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 A2 (TXA2) synthase inhibition would modulate changes in eicosanoid formation, catecholamine concentration, and platelet aggregation induced by a physical stress. We measured thromboxane B2 (TXB2), 11-dehydro-TXB2, 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha), 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 TXA2 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 TXB2 and urinary 11-dehydro-TXB2 (p less than 0.001 to p less than 0.01) and an increase in serum 6-keto-PGF1 alpha (p less than 0.001 to p less than 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 less than 0.01) platelet aggregation induced both by adenosine diphosphate and by collagen at rest. However, the exercise increased (p less than 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 TXA2 synthase inhibitor does not appear to attain the antithrombotic action during an exercise despite the occurrence of a sustained endoperoxide shunting.
Ohnishi
A
A
Department of Internal Medicine, Daisan Hospital, Tokyo, Japan.
Ishizaki
T
T
Echizen
H
H
Yasuda
K
K
Fujiwara
H
H
Tanaka
T
T
D015121:6-Ketoprostaglandin F1 alpha / Q000097:blood / Q000652:urine; D000328:Adult; D002851:Chromatography, High Pressure Liquid; D004837:Epinephrine / Q000097:blood; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D008297:Male; D009638:Norepinephrine / Q000097:blood; D005082:Physical Exertion; D010974:Platelet Aggregation / Q000187:drug effects; D013764:Tetrahydronaphthalenes / Q000494:pharmacology*; D013929:Thromboxane B2 / Q000097:blood / Q000652:urine; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors*
D007093:Imidazoles; D013764:Tetrahydronaphthalenes; D013929:Thromboxane B2; D015121:6-Ketoprostaglandin F1 alpha; C056295:nafagrel; D013930:Thromboxane-A Synthase; D009638:Norepinephrine; D004837:Epinephrine