Chronic sildenafil improves erectile function and endothelium-dependent cavernosal relaxations in rats: lack of tachyphylaxis.
OBJECTIVE
Sildenafil is a widely-prescribed effective on-demand treatment of erectile dysfunction (ED). Chronic treatment with sildenafil could help patients with ED.


METHODS
The effects of an 8-week long treatment with sildenafil (60 mg/kg/d sc) in male Sprague Dawley rats were evaluated on electrically-elicited erectile responses in vivo before and after an acute injection of sildenafil (0.3mg/kg iv). In addition, endothelium-dependent and -independent relaxations of strips of corpus cavernosum in vitro were examined. All experiments were performed 36 hours after the last injection of sildenafil.


RESULTS
Endothelium-dependent relaxations of cavernosal strips to acetylcholine were enhanced after chronic treatment with sildenafil while relaxations to A23187 or sodium nitroprusside were unchanged. Frequency-dependent erectile responses elicited by cavernous nerve stimulation were significantly improved. Moreover, the erectile responses to acute sildenafil were greater in chronically-treated rats with sildenafil.


CONCLUSIONS
This is the first report providing experimental support for chronic dosing with sildenafil which could be of use for patients that are poor responders to on-demand treatment. Chronic sildenafil may regulate the transduction pathway leading to the activation of eNOS but has no effect on NO bioavailability or on the cGMP pathway, thereby eliminating a possible concern for tachyphylaxis.
Behr-Roussel
Delphine
D
Pelvipharm, Domaine CNRS, 1 Avenue de la terrasse, Bâtiment 5, 91190 Gif sur Yvette, France.
Gorny
Diane
D
Mevel
Katell
K
Caisey
Stéphanie
S
Bernabé
Jacques
J
Burgess
Gillian
G
Wayman
Chris
C
Alexandre
Laurent
L
Giuliano
François
F
D000818:Animals; D004730:Endothelium, Vascular / Q000187:drug effects; D007172:Erectile Dysfunction / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects; D010410:Penile Erection / Q000187:drug effects*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D011687:Purines; D051381:Rats; D017207:Rats, Sprague-Dawley; D000068677:Sildenafil Citrate; D013450:Sulfones; D013618:Tachyphylaxis
D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D000068677:Sildenafil Citrate