title: Long-term continuous treatment with sildenafil ameliorates aging-related erectile dysfunction and the underlying corporal fibrosis in the rat.
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.
authors.affiliation: Division of Urology, Harbor-UCLA Medical Center, Torrance, California 90502, USA.
authors.forename: M G
authors.initials: MG
authors.lastname: Ferrini
authors.forename: I
authors.initials: I
authors.lastname: Kovanecz
authors.forename: S
authors.initials: S
authors.lastname: Sanchez
authors.forename: D
authors.initials: D
authors.lastname: Vernet
authors.forename: H H
authors.initials: HH
authors.lastname: Davila
authors.forename: J
authors.initials: J
authors.lastname: Rajfer
authors.forename: N F
authors.initials: NF
authors.lastname: Gonzalez-Cadavid
mesh_terms: D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000037:antagonists & inhibitors; D000375:Aging / Q000502:physiology*; D000818:Animals; D015153:Blotting, Western; D003094:Collagen / Q000378:metabolism; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D007172:Erectile Dysfunction / Q000188:drug therapy* / Q000473:pathology*; D005355:Fibrosis; D005837:Genitalia, Male / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008297:Male; D009130:Muscle, Smooth / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis / Q000235:genetics; D018384:Oxidative Stress / Q000502:physiology; D010413:Penis / Q000166:cytology / Q000378:metabolism; D010726:Phosphodiesterase Inhibitors / Q000627:therapeutic use*; D010879:Piperazines / Q000627:therapeutic use*; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D011687:Purines / Q000627:therapeutic use; D051381:Rats; D011916:Rats, Inbred F344; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000627:therapeutic use*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D018809:Proliferating Cell Nuclear Antigen; D011687:Purines; D013450:Sulfones; D003094:Collagen; D000068677:Sildenafil Citrate; D052247:Nitric Oxide Synthase Type II; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C517384:Pde5a protein, rat