875 RESVERATROL, A POLYPHENOLIC SIRT1 ACTIVATOR, IMPROVES ERECTILE FUNCTION IN STREPTOZOTOCIN INDUCED DIABETIC RATS

Abstract

You have accessJournal of UrologySexual Function/Dysfunction/Andrology: Basic Research II1 Apr 2010875 RESVERATROL, A POLYPHENOLIC SIRT1 ACTIVATOR, IMPROVES ERECTILE FUNCTION IN STREPTOZOTOCIN INDUCED DIABETIC RATS Shinichiro Fukuhara, Hidenobu Okuda, Keisuke Yamamoto, Jiro Nakayama, Tetsuya Takao, Yasushi Miyagawa, Akira Tsujimura, Norio Nonomura, and Akihiko Okuyama Shinichiro FukuharaShinichiro Fukuhara More articles by this author , Hidenobu OkudaHidenobu Okuda More articles by this author , Keisuke YamamotoKeisuke Yamamoto More articles by this author , Jiro NakayamaJiro Nakayama More articles by this author , Tetsuya TakaoTetsuya Takao More articles by this author , Yasushi MiyagawaYasushi Miyagawa More articles by this author , Akira TsujimuraAkira Tsujimura More articles by this author , Norio NonomuraNorio Nonomura More articles by this author , and Akihiko OkuyamaAkihiko Okuyama More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2010.02.1631AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES SIRT1 is an important enzyme for many cellular processes including cell cycle regulation, fatty acid metabolism, and life span extension. Recently, it has been reported that SIRT1 promotes endothelium-dependent vascular relaxation by activating endothelial nitric oxide synthase (eNOS) in endothelial cells, however its effect on corpus cavernosal smooth muscle relaxation remain poorly defined. Resveratrol is a polyphenolic compound, and has been reported to be an activator of SIRT1. Therefore, we investigated the effects of resveratrol on NO/cGMP pathway in human corpus cavernosal smooth muscle cells (CCSMCs) which were shown to express eNOS and synthesize NO in our previous report, and its therapeutic potential for erectile dysfunction in diabetic rats. We also examined the hypothesis that a combination of SIRT1 activation and phosphodiesterase 5 (PDE5) inhibition has synergistic effect in vitro and vivo. METHODS We measured intraceller cGMP concentration after incubation of human CCSMCs with resveratrol, PDE5 inhibitor (vardenafil), and both. In addition, to eliminate possible nonspecific effects, the cells were also incubated with sirtinol which inhibit SIRT1. Then, to investigate erectile function, four weeks after establishment of diabetes due to streptozotocin injection (50mg/kg i.p), rats treated with either only vehicle, PDE5 inhibitor (vardenafil 0.5m/kg/day p.o), resveratrol (5mg/kg/day p.o) or resveratrol plus PDE5 inhibitor. After four weeks treatment, the intracavernosal pressure (ICP) with electrical stimulation to the cavernous nerve and mean arterial pressure (MAP) were measured. RESULTS The levels of cGMP in human CCSMCs were significantly increased either by administration of PDE5 inhibitor or resveratrol compare with those of controls. A drastic synergistic increase in cGMP was observed when treated with both PDE5 inhibitor and resveratorol simultaneously. Furthermore, the effects of resveratrol on cGMP synthesis were reversed by sirtinol a specific SIRT1 inhibitor. In vivo experiments, while the ICP/MAP was significantly lower in treated with only vehicle rats, ICP/MAP in treated with resveratrol rats showed significantly higher. And more, The ICP/MAP in treated with both agents was higher than all other groups. CONCLUSIONS Resveratorol leads to enhancement of cGMP synthesis in human CCSMSs and improves erectile function in storeptozotocin induced diabetic rats, particularly with PDE5 inhibitor. Our data indicate that resveratrol has therapeutic potential for diabetic erectile dysfunction. Suita, Japan© 2010 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 183Issue 4SApril 2010Page: e342 Advertisement Copyright & Permissions© 2010 by American Urological Association Education and Research, Inc.MetricsAuthor Information Shinichiro Fukuhara More articles by this author Hidenobu Okuda More articles by this author Keisuke Yamamoto More articles by this author Jiro Nakayama More articles by this author Tetsuya Takao More articles by this author Yasushi Miyagawa More articles by this author Akira Tsujimura More articles by this author Norio Nonomura More articles by this author Akihiko Okuyama More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...