BAY 41-2272: a stimulator of soluble guanylyl cyclase induces nitric oxide-dependent penile erection in vivo.
OBJECTIVE
To determine the effectiveness of BAY 41-2272 on penile erections in an in vivo rabbit model. The nitric oxide (NO)-dependent increase of intracellular cyclic guanosine monophosphate (cGMP) by cGMP-phosphodiesterase (PDE5) inhibition has been shown to be an effective mechanism in the treatment of erectile dysfunction. Direct, NO-independent stimulation of soluble guanylyl cyclase should also lead to elevated cGMP levels in tissues and could be an attractive alternative therapeutic option for the treatment of erectile dysfunction. BAY 41-2272 is a novel non-NO-based direct stimulator of soluble guanylyl cyclase that activates purified enzyme in a synergistic fashion with NO.


METHODS
BAY 41-2272 was administered to conscious rabbits intravenously (IV) and orally (PO). Erection was assessed in a time-dependent manner by measuring the length of the uncovered penile mucosa. Erections were evaluated in the absence and presence of NO (with intravenous sodium nitroprusside [SNP] as the NO donor).


RESULTS
BAY 41-2272 only induced weak penile erections in conscious rabbits after IV (1 mg/kg) and PO (10 mg/kg) administration in the absence of an NO donor. However, the efficacy of BAY 41-2272 was potentiated by the simultaneous administration of SNP. Through simultaneous SNP administration, the effective doses of BAY 41-2272 were reduced significantly (minimal effective dose 0.1 mg/kg IV and 1 mg/kg PO).


CONCLUSIONS
The results of this study clearly demonstrated the effect of BAY 41-2272 on penile erection in the conscious rabbit model after PO and IV administration. The time-course and onset of erection was concurrent with the stimulation by exogenous NO (SNP), suggesting that this new pharmacologic mechanism of soluble guanylyl cyclase stimulation could be used in the treatment of erectile dysfunction. Because the effect is increased by SNP, it can be expected that BAY 41-2272 would have enhanced activity during sexual arousal, when NO is produced endogenously.
Bischoff
E
E
Institute of Cardiovascular Research, Bayer AG, Pharmaceutical Business Group, Wuppertal, Germany.
Schramm
M
M
Straub
A
A
Feurer
A
A
Stasch
J-P
JP
D000284:Administration, Oral; D000818:Animals; D004305:Dose-Response Relationship, Drug; D006162:Guanylate Cyclase / Q000187:drug effects* / Q000502:physiology; D007275:Injections, Intravenous; D008297:Male; D023421:Models, Animal; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D009569:Nitric Oxide / Q000008:administration & dosage / Q000494:pharmacology*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D010410:Penile Erection / Q000187:drug effects* / Q000502:physiology; D010413:Penis / Q000098:blood supply / Q000187:drug effects / Q000502:physiology; D011720:Pyrazoles / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D011817:Rabbits
C423582:3-(4-Amino-5-cyclopropylpyrimidine-2-yl)-1-(2-fluorobenzyl)-1H-pyrazolo(3,4-b)pyridine; D020030:Nitric Oxide Donors; D011720:Pyrazoles; D011725:Pyridines; D009569:Nitric Oxide; D006162:Guanylate Cyclase