Mechanisms of hypotension produced by platelet-activating factor.
Platelet-activating factor (PAF) is a phospholipid mediator that induces cardiovascular collapse and release of the secondary mediator thromboxane A2 (TxA2). To clarify mechanisms involved in this collapse and, specifically, the relative contribution of left ventricular and right ventricular dysfunction, we studied 12 open-chest pigs. PAF infusion (0.04-0.28 nmol.kg-1.min-1) induced a 5- to 120-fold increase in pulmonary vascular resistance, a 75-98% fall in cardiac output, and systemic arterial hypotension. Right ventricular failure was indicated by chamber enlargement, decreased shortening, and increased right atrial pressures. In contrast, left ventricular dysfunction was accompanied by decreases in chamber dimensions and filling pressures that were unresponsive to volume expansion. U 46619 (a stable TxA2 analogue) and mechanical pulmonary artery constriction induced changes similar to PAF. In 11 additional closed-chest pigs, TxA2 blockade with indomethacin attenuated the PAF-induced rise in pulmonary vascular resistance, right ventricular dysfunction, and systemic hypotension. A specific TxA2 synthase inhibitor, OKY-046, also diminished hemodynamic effects of PAF in six other pigs. Tachyphylaxis was not observed in five pigs repeatedly given PAF. We conclude that acute right ventricular failure as the result of severe increase in pulmonary vascular resistance is the primary mechanism early in the course of PAF-induced shock in the pig. PAF-induced release of TxA2 may contribute significantly to these events.
Laurindo
F R
FR
Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20814-4799.
Goldstein
R E
RE
Davenport
N J
NJ
Ezra
D
D
Feuerstein
G Z
GZ
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000818:Animals; D005260:Female; D007022:Hypotension / Q000139:chemically induced* / Q000503:physiopathology; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D008689:Methacrylates / Q000494:pharmacology; D010972:Platelet Activating Factor / Q000494:pharmacology*; D011450:Prostaglandin Endoperoxides, Synthetic / Q000494:pharmacology; D013552:Swine; D013928:Thromboxane A2 / Q000494:pharmacology*; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors
D008689:Methacrylates; D010972:Platelet Activating Factor; D011450:Prostaglandin Endoperoxides, Synthetic; D013928:Thromboxane A2; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D013930:Thromboxane-A Synthase; C034364:ozagrel; D007213:Indomethacin