Metformin In Vitro and In Vivo Increases Adenosine Signaling in Rabbit Corpora Cavernosa

Abstract

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.

Treatment With Metformin Improves Erectile Dysfunction in a Murine Model of Obesity Associated With Insulin Resistance

“…16 Recently, metformin was shown to increase the adenosine signaling in corpus cavernosum from the high-fat-fed rabbits via increases in NO production. 17 However, no detailed functional study has explored the effect of metformin treatment on a murine model of obesity-associated ED. Our hypothesis is that metformin reverses ED in the murine model of obesity associated with IR through improvement of NO bioavailability in the erectile tissue.…”

“…In rabbits fed with a high-fat diet, metformin ameliorated the in vitro relaxant responses to ACh in the erectile tissue, along with hyperglycemia and glucose intolerance. 17 In the flaccid state, CC and penile vessels are contracted mainly via stimulation of a1-adrenoceptors by norepinephrine derived from the sympathetic nerves. 1 Previous studies reported that ED in hypertensive and aging animals has been associated with increased a1-adrenoceptoremediated cavernosal vasoconstriction.…”

Controversial aspects of testosterone in the regulation of sexual function in late‐onset hypogonadism

“…Effects of treatment with a pharmacological dose of T to either HFD (HFD + T) or GnRH analog (GnRH analog + T) rabbits are also shown. Interestingly, in rabbit penis, expression of the androgen receptor (AR) is highly associated with genes involved in corpora cavernosa relaxation, involving both cGMP‐dependent (eg, nitric oxide, NO) 18 and AMP‐dependent (eg, adenosine) pathways 19 . According to the aforementioned studies, AR expression was closely linked to NO formation (eNOS, nNOS, DDAH1), signaling (GCsa1, GCsb1, PKG1) and degradation (PDE5).…”

A Comprehensive Review of Metabolic Syndrome Affecting Erectile Dysfunction

“…However, this is not known whether such medications help in treating MetS and ED or not. In an animal model of HFD‐induced MetS, where acetylcholine‐induced relaxation of penile strips from HFD were compared with animals fed a regular diet, metformin partially restored impaired acetylcholine‐induced relaxation in corpus cavernosum from HFD [198].…”