Introduction: In subjects with erectile dysfunction (ED) responding poorly to sildenafil, metformin was reported to improve erections.
Aims: To investigate metformins mechanism of action on erectile function, particularly focusing on adenosine (ADO), and NO signalling in an animal model of high fat diet (HFD)-induced metabolic syndrome (MetS).
Methods: In vitro contractility studies of penile strips. Penile expression of genes related to ADO- or NO-signalling 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 to 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 to RD. Accordingly, in HFD the ADO relaxant effect was potentiated as compared to 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 IC50/IC50 ratio in RD increased four folds vs HFD (RD IC50 ratio=13.75±2.96; HFD IC50 ratio=2.85±0.52). In CC from HFD, in vivo metformin i) normalized A3R, ADA, and AMPD1, ii) further decreased AMPD2, iii) increased dimethylarginine dimethylamino-hydrolase (DDAH1), 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 pre-incubation with NOS inhibitor L-NAME. Interestingly, in vivo testosterone supplementation in HFD rabbits: i) increased penile expression of AMPD2, and ii) restored ADO-induced relation, up to RD level.
Conclusion: Metformin in vitro and in vivo increases ADO signalling in CC, most probably interfering with ADO breakdown and NO formation.