Effect of SRI 63-675 on hemodynamics and blood PAF levels during porcine endotoxemia.
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.
Dobrowsky
R T
RT
Department of Anatomy, Physiological Sciences, and Radiology, College of Veterinary Medicine, North Carolina State University, Raleigh 27606.
Voyksner
R D
RD
Olson
N C
NC
D000818:Animals; D004731:Endotoxins / Q000097:blood*; D004926:Escherichia coli; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D006439:Hemodynamics / Q000187:drug effects*; D008168:Lung / Q000187:drug effects / Q000503:physiopathology; D013058:Mass Spectrometry / Q000379:methods; D010972:Platelet Activating Factor / Q000032:analysis* / Q000037:antagonists & inhibitors; D011804:Quinolines / Q000494:pharmacology*; D013552:Swine
D004731:Endotoxins; D010972:Platelet Activating Factor; D011804:Quinolines; C053130:SRI 63-675