BAY41-2272, a novel nitric oxide independent soluble guanylate cyclase activator, relaxes human and rabbit corpus cavernosum in vitro

Purpose: In cavernous smooth muscle nitric oxide (NO) activates soluble guanylate cyclase, which catalyzes the synthesis of cyclic guanosine 3′,5′-monophosphate, leading to smooth muscle relaxation, increased blood flow and penile erection. The pyrazolopyridine derivative BAY41-2272 (5-cyclopropyl-2-[1-(2-fluoro-benzyl)-1H-pyrazolo[3,4-b]pyridine-3-yl] pyrimidin-4ylamine) was identified and found to stimulate soluble guanylate cyclase in a NO independent manner. We investigated the effect of BAY41-2272 on human and rabbit corpus cavernosum. Materials and Methods: We investigated the effect of BAY41-2272 on the tone and nitrergic relaxation responses of human and rabbit cavernous strips in the absence and presence of the soluble guanylate cyclase inhibitor ODQ (1H-[1,2,4]oxadiazolo[4-3a]quinoxalin-1-one) or the NO synthase inhibitor L-NAME (N-nitro-L-arginine-methyl ester Hcl). The potency of BAY41-2272 was compared to that of another soluble guanylate cyclase activator YC-1, and the NO releasing compound spermine NONOate (N-2-aminoethyl-N-2-hydroxy-2-nitrosohydroazino-1,2-ethylenediamine). Results: BAY41-2272 resulted in concentration dependent relaxation of human and rabbit cavernosum (mean EC50 ± SEM 489.1 22.5 and 406.3 ± 21.5 Nm., respectively). The compound was 32 times more potent than YC-1 and twice as potent as spermine-NONOate. ODQ decreased the potency of BAY41-2272, such that in the presence of 30 μM. ODQ the EC50 of BAY41-2272 induced relaxation was 1,407.3 ± 158.0 and 1,902.7 ± 11.0 Nm. in human and rabbit tissues, respectively. L-NAME also inhibited relaxations elicited by BAY41-2272 in rabbit tissue. In the presence of 500 μM. L-NAME the EC50 of BAY41-2272 induced responses was 836.7 ± 46.7 Nm. BAY41-2272 at subthreshold concentrations of 30 to 50 Nm. potentiated nitrergic responses. Moreover, the inhibition of nitrergic responses by L-NAME was reversed by 0.3 to 3 μM. BAY41-2272. Conclusions: We report that a nonNO based soluble guanylate cyclase activator relaxes human and rabbit corpus cavernosum, and potentiates nitrergic responses.