Sensitivity of fatty acid cyclooxygenase from human aorta to acetylation by aspirin.

Abstract

The rate of acetylation of fatty acid cyclooxygenase (prostaglandin synthase, EC 1.14.99.1) by [acetyl-3H-aspirin was measured in microsomes from human aortas and coronary arteries and intact and disrupted human platelets. We also measured the inhibition by aspirin of prostacyclin generation from exogenous arachidonic acid in shredded human aorta. Cyclooxygenase in human aorta and coronary artery microsomes is approximately 1/250th as sensitive to aspirin as enzyme in intact platelets, and 1/60th as sensitive to aspirin as enzyme measured in a platelet microsomal preparation. On the basis of the in vitro data presented, we predict that small oral doses of aspirin are sufficient to inhibit platelet prostaglandin production but are not sufficient to substantialFy affect aorta or coronary artery prostaglandin production.

Acetylation of prostaglandin H2 synthases by aspirin is inhibited by redox cycling of the peroxidase

“…The previous observation that aspirin is less effective in sonicated than in intact platelets [10] also is likely to be related to the formation of PGG 2 and 12-HPETE from the arachidonic acid released on cell disruption.…”

“…The relative ineffectiveness of aspirin as an anti-inflammatory drug is mirrored at the cellular level by the demonstration that aspirin is 166 times more potent in inhibiting PGHS activity in the platelet than in the J774.2 macrophage cell line [8], leading to consideration that the action of aspirin might be selective for the PGHS-1 isoform. However, the potency of inhibition of PGHS-1 by aspirin ex vivo observed in normal platelets is lost in platelets of patients after coronary artery bypass grafting [9], and PGHS-1 from platelet homogenates is poorly acetylated by aspirin [10], suggesting differences in acetylation that can not be attributed to isoform selectivity. Collectively, these observations reflect considerable variability in acetylation of the PGHSs by aspirin, a variability that implies a mechanistic basis for regulating the action of the drug.…”

Eighth Gaddum Memorial Lecture University of London Institute of Education December 1980: Biological Importance of Prostacyclin

“…Some of these studies have demonstrated that: a single dose of 80 mg of aspirin reduces the activity of prostaglandin synthetase by 85% and a dose of 300 mg completely abolishes it (Burch et al, 1978); a single dose of 2 mg/kg is enough to inhibit completely the generation of MDA, measured 2 h after oral ingestion, while between 3 and 3.5 mg/kg is needed to inhibit ADP-, adrenaline-or collagen-induced aggregation (Masotti, Poggesi, Galanti, Abbate & Neri Serneri, 1979); and finally that a dose of 100 mg of aspirin reduces TXB2 release by more than 90% in serum 2 h after oral administration and by 100% after 3 to 4 h (Patrono, Ciabattoni, Pinca, Pugliese Castrucci, De Salvo, Satta & Peskar, 1980). These last authors also found that a clear dose-effect on the generation of TXB2 can only be obtained with doses below 22mg/kg of aspirin.…”

In vivo measurement of thromboxane B2 and 6-keto-prostaglandin F1 alpha in humans in response to a standardized vascular injury and the influence of aspirin.

“…[10][11][12][13][14][15][16] In this respect, studies with long-term aspirin should look not only at normal individuals but also at specific populations for whom a beneficial effect of antiplatelet therapy has been advocated (e.g., diabetics). Such individuals are significantly different from normal individuals in that they have an increased platelet turnover and decreased platelet life span,17 which may have important effects on the ability of the platelets and the vessel to recover from the effects of aspirin.…”