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.

Abstract

BACKGROUND It 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 RESULTS Fourteen 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 less than 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 V 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 less than 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). CONCLUSIONS Moderate-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.

Cardiovascular Effects of Omega-3 Free Fatty Acids.

“…Acetyl-salicylic acid (ASA; aspirin), commonly used for the secondary prevention of ischemic vascular diseases, inhibits cyclooxygenase, having a synergistic effect with n-3; in fact, Force et al [13] showed that n-3 maintain the endothelial production of PGI3 in patients treated with ASA. Moreover, Cerbone et al [14] suggested that n-3 can also inhibit ADP-and collagen-induced platelet aggregation, and consequently the production of TXA2.…”

n−3 polyunsaturated fatty acids and coronary thrombosis

“…In summary, n-3 PUFA inhibit TXB 2 production, platelet aggregation, and platelet adhesion and cause a minor prolongation of the bleeding time. However, these effects are probably marginal, and the inhibitory effect of n-3 PUFA on the production of proaggregatory thromboxanes is well below that obtained after intake of a low dose of aspirin (25). Some studies have shown that n-3 PUFA and aspirin have synergistic inhibitory effects on measures of platelet reactivity (26,27).…”

Vascular smooth muscle endothelial regulation and effects of aspirin in hypertension

“…Acetylsalicylic acid, (ASA/aspirin) has been shown to prevent pregnancy induced hypertension (PIH) in humans (48,(97)(98)(99)(100)(101)(102)(103)(104)(105)(106), and low dosages of ASA are prescribed to manage occlusive disorders like angina, myocardial infarction and to prevent re-stenosis (9,13,56,58,63,75,86,97,102,(107)(108)(109)(110)(111)(112)(113)(114)(115)(116)(117)(118)(119)(120)(121)(122)(123)(124). Aspirin has also been found to be beneficial against vascular disorders associated with diabetes (9,110,125).…”

“…Pregnancy-induced hypertension (PIH) in humans has been shown to be prevented by ASA administration (48,(97)(98)(99)(100)(101)(102)(104)(105)(106). Increasingly low aspirin dosages are being prescribed to manage and prevent various occlusive disorders such as angina, myocardial infarction and re-stenosis after angioplasty (58,63,97,101,113,115,116,120,123,131,152 ) . Aspirin reduces coronary hyperreactivity to autocoids aftert angioplasty and thus prevents re-stenosis (56,58,109,153).…”

“…Recently, ASA was found to suppress epithelial cell proliferation in rat colonic crypts (17). The beneficial effects of aspirin in vascular occlusive disease and PIH are ascribed to its blockade of the enzyme, cyclooxygenase, during the synthesis of platelet TXA 2 , a potent agonist of vascular smooth muscle contraction (37,60,63,75,108,109,112,115,116,120,122,123,139,150,152,154,155).…”