Inhibition and reversal of endotoxin-, aggregated IgG- and paf-induced hypotension in the rat by SRI 63-072, a paf receptor antagonist

Tumor necrosis factor/cachectin stimulates peritoneal macrophages, polymorphonuclear neutrophils, and vascular endothelial cells to synthesize and release platelet-activating factor.

“…Vertical bars indicate the standard deviation of the mean of different experiments (n = 3) . The assay of PAF was carried out in duplicate for 1393 acid-independent way, which was specifically inhibited by the PAF receptor antagonists SR163072 and CV3988 (29,40) . PAF activity was destroyed after base-catalyzed methanolysis (0-1% residual activity) or after treatment with phospholipase A2 (0-3% residual activity), indicating the presence of an ester linkage at sn-2 (13,37,(41)(42)(43) .…”

“…It was subsequently shown that PAF is synthesized after appropriate stimulation by monocytes/macrophages (6-9), polymorphonuclear neutrophils (7, 10, 11), platelets (12) and endothelial cells (13-15) . PAF induces aggregation and degranulation of platelets (2, 16), stimulates contraction of smooth muscle (17), promotes chemotaxis and granule secretion of neutrophils (18-19) and monocytes (20), increases vascular permeability, and alters the vascular tone (21).It was recently suggested that PAF is a mediator of endotoxic shock (22-24) on the basis of the following observations : (a) PAF is produced during endotoxic shock and experimental sepsis by Gram-negative bacteria (23-25) ; (b) infusion of experimental animals with PAF results in hypotension, decrease in cardiac output, and hypovolemic shock (26-28) ; (c) three PAF receptor antagonists (CV3988, kadsurenone, and SRI 63072) inhibit or reverse endotoxin-induced hypotension and, in this way, prolong the survival of rats (22,23,29) .Tumor necrosis factor/cachectin (TNF) is a mediator of endotoxic shock (30). Because TNF administration to experimental animals reproduces several aspects of PAF infusion (30), it seems possible that PAF is synthesized in response to…”

“…It was recently suggested that PAF is a mediator of endotoxic shock (22)(23)(24) on the basis of the following observations : (a) PAF is produced during endotoxic shock and experimental sepsis by Gram-negative bacteria (23)(24)(25) ; (b) infusion of experimental animals with PAF results in hypotension, decrease in cardiac output, and hypovolemic shock (26)(27)(28) ; (c) three PAF receptor antagonists (CV3988, kadsurenone, and SRI 63072) inhibit or reverse endotoxin-induced hypotension and, in this way, prolong the survival of rats (22,23,29) .…”

Roles of Platelet-Activating Factor and Thromboxane in Group B Streptococcus-Induced Pulmonary Hypertension in Piglets

“…In newborn piglets, PAF-induced pulmonary hypertension is in large part mediated through TxA2 (35). Because these derangements resemble those produced by endotoxemia, the intravascular release and actions of PAF have been studied and found to be significant in a guinea pig model of Salmonella endotoxemia (17), and in Escherichia coli endotoxemia models in sheep (18, 34) and rats (19,20).GBS sepsis shares much of the pathophysiology of endotoxemia. As some of its effects are mediated by cyclooxygenase and lipoxygenase products (14,(21)(22)(23), in animal models pharmacologic blockade of either eicosanoid significantly attenuates the pathophysiologic abnormalities (5-9,24) and decreases mortality (25) in this condition.…”

“…In newborn piglets, PAF-induced pulmonary hypertension is in large part mediated through TxA2 (35). Because these derangements resemble those produced by endotoxemia, the intravascular release and actions of PAF have been studied and found to be significant in a guinea pig model of Salmonella endotoxemia (17), and in Escherichia coli endotoxemia models in sheep (18, 34) and rats (19,20).…”