Prostacyclin, thromboxane A2, and prostaglandin E2 formation in atherosclerotic human carotid artery.

Abstract

Prostaglandin (PG) formation In 16 atherosclerotic human carotid endarterectomy specimens was compared systematically with that of normal carotid artery from seven white pigs and six rhesus monkeys. Prostacyclin (PGI2) formation (plcomoles 6-keto-PGF 1t /2 mln/100 ^9 homogenate protein plus 2 mM glutathlone [GSH]) of nonatheromatous Intlma adjacent proximal (276 ± 32, mean ± SEM) or distal (271 ± 14) to carotid plaque was comparable to that of normal carotid artery from white pig (272 ± 25, NS) and rhesus monkey (219 ± 41, NS), and was greater than stenotlc Intlma (156 ± 1 7 , p<0.01), sublntlmal plaque (168 ± 14, p < 0.01), and ulceratlon (65 ± 16, p<0.01 A rterial prostaglandin (PG) synthesis Is thought to be important in the maintenance of circulatory homeostasis by contributing to regulation of vascular tone and endothelial platelet adherence. Prostacyclin (PGy, the major product of arachidonic acid metabolism in normal vascular endothelium, is a potent vasodilator and inhibitor of platelet aggregation and adherence to the vessel wall. 1It has been hypothesized that PGI 2 counterbalances the proaggregatory and vasoconstrictive effects of predominantly platelet-synthesized thromboxane Aj (TXAj).1 Recent reports 2 ' 3 -4 suggest that atherosclerotic arteries differ from normal arterial tissues by producing substantially less PGI 2 , more PGE 2 , 4 and detectable levels of TXA 2 . 5 Such alterations in PG synthesis could create a localized imbalance between the intravascular actions of PGI 2 and TXAa, resulting in increased platelet deposition and arterial thrombogenicity at atherosclerotic sites.The underlying biochemical basis for reported alterations in arterial PG synthesis in atherosclerosis is unclear. Furthermore, it has not been demonstrated whether such changes in atherosclerotic patients are focal (localized only to plaque) or systemic (also found in nonatheromatous arterial tissues). The purpose of this study was to identify enzymatic changes in carotid endarterectomy Received May 26,1987; revision accepted September 9,1987. specimens that might account for these previously observed disturbances of eicosanoid metabolism and investigate the potential of glutathione (GSH), an endogenous antioxidant, to modulate PG synthesis. Methods Normal Carotid Artery SpecimensA single specimen of nonatherosclerotic human carotid artery (n = 1) was harvested with appropriate authorization from a brain-dead cadaver kidney donor. Fresh carotid arteries from young adult, white (cross-bred, market grade) pigs (n = 7) and rhesus monkeys (n = 6) were used as control specimens. The animal experiments conformed to principles of animal care established by the Tulane Medical Center Advisory Committee for Animal Resources, "Principles of Laboratory Animal Care," and the "Guide for the Care and Use of Laboratory Animals" (NIH publication No. 80-23, revised 1978). Atherosclerotic Carotid Artery SpecimensOcclusive atheromatous internal carotid artery plaques were removed from patients (n = 16) by standard carotid endarterecto...

Chronic exposure of cultured bovine endothelial cells to oxidized LDL abolishes prostacyclin release.

“…22 Taken together, all these elements suggest that Ox-LDL itself could trigger the decrease in prostacyclin synthesis observed in atherosclerotic lesions. 12 As well as inhibiting basal formation of prostacyclin, Ox-LDL chronically incubated with endothelial cells almost abolished the receptor-dependent stimulated release of prostacyclin, suggesting that the alteration is not specific for one class of receptor. Moreover, AAinduced 6-keto-PGF, a formation did not appear to be dose-dependently related.…”

“…During the atherosclerotic process, however, Ox-LDL is probably chronically in contact with the endothelial layer. Previous work showed that prostacyclin release is selectively decreased at the level of the atherosclerotic lesion compared with the surrounding area 12 as well as in smooth muscle cells isolated from atherosclerotic rabbit aorta, in which cyclooxygenase and prostacyclin synthase activities appear to be reduced. 10 The mechanism for the decrease in prostacyclin is unknown, but three lines of evidence support an oxidation-dependent alteration.…”

The Effect of Acute Ingestion of a Large Dose of Alcohol on the Hemostatic System and Its Circadian Variation

“…However, a rapid increase in shear-induced platelet activation may aggravate the imbalance between thromboxane and prostacyclin at sites of severe atherosclerosis, because it has been shown that prostacyclin synthesis is deficient in atherosclerotic carotid plaques. 32 Such an imbalance could rapidly develop during heavy alcoholic intoxication and lead to local thrombus formation if not simultaneously compensated for by enhanced prostacyclin formation. Because fairly heavy physical activity is needed to stimulate prostacyclin formation, 27 bed rest and severe alcoholic intoxication could be a harmful combination for individuals with atherosclerotic arteries.…”

Vascular responses to endothelin-1 in atherosclerotic primates.

“…36 The constrictor responses to ET-1 in mesenteric arteries are potentiated by indomethacin, suggesting a release of prostacyclin. 51 Atherosclerosis may increase 52 or decrease 53 the production of prostacyclin. Our finding, that indomethacin did not augment the constrictor effects of ET-1 on large arteries in normal and atherosclerotic monkeys, suggests that vasodilator prostaglandins are not released in response to ET-1 in the cynomolgus monkey.…”