K(+) channel blockers and cytochrome P450 inhibitors on acetylcholine-induced, endothelium-dependent relaxation in rabbit mesenteric artery.
Acetylcholine caused an endothelium-dependent relaxation in isolated rabbit mesenteric small artery in the presence of nitro L-arginine and indomethacin. The acetylcholine-induced relaxation was attenuated by high K(+) solution, suggesting that the response is mediated by a membrane potential-sensitive mechanism, presumably an endothelium-derived hyperpolarizing factor. The acetylcholine-induced relaxation was also inhibited with tetraethylammonium, 4-aminopyridine and charybdotoxin, but not with Ba(2+), apamin, iberiotoxin nor glibenclamide. The relaxation was abolished by a combination of apamin and charybdotoxin, but iberiotoxin could not replace charybdotoxin in this combination. The responses to charybdotoxin and 4-aminopyridine were synergistic but neither apamin nor iberiotoxin increased the effect of 4-aminopyridine. Clotrimazole and proadifen inhibited the acetylcholine-induced relaxation, but these drugs also inhibited the cromakalim-induced relaxation, while protoporphyrin IX inhibited the acetylcholine- but not cromakalim-induced relaxation. 17-Octadecynoic acid and 1-aminobenzotriazole did not affect the response to acetylcholine. Four regioisomers of epoxyeicosatrienoic acids did not relax endothelium-denuded artery. A gap junction inhibitor 18alpha-glycyrrhetinic acid attenuated the relaxation to acetylcholine. It is suggested that in rabbit mesenteric artery, the acetylcholine-induced, nitric oxide- and prostacyclin-independent relaxation is mainly mediated by 4-aminopyridine- and charybdotoxin-sensitive K(+) channels and that the relaxation is not mediated through cytochrome P450 enzyme metabolites. The contribution of heterocellular gap junctional communication to the relaxation is discussed.
Fujimoto
S
S
Department of Pharmacology, Nagoya City University Medical School, Kawasumi, Mizuho, Mizuho-ku, Nagoya, Japan.
Ikegami
Y
Y
Isaka
M
M
Kato
T
T
Nishimura
K
K
Itoh
T
T
D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D000109:Acetylcholine / Q000494:pharmacology*; D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology; D019806:Cromakalim / Q000494:pharmacology; D065607:Cytochrome P-450 Enzyme Inhibitors; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006034:Glycyrrhetinic Acid / Q000494:pharmacology; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects* / Q000502:physiology; D009126:Muscle Relaxation / Q000187:drug effects*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D009599:Nitroprusside / Q000494:pharmacology; D009638:Norepinephrine / Q000494:pharmacology; D026902:Potassium Channel Blockers; D011189:Potassium Chloride / Q000494:pharmacology; D011817:Rabbits; D019789:Tetraethylammonium / Q000494:pharmacology; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology
D001095:Arachidonic Acids; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D026902:Potassium Channel Blockers; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; C081565:arachidonyltrifluoromethane; D019806:Cromakalim; D009599:Nitroprusside; D019789:Tetraethylammonium; D011189:Potassium Chloride; D015126:8,11,14-Eicosatrienoic Acid; D000109:Acetylcholine; D006034:Glycyrrhetinic Acid; D009638:Norepinephrine