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Type: Artigo de periódico
Title: Soluble Guanylyl Cyclase (sgc) Degradation And Impairment Of Nitric Oxide-mediated Responses In Urethra From Obese Mice: Reversal By The Sgc Activator Bay 60-2770.
Author: Alexandre, Eduardo C
Leiria, Luiz O
Silva, Fábio H
Mendes-Silvério, Camila B
Calmasini, Fabiano B
Davel, Ana Paula C
Mónica, Fabíola Z
De Nucci, Gilberto
Antunes, Edson
Abstract: Obesity has emerged as a major contributing risk factor for overactive bladder (OAB), but no study examined urethral smooth muscle (USM) dysfunction as a predisposing factor to obesity-induced OAB. This study investigated the USM relaxant machinery in obese mice and whether soluble guanylyl cyclase (sGC) activation with BAY 60-2770 [acid 4-({(4-carboxybutyl) [2-(5-fluoro-2-{[4-(trifluoromethyl) biphenyl-4-yl] methoxy} phenyl) ethyl] amino} methyl) benzoic] rescues the urethral reactivity through improvement of sGC-cGMP (cyclic guanosine monophosphate) signaling. Male C57BL/6 mice were fed for 12 weeks with a high-fat diet to induce obesity. Separate groups of animals were treated with BAY 60-2770 (1 mg/kg per day for 2 weeks). Functional assays and measurements of cGMP, reactive-oxygen species (ROS), and sGC protein expression in USM were determined. USM relaxations induced by NO (acidified sodium nitrite), NO donors (S-nitrosoglutathione and glyceryl trinitrate), and BAY 41-2272 [5-cyclopropyl-2-[1-(2-fluoro-benzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-pyrimidin-4-ylamine] (sGC stimulator) were markedly reduced in obese compared with lean mice. In contrast, USM relaxations induced by BAY 60-2770 (sGC activator) were 43% greater in obese mice (P < 0.05), which was accompanied by increases in cGMP levels. Oxidation of sGC with ODQ [1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one] (10 μM) potentiated BAY 60-2770-induced USM responses in the lean group. Long-term oral BAY 60-2770 administration fully prevented the impairment of USM relaxations in obese mice. Reactive-oxygen species (ROS) production was enhanced, but protein expression of β1 second guanylate cyclase subunit was reduced in USM from obese mice, both of which were restored by BAY 60-2770 treatment. In conclusion, impaired USM relaxation in obese mice is associated with ROS generation and down-regulation of sGC-cGMP signaling. Prevention of sGC degradation by BAY 60-2770 ameliorates the impairment of urethral relaxations in obese mice.
Subject: Animals
Biphenyl Compounds
Dose-response Relationship, Drug
Enzyme Activation
Enzyme Activators
Guanylate Cyclase
Hydrocarbons, Fluorinated
Mice, Inbred C57bl
Muscle Relaxation
Muscle Tonus
Muscle, Smooth
Nitric Oxide
Reactive Oxygen Species
Receptors, Cytoplasmic And Nuclear
Urinary Bladder, Overactive
Citation: The Journal Of Pharmacology And Experimental Therapeutics. v. 349, n. 1, p. 2-9, 2014-Apr.
Rights: fechado
Identifier DOI: 10.1124/jpet.113.211029
Date Issue: 2014
Appears in Collections:Unicamp - Artigos e Outros Documentos

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