Platelet activating factor (PAF) involvement in endotoxin-induced hypotension in rats. studies with paf-receptor antagonist kadsurenone

Effects of endothelin‐1 on vascular permeability in the conscious rat: interactions with platelet‐activating factor

“…Enhanced plasma levels of endothelin-1 have recently been reported in pathological conditions, including ischaemia (Yasuda et al, 1990;Watanabe et al, 1990) and endotoxin shock (Morel et al, 1989) when enhanced blood PAF levels can also be detected (Doebber et al, 1985;Filep et al, 1989;Montrucchio et al, 1989;M6zes et al, 1989). Since PAF and endothelin-1 exert opposite effects on the vascular tone in most vascular beds (PAF is usually a vasodilator while endothelin-1 is a vasoconstrictor), one might assume that they could modify each other's effects on vascular permeability.…”

“…Elevated plasma concentrations of endothelin-1 and PAF have been reported under the same pathological conditions including ischaemia Mozes et al, 1989;Montrucchio et al, 1989;Yasuda et al, 1990;Watanabe et al, 1990) and endotoxin shock (Doebber et al, 1985;Morel et al, 1989). Since enhanced plasma extravasation is a characteristic feature of these conditions, it can be postulated that endothelin-1 and PAF could act together to modulate vascular permeability.…”

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

“…Therefore, PAF may be involved in a variety of immunopathological reactions triggered by different cellular effectors. In addition to its role in acute inflammatory reactions, PAF may be a mediator of shock when it is released intravascularly in massive amounts within a short period of time (23)(24)(25)(26)(27)37) . The present study shows that, after stimulation with TNF, rat peritoneal macrophages, human endothelial cells, and rat PMN synthesize and release PAF.…”

“…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) .…”