| dc.description | 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-Larginine methyl ester (L-NAME, 100 mu M), sGC, 1H-[1,2,4] oxadiazolo[4,3-a] quinoxalin-1-one (ODQ, 10 mu M) and phosphodiesterase type 5 (PDE-5), tadalafil (0.1 mu M). The potency (pEC(50)) and maximal response (E-max) 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 mu M) alone or combined with ODQ (10 mu M). For EFS-induced relaxation two protocols were used: (i) ODQ (10 mu M) was first incubated for 20 min and then BAY 60-2770 (1 mu M) was added for another 20 min (ODQ + BAY 60-2770); (ii) in different CC strips, BAY 602770 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) pEC(50) and E-max 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 E-max values. The intracellular levels of cGMP were augmented after stimulation with BAY 60-2770 (1 mu 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 mu 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. | |
