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

Abstract

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. 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). 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 microM. 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 microM. 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 microM. BAY41-2272. We report that a nonNO based soluble guanylate cyclase activator relaxes human and rabbit corpus cavernosum, and potentiates nitrergic responses.