The combination of
thromboxane (TX) synthase inhibition and
prostaglandin (PG) H2/TXA2 receptor antagonism yields enhanced antithrombotic effects as compared with either intervention alone. However, it is not known whether the enhancing effect of TX synthase inhibition is expressed also in the presence of complete blockade of
PGH2/TXA2 receptors. Thus we evaluated the antithrombotic effects of increasing doses of the
PGH2/TXA2 receptor antagonist
L 670596 alone and in combination with a dose of the TX synthase inhibitor
FCE 22178 causing > 95% inhibition of platelet TXB2 production. In the dog model of electrically induced
coronary thrombosis, occlusion time in control animals (n = 14) averaged 72 +/- 29 min.
L 670596 alone dose-dependently antagonized platelet
PGH2/TXA2 receptors and prolonged occlusion time. The addition of
FCE 22178 displaced the dose-occlusion time relation of
L 670596 in a parallel fashion without modifying receptor occupancy. In the rabbit model of
copper coil-induced
carotid artery thrombosis, occlusion was very rapid (14 +/- 4 min) in control animals (n = 17) and was not modified by either
aspirin or
FCE 22178.
L 670596 caused a dose-related receptor blockade and prolongation of occlusion time. The association with
FCE 22178 enhanced significantly the antithrombotic effect of
L 670596 at all doses. We conclude that the full therapeutic potential of
PGH2/TXA2 receptor antagonism is expressed at > 90% platelet receptor occupancy. The additive effect of TX synthase inhibition suggests that conversion of
PGH2 to
platelet-inhibitor and
vasodilator prostaglandins might be of therapeutic importance, irrespective of the extent of
PGH2/TXA2 receptor blockade.