QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: mol.104.010678v1 68/1/226    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Musicki, B. Articles by Burnett, A. L. Search for Related Content PubMed PubMed Citation Articles by Musicki, B. Articles by Burnett, A. L.

Erection Capability Is Potentiated by Long-Term Sildenafil Treatment: Role of Blood Flow-Induced Endothelial Nitric-Oxide Synthase Phosphorylation

Departments of Urology (B.M., R.E.B., T.L., M.F.K., A.L.B.) and Cardiology (H.C.C.), The Johns Hopkins Hospital, Baltimore, Maryland

Despite demonstrated clinical efficacy of sildenafil for the temporary treatment of erectile dysfunction, the possibility that sildenafil used long-term durably augments erectile ability remains unclear. We investigated whether continuous long-term administration of sildenafil at clinically relevant levels to aged rats "primes" the penis for improved erectile ability and involves nitric oxide (NO) or RhoA/Rho-kinase signaling pathways. In aged, but not young rats, sildenafil prolonged erection and increased the protein expressions of phosphorylated endothelial NO synthase (eNOS) at serine-1177 and phosphorylated Akt at serine-473 in penes. Only in the young rat penis, protein expressions of phosphodiesterase-5 and phosphomyosin phosphatase target subunit 1, a marker of Rho-kinase activity, were increased by sildenafil. Sildenafil inhibited phosphodiesterase-5 activity in penes of young and aged rats coincident with assayed free plasma levels of the drug equivalent to clinically therapeutic measurements. We conclude that erectile ability can be enhanced under preconditions of erectile impairment by long-term inhibition of phosphodiesterase-5 and that the effect is mediated by Akt-dependent eNOS phosphorylation. The lack of erectile ability enhancement in young rats by long-term phosphodiesterase-5 inhibition may relate to restrained NO signaling by phosphodiesterase-5 up-regulation, lack of incremental Akt and eNOS phosphorylation, and heightened Rho-kinase signaling in the penis.

Address correspondence to: Dr. Biljana Musicki, Department of Urology, Johns Hopkins Hospital, Marburg 405, 600 North Wolfe St., Baltimore, MD 21287. E-mail: bmusicki{at}jhmi.edu

This article has been cited by other articles:

				A. L. Burnett Molecular Pharmacotherapeutic Targeting of PDE5 for Preservation of Penile Health J Androl, January 1, 2008; 29(1): 3 - 14. [Abstract] [Full Text] [PDF]

				M.G. Ferrini, I. Kovanecz, S. Sanchez, D. Vernet, H.H. Davila, J. Rajfer, and N.F. Gonzalez-Cadavid Long-Term Continuous Treatment with Sildenafil Ameliorates Aging-Related Erectile Dysfunction and the Underlying Corporal Fibrosis in the Rat Biol Reprod, May 1, 2007; 76(5): 915 - 923. [Abstract] [Full Text] [PDF]

				T. J. Bivalacqua, A. L. Burnett, W. J. G. Hellstrom, and H. C. Champion Overexpression of arginase in the aged mouse penis impairs erectile function and decreases eNOS activity: influence of in vivo gene therapy of anti-arginase Am J Physiol Heart Circ Physiol, March 1, 2007; 292(3): H1340 - H1351. [Abstract] [Full Text] [PDF]

				B. Musicki and A. L. Burnett eNOS Function and Dysfunction in the Penis Experimental Biology and Medicine, February 1, 2006; 231(2): 154 - 165. [Abstract] [Full Text] [PDF]