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- Title
Pharmacological characterisation of the relaxation induced by the soluble guanylate cyclase activator, BAY 60-2770 in rabbit corpus cavernosum.
- Authors
Estancial, Camila S.; Rodrigues, Renata L.; De Nucci, Gilberto; Antunes, Edson; Mónica, Fabiola Z.
- Abstract
Objective To characterise the relaxation induced by the soluble guanylate cyclase ( sGC) activator, BAY 60-2770 (4-({(4-carboxybutyl) [2- (5-fluoro-2-{[4′-(trifluoromethyl) biphenyl-4-yl]methoxy}phenyl)ethyl] amino}methyl)benzoic acid) in rabbit corpus cavernosum ( CC). Material and Methods The penis from male New Zealand rabbits was removed and fours strips of CC were obtained. Concentration-response curves to BAY 60-2770 were constructed in the absence and presence of inhibitors of nitric oxide synthase, N (G)-nitro-L- arginine methyl ester (L- NAME, 100 μ m), sGC, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one ( ODQ, 10 μ m) and phosphodiesterase type 5 ( PDE-5), tadalafil (0.1 μ m). The potency ( pEC50) and maximal response ( Emax) values were determined. Then, electrical-field stimulation ( EFS)-induced contraction or relaxation was tested in the absence and presence of BAY 60-2770 (0.1 or 1 μ m) alone or combined with ODQ (10 μ m). For EFS-induced relaxation two protocols were used: (i) ODQ (10 μ m) was first incubated for 20 min and then BAY 60-2770 (1 μ m) was added for another 20 min ( ODQ + BAY 60-2770); (ii) in different CC strips, BAY 60-2770 was incubated for 20 min followed by another 20 min with ODQ ( BAY 60-2770 + ODQ). The intracellular levels of cyclic guanosine monophosphate ( cGMP) were also determined. Results BAY 60-2770 potently relaxed rabbit CC with mean ( sem) pEC50 and Emax values of 7.58 (0.19) and 81 (4)%, respectively. The inhibitors ODQ ( n = 7) or tadalafil ( n = 7) produced 4.2- and 6.3-leftward shifts, respectively in BAY 60-2770-induced relaxation without interfering with the Emax values. The intracellular levels of cGMP were augmented after stimulation with BAY 60-2770 (1 μ m) alone, whereas its co-incubation with ODQ produced even higher levels of cGMP. The EFS-induced contraction was reduced in the presence of BAY 60-2770 (1 μ m) and this inhibition was even greater when BAY 60-2770 was co-incubated with ODQ. The nitrergic stimulation induced CC relaxation, which was abolished in the presence of ODQ. BAY 60-2770 alone increased the amplitude of relaxation. Co-incubation of ODQ and BAY 60-2770 did not alter the relaxation in comparison with ODQ alone. Interestingly, when BAY 60-2770 was incubated before ODQ, EFS-induced relaxation was partly restored in comparison with ODQ alone or ODQ + BAY 60-2770. Conclusions The relaxation induced by the sGC activator, BAY 60-2770 was increased after sGC oxidation and unaltered in the absence of nitric oxide. Thus, this class of substances may have advantages over sGC stimulators or PDE-5 inhibitors for treating patients with erectile dysfunction and extensive endothelial damage.
- Subjects
GUANYLATE cyclase; TRIFLUOROMETHYL compounds; METHOXY compounds; BENZOIC acid; NITRIC oxide synthesis
- Publication
BJU International, 2015, Vol 116, Issue 4, p657
- ISSN
1464-4096
- Publication type
Article
- DOI
10.1111/bju.13105