title: eNOS-uncoupling in age-related erectile dysfunction.
abstract: Aging is associated with ED. Although age-related ED is attributed largely to increased oxidative stress and endothelial dysfunction in the penis, the molecular mechanisms underlying this effect are not fully defined. We evaluated whether endothelial nitric oxide synthase (eNOS) uncoupling in the aged rat penis is a contributing mechanism. Correlatively, we evaluated the effect of replacement with eNOS cofactor tetrahydrobiopterin (BH(4)) on erectile function in the aged rats. Male Fischer 344 'young' (4-month-old) and 'aged' (19-month-old) rats were treated with a BH(4) precursor sepiapterin (10 mg/kg intraperitoneally) or vehicle for 4 days. After 1-day washout, erectile function was assessed in response to electrical stimulation of the cavernous nerve. Endothelial dysfunction (eNOS uncoupling) and oxidative stress (thiobarbituric acid reactive substances, TBARS) were measured by conducting western blot in penes samples. Erectile response was significantly reduced in aged rats, whereas eNOS uncoupling and TBARS production were significantly increased in the aged rat penis compared with young rats. Sepiapterin significantly improved erectile response in aged rats and prevented increase in TBARS production, but did not affect eNOS uncoupling in the penis of aged rats. These findings suggest that aging induces eNOS uncoupling in the penis, resulting in increased oxidative stress and ED.
authors.affiliation: Department of Urology, The Johns Hopkins University, Baltimore, MD 21287, USA.
authors.forename: J M
authors.initials: JM
authors.lastname: Johnson
authors.forename: T J
authors.initials: TJ
authors.lastname: Bivalacqua
authors.forename: G A
authors.initials: GA
authors.lastname: Lagoda
authors.forename: A L
authors.initials: AL
authors.lastname: Burnett
authors.forename: B
authors.initials: B
authors.lastname: Musicki
mesh_terms: D000375:Aging / Q000378:metabolism; D000818:Animals; D007172:Erectile Dysfunction / Q000188:drug therapy / Q000201:enzymology*; D008297:Male; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D018384:Oxidative Stress; D010410:Penile Erection / Q000187:drug effects; D010413:Penis / Q000187:drug effects / Q000378:metabolism; D011622:Pterins / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D011916:Rats, Inbred F344; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism
chemical_list: D011622:Pterins; D017392:Thiobarbituric Acid Reactive Substances; C016727:sepiapterin; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat