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Introduction In subjects with erectile dysfunction responding poorly to sildenafil, metformin was reported to improve erections. Aims The aim of this study is to investigate metformin's mechanism of action on erectile function, particularly focusing on adenosine ( ADO) and nitric oxide ( NO) signaling in an animal model of high-fat diet ( HFD)-induced metabolic syndrome. Methods In vitro contractility studies of penile strips. Penile expression of genes related to ADO or NO signaling was also evaluated. Main Outcome Measure In vitro contractility studies were used to investigate the effect of in vivo and ex vivo metformin administration on ADO- or acetylcholine ( Ach)-induced relaxation of penile strips from HFD as compared with animals fed a regular diet ( RD). Results Expression of ADO receptor type 3 ( A3R), ADO deaminase ( ADA), AMP deaminase type 1 ( AMPD1), and 2 ( AMPD2) was decreased in HFD as compared with RD. Accordingly, in HFD the ADO relaxant effect was potentiated as compared with RD ( P < 0.02). In vivo metformin treatment in both RD and HFD significantly increased the ADO relaxing effect ( P < 0.0001 and P < 0.01, respectively, vs. relative untreated groups) although to a different extent. In fact, the half-maximal inhibitory concentration ( IC50)/ IC50 ratio in RD increased fourfold vs. HFD ( RD IC50 ratio = 13.75 ± 2.96; HFD IC50 ratio = 2.85 ± 0.52). In corpora cavernosa ( CC) from HFD, in vivo metformin (i) normalized A3R, ADA, and AMPD1; (ii) further decreased AMPD2; (iii) increased dimethylarginine dimethylamino-hydrolase; and (iv) partially restored impaired Ach-induced relaxation. Ex vivo metformin time and dose dependently increased the relaxant effect of ADO in RD. The potentiating effect of metformin on ADO-induced relaxation was significantly reduced by preincubation with NO synthase inhibitor Nω-Nitro-L-arginine methyl ester hydrochloride ( L-NAME). Interestingly, in vivo testosterone supplementation in HFD rabbits (i) increased penile expression of endothelial NO synthase and AMPD2 and (ii) restored metformin's potentiating effect on ADO-induced relaxation up to RD level. Conclusion Metformin in vivo and ex vivo increases ADO signaling in CC, most probably interfering with NO formation and ADO breakdown. Vignozzi L, Filippi S, Comeglio P, Cellai I, Morelli A, Rastrelli G, Maneschi E, Mannucci E, and Maggi M. Metformin in vitro and in vivo increases adenosine signaling in rabbit corpora cavernosa. J Sex Med 2014;11:1694-1708. [ABSTRACT FROM AUTHOR]

Introduction Metabolic syndrome ( MetS) and lower urinary tract symptoms ( LUTS) are often associated. Bladder detrusor hyper-contractility-a major LUTS determinant-is characterized by increased Ras homolog gene family, member A/Rho-associated protein kinase ( RhoA/ ROCK) signaling, which is often upregulated in MetS. Aim This study investigated the effects of tadalafil dosing on RhoA/ ROCK signaling in bladder, in a rabbit model of high-fat diet ( HFD)-induced MetS. Methods Adult male rabbits feeding a HFD for 12 weeks. A subset of HFD animals was treated with tadalafil (2 mg/kg/day, 1 week: the last of the 12 weeks) and compared with HFD and control (feeding a regular diet) rabbits. Main Outcome Measures In vitro contractility studies to evaluate the relaxant effect of the selective ROCK inhibitor, Y-27632, in carbachol precontracted bladder strips. Evaluation of RhoA activation by its membrane translocation. Immunohistochemistry for ROCK expression has been performed to evaluate ROCK expression in bladder from the different experimental groups. mRNA expression of inflammation, pro-fibrotic markers by quantitative RT-PCR has been performed to evaluate the effect of tadalafil on MetS-induced inflammation and fibrosis within the bladder. The in vitro effect of tadalafil on RhoA/ ROCK signaling in bladder smooth muscle cells was evaluated by using chemotaxis assay. Results Bladder strips from HFD rabbits showed hyper-responsiveness to Y-27632, indicating RhoA/ ROCK overactivity in HFD bladder compared with matched controls. Accordingly, the fraction of activated (translocated to the membrane) RhoA as well as ROCK expression are increased in HFD bladder. Tadalafil dosing normalized HFD-induced bladder hypersensitivity to Y-27632, by reducing RhoA membrane translocation and ROCK overexpression. Tadalafil dosing reduced mRNA expression of inflammatory, pro-fibrotic, and hypoxia markers. A direct inhibitory effect of tadalafil on RhoA/ROCK signaling in bladder smooth muscle cell was demonstrated by using chemotaxis assay. Pre-treatment with tadalafil inhibited both basal and PDGF-induced migration of bladder smooth muscle cells. Conclusions Tadalafil dosing reduced RhoA/ ROCK signaling and smooth muscle overactivity in an animal model of MetS-associated bladder alterations. Our findings suggest a novel mechanism of action of tadalafil in alleviating LUTS in MetS patients. Vignozzi L, Filippi S, Comeglio P, Cellai I, Morelli A, Maneschi E, Sarchielli E, Gacci M, Carini M, Vannelli GB, and Maggi M. Tadalafil effect on metabolic syndrome-associated bladder alterations: An experimental study in a rabbit model. J Sex Med 2014;11:1159-1172. [ABSTRACT FROM AUTHOR]