Relaxation of rabbit corpus cavernosum by selective activators of voltage-gated sodium channels: role of nitric oxide-cyclic guanosine monophosphate pathway.
OBJECTIVE
To investigate the capacity of voltage-gated Na(+) channel activators such as batrachotoxin, aconitine, veratridine, Ts1 (formerly Tityus gamma-toxin), and brevetoxin-3 to induce relaxation of rabbit isolated corpus cavernosum (RbCC) and the pharmacologic mechanisms underlying this phenomenon. The voltage-gated Na(+) channels of the corpus cavernosum are essential for erectile function. A number of biologic toxins exert their effects by modifying the properties of these channels.


METHODS
Male New Zealand white rabbits were anesthetized with pentobarbital sodium. Strips of RbCC were transferred to 10-mL organ baths containing oxygenated and warmed Krebs solution. The RbCC strips were connected to force-displacement transducers, and changes in isometric force were recorded using a PowerLab 400 data acquisition system. Corporeal smooth muscle was precontracted submaximally with phenylephrine (10 micromol/L).


RESULTS
The binding site-2 (batrachotoxin, aconitine, and veratridine) and binding site-5 (brevetoxin-3) voltage-gated Na(+) channel activators caused slow-onset RbCC relaxations, and the binding site-4 activator Ts1 produced transitory relaxations followed by a return to baseline. The Na(+)channel blockers tetrodotoxin and saxitoxin (0.1 micromol/L each) abolished the relaxations induced by these agonists. Similarly, the nitric oxide synthase inhibitor N(omega)-nitro-l-arginine methyl ester (100 micromol/L) markedly reduced the relaxations and l-arginine (1 mmol/L) restored the relaxations. The soluble guanylyl cyclase inhibitor 1H-[1,2,4] oxidiazolo[4,3-alpha] quinoxalin-1-one (10 micromol/L) reduced the relaxations, and the phosphodiesterase type 5 inhibitor sildenafil (100 nmol/L) significantly potentiated the relaxations by all activators.


CONCLUSIONS
Our results indicate that the relaxations evoked by selective activators of voltage-gated Na(+) channels are mediated by the release of nitric oxide from nitrergic nerves and the activation of the nitric oxide-cyclic guanosine monophosphate pathway in the smooth muscle cells of erectile tissue.
Fernandes de Oliveira
Juliano
J
Department of Pharmacology, Faculty of Medical Sciences, UNICAMP, Campinas, São Paulo, Brazil.
Teixeira
Cleber E
CE
Arantes
Eliane C
EC
de Nucci
Gilberto
G
Antunes
Edson
E
D000157:Aconitine / Q000494:pharmacology; D000818:Animals; D001120:Arginine / Q000494:pharmacology; D001496:Batrachotoxins / Q000494:pharmacology; D001665:Binding Sites; D006152:Cyclic GMP / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors; D066298:In Vitro Techniques; D019476:Insect Proteins; D007537:Isometric Contraction / Q000187:drug effects; D008297:Male; D008387:Marine Toxins / Q000494:pharmacology; D009130:Muscle, Smooth / Q000187:drug effects* / Q000378:metabolism; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009498:Neurotoxins / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D035964:Oxocins / Q000494:pharmacology; D010410:Penile Erection / Q000187:drug effects; D010413:Penis / Q000502:physiology*; D010879:Piperazines / Q000494:pharmacology; D011687:Purines; D011817:Rabbits; D012604:Scorpion Venoms / Q000494:pharmacology; D000068677:Sildenafil Citrate; D062687:Sodium Channel Agonists; D026941:Sodium Channel Blockers / Q000494:pharmacology; D015222:Sodium Channels / Q000378:metabolism; D013450:Sulfones; D014701:Veratridine / Q000494:pharmacology; D000095702:Polyether Toxins
D000157:Aconitine; D001120:Arginine; D001496:Batrachotoxins; D006152:Cyclic GMP; D006162:Guanylate Cyclase; D019476:Insect Proteins; D008387:Marine Toxins; D019331:NG-Nitroarginine Methyl Ester; D009498:Neurotoxins; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D035964:Oxocins; D010879:Piperazines; D011687:Purines; D012604:Scorpion Venoms; D000068677:Sildenafil Citrate; D062687:Sodium Channel Agonists; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D013450:Sulfones; D014701:Veratridine; C120263:scorpion toxin Ts1, Tityus; C053342:brevetoxin; D000095702:Polyether Toxins