Effect of SRI 63-675 on hemodynamics and blood PAF levels during porcine endotoxemia

• Published in: The American journal of physiology Vol. 260; no. 5 Pt 2; p. H1455
• Main Authors: Dobrowsky, R T, Voyksner, R D, Olson, N C
• Format: Journal Article
• Language: English
• Published: United States 01.05.1991
• Subjects: Animals; Endotoxins - blood; Escherichia coli; Heart - drug effects; Heart - physiopathology; Hemodynamics - drug effects; Lung - drug effects; Lung - physiopathology; Mass Spectrometry - methods; Platelet Activating Factor - analysis; Platelet Activating Factor - antagonists & inhibitors; Quinolines - pharmacology; Swine
• ISSN: 0002-9513; 2163-5773
• DOI: 10.1152/ajpheart.1991.260.5.h1455

We evaluated the effect of SRI 63-675, a specific platelet-activating factor (PAF) receptor antagonist, on hemodynamics and PAF biosynthesis during 4 h of porcine endotoxemia. Hexadecyl PAF was extracted from blood, purified by normal-phase and reverse-phase high-performance liquid chromatography (RP-HPLC), and quantitated by stable isotope dilution and thermospray mass spectrometry. Infusion of either saline or SRI 63-675 alone caused no change in hexadecyl PAF concentrations. In contrast, endotoxin increased blood hexadecyl PAF concentrations from 1.5 +/- 0.1 ng/ml at 0 h (baseline) to a peak value of 8.3 +/- 1.9 ng/ml at 0.5 h of endotoxemia (P less than 0.05). Blood PAF levels gradually declined toward the baseline value after 0.5 h of endotoxemia. Because endotoxin did not modify plasma acetylhydrolase activity ex vivo, the increased hexadecyl PAF levels were probably secondary to increased PAF biosynthesis and not decreased biodegradation. Bioassay of RP-HPLC fractions that were derived from endotoxemic blood and that eluted at a retention time consistent with [3H]alkyl PAF caused aggregation of washed rabbit platelets that was inhibited by SRI 63-675. The PAF receptor antagonist blocked the 0.5 h endotoxin-induced increase in blood hexadecyl PAF concentration concomitant with blockade of thrombocytopenia. The endotoxin-induced pulmonary hypertension, decreased cardiac index, and increases in pulmonary vascular resistance and alveolar-arterial O2 gradient were attenuated by SRI 63-675. The data suggest that PAF-stimulated PAF biosynthesis may substantially contribute to blood hexadecyl PAF levels and cardiopulmonary dysfunction during the initial phase of endotoxemia.