title: BAY41-2272, a novel nitric oxide independent soluble guanylate cyclase activator, relaxes human and rabbit corpus cavernosum in vitro.
abstract: OBJECTIVE
  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.
  
  
  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.affiliation: Wolfson Institute for Biomedical Research, University College London, United Kingdom.
authors.forename: Jas S
authors.initials: JS
authors.lastname: Kalsi
authors.forename: Rowland W
authors.initials: RW
authors.lastname: Rees
authors.forename: Adrian J
authors.initials: AJ
authors.lastname: Hobbs
authors.forename: Michael
authors.initials: M
authors.lastname: Royle
authors.forename: Phil D
authors.initials: PD
authors.lastname: Kell
authors.forename: David J
authors.initials: DJ
authors.lastname: Ralph
authors.forename: Salvador
authors.initials: S
authors.lastname: Moncada
authors.forename: Selim
authors.initials: S
authors.lastname: Cellek
mesh_terms: D000818:Animals; D006162:Guanylate Cyclase / Q000009:adverse effects / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects*; D009130:Muscle, Smooth / Q000187:drug effects* / Q000502:physiology*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D010069:Oxadiazoles / Q000494:pharmacology; D010413:Penis / Q000187:drug effects* / Q000502:physiology*; D011720:Pyrazoles / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D011810:Quinoxalines / Q000494:pharmacology; D011817:Rabbits
chemical_list: C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; C423582:3-(4-Amino-5-cyclopropylpyrimidine-2-yl)-1-(2-fluorobenzyl)-1H-pyrazolo(3,4-b)pyridine; D010069:Oxadiazoles; D011720:Pyrazoles; D011725:Pyridines; D011810:Quinoxalines; D019001:Nitric Oxide Synthase; D006162:Guanylate Cyclase; D019331:NG-Nitroarginine Methyl Ester