Effects of a sustained thromboxane synthase inhibition on exercise‐induced changes in eicosanoid formation, catecholamine concentration, and platelet aggregation in humans

In an effort to characterize an interaction between the eicosanoids and sympathoadrenal system on platelet aggregation, we tried to determine if a sustained thromboxane A 2 (TXA 2 ) synthase inhibition would modulate changes in eicosanoid formation, catecholamine concentration, and platelet aggregation induced by a physical stress. We measured thromboxane B 2 (TXB 2 ), ll‐dehydro‐TXB 2 , 6‐ketoprostaglandin F 1α (6‐keto‐PGF 1α ), norepinephrine, and epinephrine in vivo and platelet aggregation ex vivo before and after a treadmill exercise with and without the oral doses (400 mg twice daily for 7 days) of a new selective TXA 2 synthase inhibitor (DP‐1904) in nine healthy male subjects. The exercise tests performed on the pretreatment day (day 0) and posttreatment day (day 7) gave a similar result. DP‐1904 caused a decrease in serum and urinary TXB 2 and urinary ll‐dehydro‐TXB 2 ( p < 0.001 to p < 0.01) and an increase in serum 6‐keto‐PGF 1α ( p < 0.001 to p < 0.05) throughout the dosing interval on days 4 and 7. Despite the drug effect on eicosanoid formation at rest and after exercise, the exercise‐induced plasma norepinephrine and epinephrine concentrations did not differ between days 0 and 7. The 7‐day treatment decreased ( p < 0.01) platelet aggregation induced both by adenosine diphosphate and by collagen at rest. However, the exercise increased ( p < 0.01) platelet aggregation by the two aggregators, resulting in the disappearance of the drug‐induced antiaggregatory effects observed at rest. The treatment with a TXA 2 synthase inhibitor does not appear to attain the antithrombotic action during an exercise despite the occurrence of a sustained endoperoxide shunting. Clinical Pharmacology and Therapeutics (1992) 51, 454–464; doi: 10.1038/clpt.1992.46