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 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. CONCLUSIONS: We report that a nonNO based soluble guanylate cyclase activator relaxes human and rabbit corpus cavernosum, and potentiates nitrergic responses.
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 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. CONCLUSIONS: We report that a nonNO based soluble guanylate cyclase activator relaxes human and rabbit corpus cavernosum, and potentiates nitrergic responses.
Authors: Oleg V Evgenov; Pál Pacher; Peter M Schmidt; György Haskó; Harald H H W Schmidt; Johannes-Peter Stasch Journal: Nat Rev Drug Discov Date: 2006-09 Impact factor: 84.694
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