Mediation of arachidonic acid metabolite(s) produced by endothelial cytochrome P-450 3A4 in monkey arterial relaxation.
We investigated mechanisms of endothelium-dependent relaxation by acetylcholine resistant to indomethacin and N(G)-nitro-L-arginine and sensitive to cytochrome P-450 (CYP) inhibitors or charybdotoxin + apamin in the monkey lingual artery. Treatment with quinacrine, an inhibitor of phospholipase A2, abolished the relaxation by acetylcholine. However, treatment with alpha-glycyrrhetinic acid, an inhibitor of gap junctions, or catalase, an enzyme which dismutates hydrogen peroxide to form water and oxygen, did not affect the relaxation by acetylcholine. Immunohistochemistry demonstrated the presence of CYP3A4 in endothelial cells of the artery. Anti-CYP3A4 antibody inhibited relaxations by products of arachidonic acid incubated with human liver microsomes rich in CYPs in the endothelium-denuded artery. Purified CYP3A4 produced epoxyeicosatrienoic acids (EETs) from arachidonic acid, and the production was abolished by a selective CYP3A inhibitor, ketoconazole. It may be concluded that endothelium-derived relaxing substance(s) other than nitric oxide and prostanoids in the monkey lingual artery opens charybdotoxin + apamin-sensitive K+ channels in smooth muscle cells, and arachidonic acid metabolite(s) produced by endothelial CYP3A4 is likely to be the major substance.
Ayajiki
Kazuhide
K
Department of Pharmacology, Shiga University of Medical Science, Seta, Ohtsu, Japan.
Fujioka
Hideyuki
H
Toda
Noboru
N
Okada
Shigeru
S
Minamiyama
Yukiko
Y
Imaoka
Susumu
S
Funae
Yoshihiko
Y
Watanabe
Shuji
S
Nakamura
Akio
A
Okamura
Tomio
T
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism*; D001681:Biological Assay; D002317:Cardiovascular Agents / Q000494:pharmacology; D002384:Catalysis; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism*; D018076:DNA, Complementary; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D015870:Gene Expression; D007150:Immunohistochemistry; D007213:Indomethacin / Q000494:pharmacology; D008251:Macaca; D008297:Male; D019335:Nitroarginine / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*; D014665:Vasodilator Agents / Q000494:pharmacology
D002317:Cardiovascular Agents; D018076:DNA, Complementary; D004791:Enzyme Inhibitors; D014665:Vasodilator Agents; D019335:Nitroarginine; D016718:Arachidonic Acid; D003577:Cytochrome P-450 Enzyme System; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D000109:Acetylcholine; D007213:Indomethacin