ABSTRACT
In strips of lingual arteries of the monkey, acetylcholine produced endotheliumdependent relaxations which were not or only slightly attenuated by indomethacin, and significantly attenuated by N G-nitro-L-arginine ( L - N A ) . The response to acetylcholine resistant to L - N A and indomethacin was abolished in the strips exposed to high K + . Glibenclamide, iberiotoxin or apamin alone did not affect the relaxation, but charyb dotoxin partially inhibited it, while the remaining relaxation was abolished by add itional treatment with apamin. The acetylcholine-induced relaxation resistant to L - N A and indomethacin was inhibited by non-selective cytochrome P450 monoxygenase (CYP) inhibitors (metyrapone, proadifen and 17-octadecynoic acid) and selective C Y P 3 A inhibitors (ketoconazole and progesterone). Selective inhibitors of other C Y P isoforms (debrisoquine, lauric acid and sulfaphenazole) did not reduce the response to acetylcholine. Filtrate of the reaction mixture containing human liver microsomes rich in C Y P s , arachidonic acid and N A D P H incubated at 37 °C relaxed arteries without endothelium, used as bioassay tissues. The relaxation was abolished by high K + , and was suppressed by the combined treatment with charybdotoxin plus apamin, but not with iberiotoxin. Further, the relaxations were markedly inhibited by incubation with ketoconazole, progesterone or ant i -CYP3A4 antibody. The presence of C Y P 3 A 4 was detected immunohistochemically in the endothelium of the monkey lingual artery. In conclusion, the endothelium-dependent relaxation of the monkey lingual artery is medi ated mainly by N O and by a charybdotoxin plus apamin-sensitive calcium-dependent K + channel opening substance(s) that may be a CYP3A4-derived metabolite(s) of arachidonic acid.
