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.
- Activating factor
- Pulmonary hypertension