Endocrine Abstracts

Increased RhoA/Rho-kinase (ROK) signalling is known to impair erectile function. Spontaneously hypertensive rats (SHR) over-express penile RhoA and show an impaired erectile response. We tested treatments known to inhibit RhoA activation, on erectile function and sildenafil responsiveness in SHR. SHR have been treated for two weeks with atorvastatin (5 and 30 mg/Kg/day), or with elocalcitol (30 μg/Kg/day), a vitamin D receptor (VDR) agonist. The normotensive Wistar Kyoto (WKY) rats have been used as controls. At the selected doses, neither atorvastatin affected cholesterol, nor elocalcitol affected calcaemia in both SHR and WKY. In WKY, sildenafil (25 mg/Kg by oral gavage) greatly increased erectile function, evaluated as intracavernous pressure/mean arterial pressure (ICP/MAP) ratio after electrical stimulation (ES) of the cavernous nerve. In SHR, both basal and sildenafil-stimulated ICP/MAP ratio were depressed. Atorvastatin did not affect basal ICP/MAP at any concentration tested. However, it dose-dependently increased sildenafil effect on ES-induced erection, significantly potentiated by 30 mg/Kg dosing. At this dose, atorvastatin normalized the over-expression of RhoA mRNA (real time RT-PCR) observed in SHR, without affecting other genes such as ROK1, ROK2, PDE5, nNOS, eNOS. Conversely, elocalcitol, at a dose known to ameliorate bladder overactivity by inhibiting RhoA activation, failed to restore ICP/MAP ratio, sildenafil responsiveness and RhoA expression in SHR. Finally, SHR rats expressed high levels of VDR mRNA in the bladder (almost 5-fold increase over WKY), but not in corpora cavernosa (CC). In conclusion, our data confirm that an increased RhoA signalling impairs erectile function and sildenafil responsiveness in SHR. Atorvastatin, at a dose unable to affect lipids, ameliorates sildenafil effectiveness and down-regulates RhoA expression. Conversely, elocalcitol was ineffective in restoring erectile function in SHR, either alone or with sildenafil. The differential quantitative VDR expression in bladder and CC suggests a plausible mechanism for the tissue-specific effect of elocalcitol on RhoA/ROK contractile pathway.