Journal of Andrology
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Published-Ahead-of-Print August 15, 2007, DOI:10.2164/jandrol.107.003152

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Atorvastatin but not elocalcitol increases sildenafil responsiveness in Spontaneously Hypertensive Rats by regulating the RhoA/ROCK pathway

Benedetta Fibbi , Annamaria Morelli , Mirca Marini , Xin-Hua Zhang , Rosa Mancina , Linda Vignozzi , Sandra Filippi , Aravinda Chavalmane , Enrico Silvestrini , Enrico Colli , Luciano Adorini , Gabriella B Vannelli , and Mario Maggi *

* To whom correspondence should be addressed. E-mail: m.maggi{at}dfc.unifi.it.

Spontaneously hypertensive rats (SHR) are characterized by impaired erectile function and by overactivity of the pro-contractile RhoA/Rho-kinase (RhoA/ROCK) pathway, as compared to their normotensive counterpart, Wistar Kyoto rats. By measuring intracavernous pressure/mean arterial pressure (ICP/MAP) ratio after electrostimulation of the cavernous nerve, we confirmed these findings and showed that also responsiveness to sildenafil (25 mg/kg by oral gavage) is hampered in SHR. A two-week treatment with atorvastatin (5 and 30 mg/kg) improved sildenafil-induced ICP/MAP increase and normalized RhoA and ROCK2 over-expression (qRT-PCR) in SHR corpora cavernosa (CC). Conversely, other genes, nNOS, eNOS and PDE5, were unaffected. In human foetal smooth muscle cells derived from CC (hfPSMC), atorvastatin inhibited RhoA membrane translocation and ROCK activity as well as RhoA-dependent biological functions, like cell migration and proliferation. Atorvastatin effect on migration was dose-dependently rescued by geranylgeranyl pyrophosphate, suggesting the involvement of RhoA geranylgeranylation. In hfPSMC, atorvastatin decreased the expression of RhoA-dependent genes as ROCK2, desmin, alfa-smooth muscle actin, SM22alfa and myocardin. In contrast to atorvastatin, elocalcitol, a vitamin D analogue, which also interferes with RhoA activation in SHR bladder, was unable to restore penile responsiveness to sildenafil. In conclusion, atorvastatin, but not elocalcitol, ameliorates sildenafil-induced penile erections in SHR rats, likely by interfering with RhoA/ROCKs signaling within the penis.


Key words: Erectile Dysfunction • Phosphodiesterase 5 inhibitor • RhoA-dependent genes • SHR rat model • human penile smooth muscle cells






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Copyright © 2007 by The American Society of Andrology.