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Division of Urology,3 Urology Research Laboratory, Los Angeles Biomedical Research Institute,4 Harbor-UCLA Medical Center, Torrance, California 90502
Department of Urology,5 David Geffen School of Medicine at UCLA, Los Angeles, California 90095
ABSTRACT
Aging-related erectile dysfunction is characterized by a loss of smooth muscle cells (SMCs) and fibrosis in the corpora cavernosa, and functionally by corporal veno-occlusive dysfunction (CVOD). Phosphodiesterase 5 (PDE5A) inhibitors, in part via upregulating inducible nitric oxide synthase (NOS2A), have antifibrotic properties in penile tissues. We aimed to determine whether in the aged rat the chronic long-term treatment with sildenafil ameliorates corporal SMC loss and fibrosis, stimulates NOS2A induction, and corrects the associated CVOD. Aged male rats (20 mo old) received sildenafil in their drinking water (20 mg/kg per day) or plain water for 45 days, and untreated young rats (5 mo old) served as controls (n = 8 per group). CVOD was assessed by dynamic infusion cavernosometry (DIC). Collagen:SMC (Masson trichrome) and collagen III:I (picrosirius red) ratios, SMC content (alpha-smooth muscle actin [ACTA2]), cell proliferation (proliferating nuclear antigen [PCNA]), apoptotic death (TUNEL), and NOS2A induction were measured by histochemistry and immunohistochemistry followed by quantitative image analysis. Collagen content was determined by hydroxyproline assay, and transforming growth factor beta-1 (TGFB1); xanthine oxidoreductase (XDH); ACTA2; NOS2A; and the Rho kinase inhibitor protein tyrosine phosphatase, nonreceptor type 11 (PTPN11), and activator, VAV, were measured by quantitative Western blot. In the aged rats treated with sildenafil, the erectile response by DIC was normalized, and the corporal SMC:collagen ratio and SMC number were increased. In addition, sildenafil reduced the corporal collagen content without affecting the collagen III:I ratio, increased the PCNA:apoptosis ratio, and stimulated NOS2A induction, although there was no effect on XDH, TGFB1, PTPN11, or VAV levels. These data show that long-term PDE5A treatment corrected CVOD in the aged rat and partially reversed the aging-related fibrosis and loss of SMC in the corpora cavernosa without affecting TGFB1 or PTPN11 levels, which are markers of oxidative stress. It may be speculated that similar effects may be achieved with this paradigm in men.
aging,, apoptosis, cGMP, collagen, corporal veno-occlusive dysfunction, inducible nitric oxide synthase, nitric oxide, PDE5A inhibitors, penis, phosphodiesterases, ROS, smooth muscle, TGFB1
1Supported by investigator-initiated research grants from Pfizer Corporation and National Institutes of Health (NIH) grant R01DK-53069 and, in certain aspects, NIHG12RR-03026. M.G.F. also is supported by grant N1 P20 MD000545 from the National Center on Minority Health and Health Disparities at the NIH.
Correspondence: 2Nestor F. Gonzalez-Cadavid, LA BioMed at Harbor-UCLA Medical Center, Urology Research Laboratory, Bldg. F-6, 1124 West Carson St., Torrance, CA 90502. FAX: 310 222 1914; e-mail: ncadavid{at}ucla.edu
This article has been cited by other articles:
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  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]
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