Vas deferens smooth muscle responses to the nitric oxide-independent soluble guanylate cyclase stimulator BAY 41-2272.
The nitric oxide-cGMP signaling pathway modulates the ejaculatory functions. The nitric oxide (NO)-independent soluble guanylate cyclase haem-dependent stimulator BAY 41-2272 potently relaxes different types of smooth muscles. However, no study investigated its effects in vas deferens smooth muscle. Therefore, we designed experiments to evaluate the in vitro relaxing responses of vas deferens to BAY 41-2272. The effects of prolonged oral intake with BAY 41-2272 in vas deferens contractions of rats treated chronically with the NO synthase inhibitor N(ω)-nitro-L-arginine methyl ester (L-NAME) were also investigated. BAY 41-2272 (0.001-100 μM) produced concentration-dependent relaxations in the prostatic and epididymal portions of vas deferens, an effect markedly reduced by the soluble guanylate cyclase inhibitor ODQ (100 μM). BAY 41-2272 significantly increased cGMP levels that were fully prevented by ODQ. In separate protocols, rats received L-NAME (20mg/rat/day) concomitantly with BAY 41-2272 (10mg/kg/day, 4 weeks), after which vas deferens contractions to electrical-field stimulation and noradrenaline were achieved. Electrical-field stimulation (1-32 Hz) evoked frequency-dependent contractions that were significantly enhanced in L-NAME-treated rats. Co-treatment with BAY 41-2272 fully reversed the increased contractile responses in L-NAME group. Noradrenaline (0.01-100 μM)-induced contractions were also greater in L-NAME-treated rats, and that was normalized by BAY 41-2272. In conclusion, BAY 41-2272 potently relaxes in vitro rat vas deferens smooth muscle and elevates the cGMP levels in an ODQ-sensitive manner. Moreover, prolonged oral intake with BAY 41-2272 restores the enhanced contractile vas deferens activity in rats treated with L-NAME. NO-independent soluble guanylate cyclase stimulators may be an alternative treatment for premature ejaculation.
Department of Pharmacology, Faculty of Medical Sciences, University of Campinas (UNICAMP), Campinas, SP, Brazil.
Fábio H
FH
da Silva
Mário A
MA
Claudino
Fernando R
FR
Báu
Julio A
JA
Rojas-Moscoso
Fabíola Z
FZ
Mónica
Gilberto
G
De Nucci
E
E
Antunes
D000818:Animals; D006152:Cyclic GMP / Q000096:biosynthesis; D004558:Electric Stimulation; D006162:Guanylate Cyclase; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology*; D009569:Nitric Oxide / Q000378:metabolism; D009638:Norepinephrine / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists*; D000071756:Soluble Guanylyl Cyclase; D013997:Time Factors; D014649:Vas Deferens / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology*
C423582:3-(4-Amino-5-cyclopropylpyrimidine-2-yl)-1-(2-fluorobenzyl)-1H-pyrazolo(3,4-b)pyridine; D011720:Pyrazoles; D011725:Pyridines; D018160:Receptors, Cytoplasmic and Nuclear; D009569:Nitric Oxide; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase; D006152:Cyclic GMP; D009638:Norepinephrine