In vivo enhancement of platelet activating factor-induced prostacyclin production by OKY-046, a selective inhibitor of thromboxane a₂ synthase

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 TXA₂ synthase 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-PGF 1α). 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 TXB₂ was 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). TXB₂ levels 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-PGF 1α 6 ± 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 TXB₂ and 100 increase in plasma 6-keto-PGF 1α. 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.