Sildenafil inhibits superoxide formation and prevents endothelial dysfunction in a mouse model of secondhand smoke induced erectile dysfunction.
OBJECTIVE
We determined the effect of passive secondhand cigarette smoke on 1) erectile function in vivo, 2) molecular mechanisms involved in penile vascular function, and 3) erectile function and penile molecular signaling in the presence of phosphodiesterase type 5 inhibitor therapy.


METHODS
Four groups of mice were used, including group 1--controls, group 2--mice exposed to 3 weeks of secondhand smoke (5 hours per day for 5 days per week), group 3--control plus sildenafil (100 mg/kg per day) and group 4--smoke exposed plus sildenafil (100 mg/kg per day). Cavernous nerve electrical stimulation and intracavernous injection of acetylcholine were done to assess erectile function. Constitutive and inducible nitric oxide synthase activity, reactive oxygen species generation, nitrotyrosine formation and superoxide anion levels were assessed.


RESULTS
Decreased erectile responses to cavernous nerve electrical stimulation and impaired endothelium dependent erectile responses to ACh in mice exposed to secondhand smoke were observed. Superoxide anion was increased in endothelial and corporeal smooth muscle cells of smoking mouse penises. In mice exposed to secondhand smoke constitutive nitric oxide synthase activity was decreased, and inducible nitric oxide synthase activity, reactive oxygen species generation and nitrotyrosine formation increased. Sildenafil therapy restored constitutive nitric oxide synthase activity in the penis of smoking mice, decreased inducible nitric oxide synthase activity, reactive oxygen species generation and nitrotyrosine formation, and improved erectile responses to cavernous nerve electrical stimulation and acetylcholine.


CONCLUSIONS
Short-term exposure to secondhand smoke impairs erectile function through excessive penile reactive oxygen species signaling and inducible nitric oxide synthase activity. Decreased penile constitutive nitric oxide synthase activity may be attributable to the decreased endothelial nitric oxide synthase activity resulting from increased oxidative stress. Sildenafil therapy restored nitric oxide synthase activity and decreased reactive oxygen species signaling, resulting in improved erectile function.
Bivalacqua
Trinity J
TJ
Department of Urology, The Johns Hopkins Medical Institution, The James Buchanan Brady Urological Institute, Baltimore, Maryland 21287, USA. tbivala1@jhmi.edu
Sussan
Thomas E
TE
Gebska
Melina A
MA
Strong
Travis D
TD
Berkowitz
Dan E
DE
Biswal
Shyam
S
Burnett
Arthur L
AL
Champion
Hunter C
HC
D000284:Administration, Oral; D000818:Animals; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D007172:Erectile Dysfunction / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019001:Nitric Oxide Synthase / Q000187:drug effects / Q000378:metabolism*; D010410:Penile Erection / Q000187:drug effects / Q000502:physiology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D011687:Purines / Q000494:pharmacology; D011897:Random Allocation; D017382:Reactive Oxygen Species / Q000378:metabolism; D012016:Reference Values; D012680:Sensitivity and Specificity; D015398:Signal Transduction; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000494:pharmacology*; D013481:Superoxides / Q000378:metabolism*; D014028:Tobacco Smoke Pollution / Q000009:adverse effects
D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D017382:Reactive Oxygen Species; D013450:Sulfones; D014028:Tobacco Smoke Pollution; D013481:Superoxides; D000068677:Sildenafil Citrate; D019001:Nitric Oxide Synthase