Increased prostacyclin and thromboxane A2 biosynthesis in atherosclerosis.
It has been proposed that atherosclerotic arteries produce less prostacyclin (PGI2) than nonatherosclerotic arteries do, thereby predisposing arteries to vasospasm and thrombosis in vivo. We reexamined this concept by measuring spontaneous as well as arachidonate-induced PGI2 biosynthesis in aortic segments from nonatherosclerotic and cholesterol-fed atherosclerotic New Zealand White rabbits. Thromboxane A2 (TXA2) generation was also measured. Formation of PGI2, as well as TXA2, as measured by radioimmunoassay (RIA) of their metabolites, was increased in atherosclerotic aortic segments relative to nonatherosclerotic segments (P less than or equal to 0.05) at 0, 5, 10, 15, and 30 min of incubation with arachidonate. Pretreatment of arterial segments with indomethacin inhibited PGI2 as well as TXA2 formation, whereas pretreatment with the selective TXA2 inhibitor OKY-046 inhibited only TXA2 release, thus confirming the identity of icosanoids. To confirm the RIA data, aortic segments were incubated with [14C]arachidonate prior to stimulation with unlabeled arachidonate. The uptake of arachidonate was similar, but the release of incorporated [14C]arachidonate was significantly (P less than or equal to 0.05) greater in atherosclerotic segments than in nonatherosclerotic ones. Conversions of released [14C]arachidonate to 6-keto[14C]prostaglandin F1 alpha and [14C]thromboxane B2 were similar in the two types of aortic segments. Thus, synthesis of PGI2 as well as TXA2 is increased in atherosclerosis, and this alteration in arachidonate metabolism is related to increased release of arachidonate.
D000818:Animals; D001012:Aorta, Abdominal / Q000187:drug effects / Q000378:metabolism*; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000378:metabolism; D001161:Arteriosclerosis / Q000378:metabolism*; D004036:Diet, Atherogenic; D011464:Epoprostenol / Q000096:biosynthesis*; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D007700:Kinetics; D008297:Male; D011817:Rabbits; D012016:Reference Values; D013928:Thromboxane A2 / Q000096:biosynthesis*
D001095:Arachidonic Acids; D016718:Arachidonic Acid; D013928:Thromboxane A2; D011464:Epoprostenol; D007213:Indomethacin