Peter C. Weber

Aspirin-induced decline in prostacyclin production in patients with coronary artery disease is due to decreased endoperoxide shift. Analysis of the effects of a combination of aspirin and n-3 fatty acids on the eicosanoid profile.

BackgroundIt was the purpose of this study to determine the effects of the combination of aspirin (ASA) and fish oil, which is rich in n-3 polyunsaturated fatty acids, on the eicosanoid profile of patients with coronary artery disease. Specifically, we wanted to determine whether the ASA-induced reduction in prostacyclin production is due to inhibition of endothelial cell cyclooxygenase or to reduced endoperoxide shift from platelets and whether ASA negates the potentially beneficial effects of fish oil on the eicosanoid profile. Methods and ResultsFourteen patients with clinically stable but advanced coronary artery disease received 12 g (n = 8) or 16 g (n = 6) of fish oil concentrate containing 6 or 8 g of n-3 fatty acids for 6 weeks. In addition to the fish oil, patients received increasing daily doses of ASA (50 mg, 100 mg, 325 mg, and 1,300 mg; the latter in four divided doses). Each dose was taken for 2 weeks. With fish oil supplementation, red blood cell phospholipid fatty acid content of arachidonic acid (AA) decreased and of eicosapentaenoic acid (EPA) increased so that EPA as a percent of AA increased from 2% to 26%. Serum thromboxane B2, which represents the production of TXA2 by maximally stimulated platelets, was suppressed by 38% on fish oil alone and by 97% or greater on all doses of ASA. Excretion of PGI2-M, the main urinary metabolite of PGI2 (derived from AA), fell from 50 % 4 ng/g of creatinine to 42 % 2 ng/g on fish oil alone (p = 0.02). On 50 mg of ASA per day, PGI2-M excretion was 26 % 2 ng/g of creatinine (p < 0.001 versus fish oil alone). On 100 mg and 325 mg of ASA per day, PGI2-M was 24 % 3 ng/g and 27 % 3 ng/g, respectively (p = NS versus value on 50 mg per day). PGI3-M, the main urinary metabolite of PGI3 (derived from EPA), increased from 0.2 ± 0.1 ng/g of creatinine to 4.9 % 0.7 ng/g on fish oil alone (p < 0.001). In contrast with the marked ASA-induced decline in PGI2-M, PGI3-M excretion was not affected by the addition of ASA, even at the higher doses (4.6 % 0.7 ng/g and 4.9 % 0.5 ng/g on 325 mg per day and 325 mg four times daily, respectively). ConclusionsModerate-dose (325 mg per day or less) ASA taken once daily has no effect on PGI3 production despite significantly reducing PGI2 production. This suggests that endothelial cell cyclooxygenase is minimally inhibited by such doses of ASA and that a large percent of the PGI2 produced in patients with advanced coronary artery disease derives from the transfer of prostaglandin endoperoxides from activated platelets to endothelial cells. The loss of these substrates accounts for the decrease in PGI2 with moderate-dose ASA. Thus, the ASA-induced decrease in PGI2 may in large part be an unavoidable consequence of ASA-induced platelet cyclooxygenase inhibition. ASA does not negate the potentially beneficial effects of n-3 fatty acids on the eicosanoid profile.

Effects of dietary omega 3 fatty acids on vascular contractility in preanoxic and postanoxic aortic rings.

BackgroundVasomotor reactivity may contribute to the pathophysiology of ischemic injury. The atherosclerotic vessel may be particularly susceptible to vasoconstriction because of the damaged endothelial layer with resultant loss of vasodilatory factors. While dietary o3 fatty acids have been proposed to protect against vascular occlusion, it is not clear to what extent this results from alterations in the function of platelets or from changes intrinsic to the blood vessel itself. Methods and ResultsThe effects of dietary supplementation with fish oils on vascular contractility were examined in endothelialized and de-endothelialized aortic rings under preand postanoxic conditions. De-endothelialization was defined functionally by the loss of acetylcholine-induced vasodilation in norepinephrine-preconstricted aortic rings from rats fed normal rat chow. Three groups of rats were fed diets containing either 20% menhaden oil or 20% beef tallow, both supplemented with 3% corn oil or 23% corn oil for longer than 4 weeks. All animals received vitamin E. Under well-oxygenated conditions, de-endothelialized aortic rings from rats fed fish oil and corn oil contracted to similar extents with norepinephrine and vasopressin and less than rings from rats fed beef tallow. Endothelialized (intact) and de-endothelialized rings from rats fed fish oil relaxed more in response to acetylcholine than rings from rats fed beef tallow and corn oil. After anoxic exposure and reoxygenation, KCI-induced contraction of intact rings from rats fed fish oil and corn oil was similar and less than rings from rats fed beef tallow. Intact and de-endothelialized rings from rats fed fish oil relaxed more to acetylcholine than did rings from rats fed beef tallow and corn oil. ConclusionsUnder preanoxic or postanoxic conditions, rings from rats fed fish oil and corn oil contracted less than rings from rats fed beef tallow. The relaxation response to acetylcholine, however, was greater in rings from rats fed fish oil than from rats fed either corn oil or beef tallow. These vascular effects of fish oil feeding may result in increased blood flow to ischemic and reperfused tissues in vivo.

n-3 Fatty Acids and the Eicosanoid System

Cardiovascular diseases are rare among Eskimos living on their traditional maritime diet even though this diet is high in calories, rich in fat and relatively low in “classical” polyunsaturated fatty acids of the n-6 type, but rich in polyunsaturated n-3 fatty acids (2,6,13). Furthermore, although it had already been observed almost 30 years ago that fish oil reduces blood fat levels even more than n-6 fatty acid rich vegetable oil do (1), the potential of the n-3 fatty acids — contained neither in butter nor margarine in any relevant amount — in atherothrombotic and chronic inflammatory diseases was not recognized for a long time.