Hepoxilin A3 (HxA3) is formed by the rat aorta and is metabolized into HxA3-C, a glutathione conjugate.
In this paper we describe the release of hepoxilin A3 (HxA3) by intact pieces of the rat thoracic aorta and its stimulation by exogenous arachidonic acid but not by the calcium ionophore A23187. Homogenates of the rat aorta metabolize HxA3 via two competing pathways; one involves hepoxilin epoxide hydrolase to form the trihydroxy metabolite, trioxilin A3 (TrXA3), and a second pathway involves conjugation of HxA3 with glutathione via glutathione S-transferase to form a glutathione conjugate, which we refer to as hepoxilin A3-C (HxA3-C), a name based upon the accepted nomenclature for the glutathione conjugate leukotriene C. The formation of HxA3-C was dependent on the presence of reduced glutathione in the incubation medium. HxA3-C formation was greatly enhanced in the presence of TCPO, an epoxide hydrolase inhibitor which blocks utilization of the substrate via hepoxilin epoxide hydrolase. Comparison of HxA3-C formation by several arteries and veins indicated that glutathione conjugation was more evident in veins than arteries. The aorta from spontaneously hypertensive rats was essentially similar in HxA3-C formation to aorta from local normotensive Wistar rats although the aorta from the normotensive Wistar Kyoto rats was much more active than aorta from either of the two other rat types. The biological activity of HxA3 and HxA3-C was investigated on isolated helicoidal strips of the rat aorta. While both compounds were inactive on their own, HxA3 and to a lesser extent HxA3-C potentiated the contractile response induced by norepinephrine. The present results provide evidence of the presence in rat aorta of a new pathway of arachidonic acid metabolism whose products may possess potential regulatory properties on vascular tissue.
Research Institute, Hospital for Sick Children, Toronto, Canada.
O
O
Laneuville
E J
EJ
Corey
R
R
Couture
C R
CR
Pace-Asciak
D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism*; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000494:pharmacology; D000001:Calcimycin / Q000494:pharmacology; D004851:Epoxide Hydrolases / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains; D014661:Vasoconstriction; D005723:gamma-Glutamyltransferase / Q000378:metabolism
D001095:Arachidonic Acids; C061163:11-glutathionylhepoxilin A3; C069476:hepoxillin A3-D; D016718:Arachidonic Acid; D000001:Calcimycin; C019121:8,11,12-trihydroxy-5,9,14-eicosatrienoic acid; C038243:8-hydroxy-11,12-epoxyeicosa-5,9,14-trienoic acid; D005723:gamma-Glutamyltransferase; D004851:Epoxide Hydrolases; C063758:hepoxilin epoxide hydrolase; D015126:8,11,14-Eicosatrienoic Acid; D005978:Glutathione