Metformin in vitro and in vivo increases adenosine signaling in rabbit corpora cavernosa.
BACKGROUND
In subjects with erectile dysfunction responding poorly to sildenafil, metformin was reported to improve erections.


OBJECTIVE
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.


METHODS
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 (A3 R), 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 A3 R, 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 N(ω) -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.


CONCLUSIONS
Metformin in vivo and ex vivo increases ADO signaling in CC, most probably interfering with NO formation and ADO breakdown.
Sexual Medicine and Andrology Unit, Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy.
Linda
L
Vignozzi
Sandra
S
Filippi
Paolo
P
Comeglio
Ilaria
I
Cellai
Annamaria
A
Morelli
Giulia
G
Rastrelli
Elena
E
Maneschi
Edoardo
E
Mannucci
Mario
M
Maggi
D000659:AMP Deaminase / Q000378:metabolism; D000241:Adenosine / Q000378:metabolism*; D000818:Animals; D059305:Diet, High-Fat; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007172:Erectile Dysfunction / Q000188:drug therapy; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D008297:Male; D008687:Metformin / Q000494:pharmacology*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010410:Penile Erection / Q000187:drug effects*; D010413:Penis / Q000187:drug effects / Q000378:metabolism; D011817:Rabbits; D018047:Receptors, Purinergic P1 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013739:Testosterone / Q000627:therapeutic use
D004791:Enzyme Inhibitors; D007004:Hypoglycemic Agents; D018047:Receptors, Purinergic P1; D013739:Testosterone; D008687:Metformin; D052250:Nitric Oxide Synthase Type III; D000659:AMP Deaminase; D000241:Adenosine; D019331:NG-Nitroarginine Methyl Ester
Adenosine; Erection; Metformin