muscle Contraction medicine.drug |
| Zdroj: | European Journal of Pharmacology. 645:158-164 |
| ISSN: | 0014-2999 |
| Popis: | 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 (pEC(50)=6.68+/-0.14). Prior incubation with the NO synthesis inhibitor l-NAME (100 microM) or the soluble guanylyl cyclase inhibitor ODQ (10 microM) 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 (0.01-1 microM) or electrical field stimulation (EFS, 1-32 Hz). BAY 41-2272 (1 microM) 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 1 microM) 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 Ca(2+) entry blockade. |
| Databáze: | OpenAIRE |
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