Prevention of the Generalized Shwartzman Reaction by Bradykinin and Prostaglandins

Abstract

We have investigated, in the pregnant rat, the implications of Hageman factor and prekallikrein activation in the pathogenesis of the generalized Shwartzman reaction (GSR). We have found that unlike the hyperlipemia animal, the pregnant rat, which develops the GSR after a single injection of endotoxin (S. typhosa 0.4 mg) on day 20 of gestation, does not consume prekallikrein. Prekallikrein was estimated by measurement on TAME of the arginine esterase activity generated by kallikrein upon addition of active Hageman factor to the test plasma. Bradykinin triacetate (2 or 4 μg/kg/min.), prostaglandin (PG) E-, (0.3 μg/kg/min.), PGA2 (1.0 μg/kg/min.) or isoproterenol (0.66 μg/kg/min.) when given as a slow infusion over 4 hours, from the time of the endotoxin to the sacrifice of the animals, were found to prevent the GSR. On the other hand, aspirin (150 mg/kg) or propranolol (2 mg/kg) given before endotoxin enhance the incidence or severity of the GSR. Furthermore, aspirin markedly reduces the prevention generated by bradykinin infusion and to a less extent that of isoproterenol. Finally, indomethacin (7 mg/kg) given twice daily for 3 days sensitizes the male rat to the GSR, since a single injection of endotoxin triggers deposition of fibrin in the glomerular capillaries. It is concluded that bradykinin generates the release of PG’s and that together they prevent, like the α-adrenergic and the D-serotoninergic blocking agents and or like a β-adrenergic stimulation, the renal vasomotor reactions found necessary for the GSR. These results support the hypothesis that impairment of kinin generation may possibly account for the sensitization of the pregnant rat to the GSR.