14,15-Epoxyeicosatrienoic acid inhibits platelet aggregation in mouse cerebral arterioles.
OBJECTIVE
Epoxygenase metabolites of arachidonic acid are produced by several tissues and have been shown to inhibit in vitro platelet aggregation. The purpose of the present investigation was to determine whether 14,15- or 8,9-epoxyeicosatrienoic acid, epoxygenase derivatives of arachidonic acid, affect the speed of platelet aggregation in in vivo mouse cerebral arterioles.


METHODS
We performed a craniectomy in 116 anesthetized male mice and observed the pial arterioles by microscopy. We induced in situ platelet aggregation using a mercury light and intravascularly injected fluorescein dye.


RESULTS
Indomethacin (0.5 mg/kg i.p.), a known cyclooxygenase inhibitor, and 14,15-epoxyeicosatrienoic acid (0.3 mg/kg i.v.) increased the time necessary for the light plus dye to induce the first arterial platelet aggregate by 35% and 26%, respectively, whereas 8,9-epoxyeicosatrienoic acid (0.3 mg/kg i.v.) had no effect. Analysis of mouse serum by radioimmunoassay showed that the degree of inhibition of platelet aggregation by indomethacin and epoxyeicosatrienoic acids correlated with the degree of inhibition of thromboxane production.


CONCLUSIONS
We conclude that 14,15-epoxyeicosatrienoic acid is a potent inhibitor of in vivo platelet aggregation but cannot conclusively confirm that its effect on aggregation occurs via its reduction of platelet thromboxane A2. Because epoxyeicosatrienoic acids are produced by several tissues, including brain and vascular tissue, they may be important in vivo modulators of platelet aggregation and hemostasis.
Heizer
M L
ML
Department of Pharmacology and Toxicology, Medical College of Virginia, Virginia Commonwealth University, Richmond.
McKinney
J S
JS
Ellis
E F
EF
D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D001160:Arterioles / Q000187:drug effects; D001792:Blood Platelets / Q000378:metabolism; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D007213:Indomethacin / Q000494:pharmacology; D051379:Mice; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D013929:Thromboxane B2 / Q000096:biosynthesis
D010975:Platelet Aggregation Inhibitors; D013929:Thromboxane B2; C050715:8,9-epoxyeicosatrienoic acid; C046782:14,15-epoxy-5,8,11-eicosatrienoic acid; D015126:8,11,14-Eicosatrienoic Acid; D007213:Indomethacin