title: 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.
  
  
  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.
authors.affiliation: Medical Service, Massachusetts General Hospital, Boston 02114.
authors.forename: T
authors.initials: T
authors.lastname: Force
authors.forename: R
authors.initials: R
authors.lastname: Milani
authors.forename: P
authors.initials: P
authors.lastname: Hibberd
authors.forename: R
authors.initials: R
authors.lastname: Lorenz
authors.forename: W
authors.initials: W
authors.lastname: Uedelhoven
authors.forename: A
authors.initials: A
authors.lastname: Leaf
authors.forename: P
authors.initials: P
authors.lastname: Weber
mesh_terms: D000368:Aged; D016718:Arachidonic Acid / Q000378:metabolism; D001241:Aspirin / Q000494:pharmacology*; D003327:Coronary Disease / Q000378:metabolism*; D015777:Eicosanoids / Q000378:metabolism*; D015118:Eicosapentaenoic Acid / Q000378:metabolism; D011464:Epoprostenol / Q000096:biosynthesis*; D005260:Female; D005395:Fish Oils / Q000494:pharmacology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010743:Phospholipids / Q000378:metabolism; D011449:Prostaglandin Endoperoxides / Q000378:metabolism*; D013931:Thromboxanes / Q000096:biosynthesis
chemical_list: D015777:Eicosanoids; D005395:Fish Oils; D010743:Phospholipids; D011449:Prostaglandin Endoperoxides; D013931:Thromboxanes; D016718:Arachidonic Acid; D015118:Eicosapentaenoic Acid; D011464:Epoprostenol; D001241:Aspirin