Journal of Andrology
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Published-Ahead-of-Print August 15, 2007, DOI:10.2164/jandrol.107.003152
Journal of Andrology, Vol. 29, No. 1, January/February 2008
Copyright © American Society of Andrology
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{dagger}, XIN-HUA ZHANG*, ROSA MANCINA*, LINDA VIGNOZZI*, SANDRA FILIPPI{ddagger}, ARAVINDA CHAVALMANE*, ENRICO SILVESTRINI*, ENRICO COLLI§, LUCIANO ADORINI§, GABRIELLA BARBARA VANNELLI{dagger} AND MARIO MAGGI*

From the * Andrology Unit, Department of Physiopathology, Center for Research, Transfer and High Education DENOTHE, the {dagger} Department of Anatomy, Histology and Forensic Medicine, and the {ddagger} Interdepartmental Laboratory of Functional and Cellular Pharmacology of Reproduction, Departments of Pharmacology and Clinical Physiopathology, University of Florence, Florence, Italy; and § Bioxell, Milan, Italy.

Correspondence to: Dr Mario Maggi, Andrology Unit, Department of Clinical Physiopathology, University of Florence, V.le G. Pieraccini, 6, 50139 Florence, Italy (e-mail: m.maggi{at}dfc.unifi.it).


Spontaneously hypertensive rats (SHR) are characterized by impaired erectile function and overactivity of the procontractile RhoA/Rho-associated, coiled-coil–containing protein kinase (RhoA/ROCK) pathway, as compared with their normotensive counterpart, Wistar-Kyoto rats. By measuring the intracavernous pressure:mean arterial pressure (ICP:MAP) ratio after electrostimulation of the cavernous nerve, we confirmed these findings and showed that responsiveness to sildenafil (25 mg/kg by oral gavage) also is hampered in SHR. A 2-week treatment with atorvastatin (5 and 30 mg/kg) improved the sildenafil-induced ICP:MAP increase and normalized RhoA and ROCK2 overexpression in SHR corpora cavernosa (CC). Conversely, other genes, neuronal nitric oxide synthase (NOS), endothelial NOS, and phosphodiesterase 5, were unaffected. In human fetal smooth muscle cells derived from CC (hfPSMC), atorvastatin inhibited RhoA membrane translocation and ROCK activity, as well as RhoA-dependent biologic functions like cell migration and cell proliferation. Atorvastatin's effect on migration was rescued in a dose-dependent manner by geranylgeranyl pyrophosphate, suggesting the involvement of RhoA geranylgeranylation. In hfPSMC, atorvastatin decreased the expression of RhoA-dependent genes such as ROCK2, desmin, {alpha}-smooth muscle actin, SM22{alpha}, and myocardin. In contrast to atorvastatin, elocalcitol, a vitamin D analog that 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, likely by interfering with RhoA/ROCK signaling within the penis.

     Key words: Erectile dysfunction, phosphodiesterase 5 inhibitor, human penile smooth muscle cells, RhoA-dependent genes, SHR model






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Copyright © 2008 by The American Society of Andrology.