The effects of (E)-3-[p-(1H-imidazol-1-ylmethyl)phenyl]-2-propenoic
acid (OKY-046) on
thromboxane A2 (TXA2)
synthetase in vitro and on experimental animal models of
sudden death and
cerebral infarction were studied. IC50 values of
OKY-046 for the TXA2
synthetase of human, rabbit, dog and guinea pig washed platelets were 0.004, 0.004, 0.26 and 2.4 microM, respectively.
OKY-046 at concentrations up to 1 mM, however, did not inhibit
prostacyclin (
PGI2) synthetase from bovine aorta microsomes or
cyclooxygenase and
PGE2 isomerase from sheep seminal vesicle microsomes. Similarly, platelet
12-lipoxygenase was not affected by
OKY-046. Evidence for a re-direction of arachidonate metabolism from
thromboxane synthesis toward PGI2 synthesis was obtained using rat peritoneal cells. Namely,
OKY-046 increased PGI2 production accompanied by an inhibition of TXA2 production at a concentration of more than 1 microM.
OKY-046 at a dose of 0.1 mg/kg (i.v.) in dogs inhibited the aortic and mesenteric arterial contraction of rabbit induced by the addition of arachidonate to extracorporated blood of the dogs.
OKY-046 at a dose of 0.3 mg/kg (i.v.) prevented the arachidonate-induced
sudden death and also decreased the incidence of
cerebral infarction induced by injection of arachidonate into the internal carotid artery in rabbits.
Aspirin also decreased the incidence of
cerebral infarction at a dose of 30 mg/kg (i.v.). These results suggest that
OKY-046 may be valuable for the treatment of cerebrovascular and
cardiovascular diseases associated with vasoconstriction and
thrombosis due to TXA2.