Circulation, Vol 84, 2286-2293, Copyright © 1991 by American Heart Association
T Force, R Milani, P Hibberd, R Lorenz, W Uedelhoven, A Leaf and P Weber
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.
ARTICLES
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
Medical Service, Massachusetts General Hospital, Boston 02114.
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