Evidence of a role for PAF-acether in the pathophysiology of the shock state.

The pathophysiology of the shock state includes a variety of hemodynamic changes such as systemic hypotension, pulmonary hypertension and increased vascular permeability leading to the extravasation of protein rich plasma. These changes can be initiated by different etiological factors, but many of them have been related to the stimulation of activation systems (complement, kinins, etc.) or to the generation of inflammatory mediators. The purpose of the present study has been to obtain evidence of the involvement of paf-acether in the pathogenesis of the shock state initiated in rat and mouse by Gram-negative bacteria and soluble aggregates of immunoglobulin G. The injection of 1-2 MDa aggregates of immunoglobulin G to normal Sprague-Dawley rats, induced a dose-dependent systemic hypotension which appeared about five minutes after completion of the intravenous challenge. Simultaneously, extravasation of protein-rich plasma occurred as judged from the finding of an increased clearance of 125I-BSA. In similar experiments in mice, a reduction of the vascular volume was observed using 51Cr-labelled homologous red blood cells. Under these conditions, a lipid compound analogous to paf-acether was obtained from the liver and the spleen of these animals. The generation of this compound preceded the development of blood volume depletion and could be suppressed by either quinacrine or depletion of mononuclear phagocytes by total irradiation with 700 rads. The previous treatment of the rats with the compound BN 52021 (a specific antagonist of the paf-acether receptor) at a dose of 5mg/kg, i.v., prevented the appearance of hypotension and extravasation in response to an i.v. challenge with soluble aggregates of immunoglobulin G. Interestingly, the reversal of hypotension was also observed when BN 52021 was infused after the immunoaggregates (5mg/kg). The possible involvement of paf-acether in the hemodynamic changes of Gram-negative sepsis was studied in rats which had received an intraperitoneal inoculation of E. coli. The animals inoculated with the doses of bacteria which produced mortality showed a time- and dose-dependent increase of vascular permeability as judged from the presence of abundant peritoneal exudate and the reduction of the circulating volume. Simultaneously, significant amounts of paf-acether could be obtained from the peritoneal exudate and from the spleen preceding to the development of the circulating volume depletion.(ABSTRACT TRUNCATED AT 400 WORDS)