Recent in vivo and in vitro studies suggest that nitric oxide or a nit
ric-oxide-like substance mediates nonadrenergic, noncholinergic relaxa
tion of trabecular smooth muscle through activation of the cyclic guan
osine monophosphate (cGMP) pathway. In 60 Sprague-Dawley rats, we inve
stigated the effect of intracavernous administration of different drug
s known to act at different levels of the cyclic adenosine monophospha
te (cAMP) and cGMP pathways. Neither cAMP nor drugs that stimulate ade
nylate cyclase activity (vasoactive intestinal peptide, prostaglandin
E(I), calcitonin gene-related peptide) provoked any change in the basa
l intracavernous pressure. N-ethylmaleimide, an inhibitor of the enzym
e adenylate cyclase, did not modify the response to electrostimulation
of the cavernous nerve, indicating that the cAMP pathway does not pla
y a significant role in penile erection in rats. However, intracaverno
us administration of methylene blue, a guanylate cyclase inhibitor, si
gnificantly reduced the response to electrostimulation (p=0.001). Dire
ct intracavernous injection of cGMP caused a statistically significant
, dose-dependent increase in intravernous pressure that was not signif
icantly inhibited by methylene blue. Sodium nitroprusside, a nitric ox
ide releaser and therefore a guanylate cyclase activator, caused a dos
e-dependent increase in intracavernous pressure (p<0.05) that was inhi
bited almost completely by methylene blue (p=0.002), supporting the th
eory that nitric oxide activates the synthesis of cGMP and that cGMP c
auses cavernous smooth muscle relaxation. Papaverine elicited an intra
cavernous pressure increase that was not affected by methylene blue or
N-ethylmaleimide, indicating that papaverine acts through an independ
ent pathway. N-methyl-D-aspartate and L-glutamic acid, excitatory amin
o acids that act in the central nervous system by stimulating nitric o
xide synthase, had no effect on the intracavernous pressure. 5-Hydroxy
tryptamine, which is believed to cause presynaptic inhibition of relea
se of excitatory amino acids, caused a potent inhibition of the cavern
ous response to electrostimulation (p<0.001). It appears that cavernou
s smooth muscle relaxation is mediated by the release of a nitric-oxid
e-like substance with subsequent activation of guanylate cyclase. The
cAMP system seems to play no important role in this mechanism in the r
at.