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Recent evidence suggests that the platelet-inhibitory drugs sulfin-pyrazone and ibuprofen may have value in treatment of coronary artery disease. However, these drugs do not only block platelet aggregation, but also block synthesis by blood vessels of prostaglandins that promote vasodilation. Platelets may differ from blood vessels in their sensitivity to sulfinpyrazone or ibuprofen. In theory, optimal doses for coronary disease would inhibit potentially deleterious platelet aggregation but not interfere with synthesis of possibly beneficial vasodilator prostaglandins. To determine whether it was possible to identify such optimal doses we measured the effects of intravenous sulfinpyrazone, 0.3–100 mg/kg (n= 9), or sodium ibuprofen, 0.1–3 mg/kg (n= 7), on vasodilation induced by the protaglandin precursor arachidonic acid. We also assessed drug effects on in vitroplatelet aggregation in the same animals. Both sulfinpyrazone and ibuprofen caused a dose-related reduction in flow increment after arachidonic acid. Sulfinpyrazone, ≥10 mg/kg, and ibuprofen, ≥1 mg/kg, produced a mean reduction of least 60 (p< 0.02 for each) in the vasodilator response to 1 mg arachidonic acid. Sulfinpyrazone, 0.3 mg/kg, and ibuprofen, 0.1 mg/kg, had no consistent effects on flow. Flow rise after intracoronary prostaglandin E2was undiminished by sulfinpyrazone or ibuprofen. Sulfinpyrazone, ≥10 mg/kg, and ibuprofen, ≥1 mg/kg, markedly inhibited platelet aggregation induced by adenosine diphosphate, 2.3 x 10-5M (p< 0.01 for each). Sulfinpyrazone, 0.3 mg/kg, and ibuprofen, 0.1 mg/kg, failed to alter platelet aggregation. Hence, sulfinpyrazone and ibuprofen doses inhibiting platelet function also produced comparable inhibition of arachidonic acid-induced coronary vasodilation, presumably by interfering with arachidonic acid conversion to vasodilator prostaglandins. Neither sulfinpyrazone nor ibuprofen, administered acutely, appears to have an “optimal” dose that in

Platelet-activating factor (PAF) a likely mediator of endototin action. causes thromhovane A, (TXA2) release and pulmonary hypertension in pigs. We examined the effect of selective TXA2synthase inhihition with OKY 046 on cyclooxygenase metabolites during PAF-induced pulmonary hypertension. Sig closed-chest pigs received PAF in escalating doses (0.1, 0.3, and 3.0 nmol intravenously, i.v.) before and after (E)-3[4-(1-imidazolyl methyl) phenyl]-Z-propenoic acid hydrochloride monohydrate OKY-046. 10-mg kg i.v. bolus plus 20-mg kg h infusion. Plasma samples at peak PAF effect had radioimmunoassay (RAI) for the stahle metabolites of TXA2(TXB2) and prostacyclin (6-keto-PGF1α). Tachyphylaxis was not noted in 5 control pigs given sequential repeats of the PAF dosing series. Pulmonary vascular resistance (PVR) was 240 ± 30 (SE) dynesem at baseline and increased to 3.100 ± 1.300 alter 1.0 nmol PAF (p 0.05). When the same amount of PAF was given after OKY-046. PVR increased only to 820 ± 280 dynes 8 cm TXB2was 34 ± 7 pg 0.1 ml at baseline and increased to 70 ± 4 pg 0.1 ml with PAF 1.0 nmol (p 0.001). TXB2levels were unchanged from 34 ± 4 pg 0.1 ml when PAP 1.0 nmol was administered alter OKY-046 INS vs. pre-OKY-046). In contrast. 6-keto-PGF1α6 ± 2 pg 0.1 ml at baseline increased to 24 ± 4 pg 0.1 ml after PAF 1.0 nmol and increased further to 50 ± 4 pg 0.1 ml when PAF 1.0 nmol was given after OKY-046 (p 0.05 vs. pre-OKY-046). Thus, OKY-046 attenuation ofa PAF induced increase in PVR was associated with a 50 reduction in plasma TXB2and 100 increase in plasma 6-keto-PGF1α. The latter may reflect arachidonate shunting to prostacyclin production with dual beneficial effects at the site of PAF action: decrease in vasomotor tone, and dispersion of platelet aggregates.