Long-term oral treatment with BAY 41-2272 ameliorates impaired corpus cavernosum relaxations in a nitric oxide-deficient rat model.
OBJECTIVE
• To investigate the potential beneficial effects of 4-week oral treatment with 5-cyclopropyl-2-[1-(2-fluoro-benzyl)-1Hpyrazolo[3,4-b]pyridin-3-yl]-pyrimidin-4-ylamine (BAY 41-2272), a nitric oxide (NO)-independent soluble guanylate cyclase activator, on impaired rat corpus cavernosum relaxations in NO-deficient rats.


METHODS
• Male Wistar rats were divided into four groups: Control, N (G)-nitro-L- arginine methyl ester (L-NAME; 20 mg/rat/day), BAY 41-2272 (20 mg/kg/day) and L-NAME + BAY 41-2272. • Rats were treated with L-NAME concomitantly with BAY 41-2272 for 4 weeks. • Concentration-response curves to acetylcholine (ACh) and sodium nitroprusside (SNP), along with the nitrergic relaxations (1-32 Hz) were obtained in rat corpus cavernosum (RaCC). • The RaCC contractile responses to the α₁ -adrenoceptor agonist phenylephrine (PE) were obtained.


RESULTS
• Acetylcholine (0.01-1000 µmol/L) produced concentration-dependent relaxing responses in RaCC that were significantly enhanced (P < 0.05) in BAY 41-2272-treated rats. • The ACh-induced relaxations were largely reduced in L-NAME-treated rats, and co-treatment with BAY 41-2272 failed to significantly modify these impaired relaxations. • The SNP-induced relaxations were modified neither by L-NAME nor by co-treatment with BAY 41-2272. • The nitrergic relaxations were significantly amplified in BAY 41-2272-treated rats (at 16 and 32 Hz). A significant reduction in the nitrergic relaxations was observed in L-NAME-treated rats, an effect largely restored by co-treatment with BAY 41-2272. • The contractile RaCC responses produced by PE (0.001-100 µmol/L) were significantly higher (P < 0.05) in L-NAME-treated rats, and co-treatment of L-NAME with BAY 41-2272 nearly restored these enhanced contractile responses.


CONCLUSIONS
• Four-week therapy with BAY 41-2272 prevents the impaired corpus cavernosum relaxations of rats treated chronically with L-NAME, indicating that accumulation of cyclic guanosine monophosphate into erectile tissue counteracts the NO deficiency.
Claudino
Mário A
MA
Department of Pharmacology, Faculty of Medical Sciences, University of Campinas (UNICAMP), Campinas (Sao Paulo), Brazil.
da Silva
Fabio H
FH
Mónica
Fabíola Z T
FZ
Rojas-Moscoso
Julio A
JA
De Nucci
Gilberto
G
Antunes
Edson
E
D000818:Animals; D006152:Cyclic GMP / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D007172:Erectile Dysfunction / Q000188:drug therapy* / Q000503:physiopathology; D006162:Guanylate Cyclase / Q000378:metabolism; D008297:Male; D009125:Muscle Relaxants, Central / Q000494:pharmacology*; D019331:NG-Nitroarginine Methyl Ester / Q000627:therapeutic use; D009569:Nitric Oxide / Q000172:deficiency*; D010410:Penile Erection / Q000187:drug effects* / Q000502:physiology; D011720:Pyrazoles / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar
C423582:3-(4-Amino-5-cyclopropylpyrimidine-2-yl)-1-(2-fluorobenzyl)-1H-pyrazolo(3,4-b)pyridine; D004791:Enzyme Inhibitors; D009125:Muscle Relaxants, Central; D011720:Pyrazoles; D011725:Pyridines; D009569:Nitric Oxide; D006162:Guanylate Cyclase; D006152:Cyclic GMP; D019331:NG-Nitroarginine Methyl Ester