ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Endocrine Abstracts (2008) 16 P224

Atorvastatin ameliorates penile erection and sildenafil responsiveness in two distinct animal models of chemical diabetes and inhibits high glucose-induced alterations in human penile smooth muscle cells

Annamaria Morelli, Sandra Filippi, Linda Vignozzi, Xin-Hua Zhang, Rosa Mancina, Benedetta Fibbi, Aravinda Chavalmane, Enrico Silvestrini & Mario Maggi

University of Florence, Florence, Italy.

One of the proposed mechanisms responsible for Diabetes mellitus (DM)-associated erectile (ED) dysfunction is overactivity of RhoA/ROCK signalling. Because statins may decrease RhoA activation, we investigated whether atorvastatin ameliorated DM-induced ED in alloxan-treated (100 mg/kg) rabbits (in vitro studies) and streptozotocin-treated (STZ, 50 mg/kg) rats (in vivo studies). A subgroup of diabetic animals received atorvastatin 5 mg/kg per daily 2 weeks before sacrifice. In diabetic animals, atorvastatin treatment did not affect glycaemia, cholesterol blood levels and the diabetes-induced hypogonadal state. In alloxan-rabbits, atorvastatin did not ameliorate DM-induced acetylcholine hypo-responsiveness, while normalized DM-induced hypersensitivity to the contractile effect of Endothelin-1 and to the relaxant effect of the ROCK inhibitor Y27632. In STZ-rats penile tissue, ROCK1 mRNA resulted increased, nNOS mRNA decreased. These effects were not normalized by atorvastatin, which, in contrast, completely restored the DM-induced hypersensitivity to Y27632, intracavernously injected. Moreover, atorvastatin ameliorated the DM-induced impairment of penile erection obtained by electrostimulation of the cavernous nerve and normalized the sildenafil effect on erectile function, decreased by DM. We then studied in vitro effect of atorvastatin on RhoA/ROCK in human foetal penile SM cells (hfPSMCs) activated by increasing concentration of glucose (5, 22 and 40 mM). In hfPSMCs, high-glucose (22 and 40 mM) stimulated RhoA activation, along with migration, proliferation and RhoA-mediated gene transcription. Atorvastatin (1 μM) restored all the high glucose-induced effects, whereas was ineffective in the presence of geranyl–geranyl pyrophosphate, the product reduced by statins and required for RhoA activation. Accordingly, in atorvastatin-treated hfPSMCs RhoA was less expressed at the membrane (active form) and RhoA-dependent genes (ROCK2, myocardin, MKL1, SM22α, desmin, and α-SMA) was down-regulated. In conclusion, atorvastatin, most probably by inhibiting RhoA, is able to decrease the DM-induced ED and also to restore sildenafil responsiveness. This data are in keeping with clinical reports showing that atorvastatin ameliorates sildenafil-induced erections, in otherwise unresponsive subjects.