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 endotoxin action, causes thromboxane A2 (TXA2) release and pulmonary hypertension in pigs. We examined the effect of selective TXA2 synthase inhibition with OKY-046 on cyclooxygenase metabolites during PAF-induced pulmonary hypertension. Six closed-chest pigs received PAF in escalating doses (0.1, 0.3, 1.0, 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 (RIA) for the stable metabolites of TXA2 (TXB2) and prostacyclin (6-keto-PGF1 alpha). Tachyphylaxis was not noted in 5 control pigs given sequential repeats of the PAF dosing series. Pulmonary vascular resistance (PVR) was 240 +/- 30 (SE) dyne s cm-5 at baseline and increased to 3,100 +/- 1,300 after 1.0 nmol PAF (p less than 0.05). When the same amount of PAF was given after OKY-046, PVR increased only to 820 +/- 280 dynes/s/cm-5. 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 less than 0.001). TXB2 levels were unchanged from 34 +/- 4 pg/0.1 ml when PAF 1.0 nmol was administered after OKY-046 (NS vs. pre-OKY-046). In contrast, 6-keto-PGF1 alpha, 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 +/- 8 pg/0.1 ml when PAF 1.0 nmol was given after OKY-046 (p less than 0.05 vs. pre-OKY-046).(ABSTRACT TRUNCATED AT 250 WORDS)
Davenport
N J
NJ
Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD 20814-4799.
Goldstein
R E
RE
Feuerstein
G Z
GZ
D015121:6-Ketoprostaglandin F1 alpha / Q000097:blood; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D011464:Epoprostenol / Q000096:biosynthesis*; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D008297:Male; D008689:Methacrylates / Q000494:pharmacology*; D010972:Platelet Activating Factor / Q000494:pharmacology*; D013552:Swine; D013928:Thromboxane A2 / Q000378:metabolism; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors*; D014655:Vascular Resistance / Q000187:drug effects
D008689:Methacrylates; D010972:Platelet Activating Factor; D013928:Thromboxane A2; D015121:6-Ketoprostaglandin F1 alpha; D011464:Epoprostenol; D013930:Thromboxane-A Synthase; C034364:ozagrel