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Métodos Terapêuticos e Terapias MTCI
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1.
Am J Physiol Renal Physiol ; 311(1): F85-93, 2016 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-27122537

RESUMO

Activators of soluble guanylyl cyclase (sGC) interact directly with its prosthetic heme group, enhancing the enzyme responsiveness in pathological conditions. This study aimed to evaluate the effects of the sGC activator BAY 58-2667 on voiding dysfunction, protein expressions of α1 and ß1 sGC subunits and cGMP levels in the bladder tissues after cyclophosphamide (CYP) exposure. Female C57BL/6 mice (20-25 g) were injected with CYP (300 mg/kg ip) to induce cystitis. Mice were pretreated or not with BAY 58-2667 (1 mg/kg, gavage), given 1 h before CYP injection. The micturition patterns and in vitro bladder contractions were evaluated at 24 h. In freely moving mice, the CYP injection produced reduced the micturition volume and increased the number of urine spots. Cystometric recordings in CYP-injected mice revealed significant increases in basal pressure, voiding frequency, and nonvoiding contractions (NVCs), along with decreases in bladder capacity, intercontraction interval, and compliance. BAY 58-2667 significantly prevented the micturition alterations observed in both freely moving mice and cystometry and normalized the reduced in vitro carbachol-induced contractions in the CYP group. Reduced protein expressions of α1 and ß1 sGC subunits and of cGMP levels were observed in the CYP group, all of which were prevented by BAY 58-2667. CYP exposure significantly increased reactive-oxygen species (ROS) generation in both detrusor and urothelium, and this was normalized by BAY 58-2667. The increased myeloperoxidase and cyclooxygenase-2 activities in the bladders of the CYP group remained unchanged by BAY 58-2667. Activators of sGC may constitute a novel and promising therapeutic approach for management of interstitial cystitis.


Assuntos
Benzoatos/uso terapêutico , Cistite/tratamento farmacológico , Cistite/fisiopatologia , Ativadores de Enzimas/uso terapêutico , Guanilil Ciclase Solúvel/efeitos dos fármacos , Bexiga Urinária/fisiopatologia , Alquilantes , Animais , Carbacol/farmacologia , AMP Cíclico/metabolismo , Ciclo-Oxigenase 2/metabolismo , Ciclofosfamida , Cistite/induzido quimicamente , Edema/induzido quimicamente , Edema/fisiopatologia , Edema/prevenção & controle , Camundongos , Camundongos Endogâmicos C57BL , Antagonistas Muscarínicos/farmacologia , Peroxidase/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Bexiga Urinária/metabolismo
2.
J Pharmacol Exp Ther ; 349(1): 2-9, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24421320

RESUMO

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 ß1 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.


Assuntos
Benzoatos/uso terapêutico , Compostos de Bifenilo/uso terapêutico , Ativadores de Enzimas/uso terapêutico , Guanilato Ciclase/metabolismo , Hidrocarbonetos Fluorados/uso terapêutico , Óxido Nítrico/metabolismo , Obesidade/tratamento farmacológico , Receptores Citoplasmáticos e Nucleares/metabolismo , Uretra/efeitos dos fármacos , Animais , Benzoatos/administração & dosagem , Compostos de Bifenilo/administração & dosagem , Relação Dose-Resposta a Droga , Ativação Enzimática , Ativadores de Enzimas/administração & dosagem , Hidrocarbonetos Fluorados/administração & dosagem , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Relaxamento Muscular/efeitos dos fármacos , Tono Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Músculo Liso/enzimologia , Músculo Liso/metabolismo , Obesidade/complicações , Obesidade/enzimologia , Obesidade/fisiopatologia , Espécies Reativas de Oxigênio/metabolismo , Guanilil Ciclase Solúvel , Uretra/enzimologia , Uretra/metabolismo , Bexiga Urinária Hiperativa/enzimologia , Bexiga Urinária Hiperativa/etiologia , Bexiga Urinária Hiperativa/fisiopatologia , Bexiga Urinária Hiperativa/prevenção & controle
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