Prevention of endotoxin-induced gastrointestinal damage by CV-3988, an antagonist of platelet-activating factor

Abstract

The effects of endotoxin have been postulated to be mediated in large part by release of endogenous platelet-activating factor (PAF) due to the similarity of their hemodynamic and gastric effects in anesthetized animals, and to the ability of PAF inhibitors to ameliorate endotoxin's effects. We chose to examine the relationship with doses that would not produce circulatory shock, in unrestrained conscious animals, in order to mimic clinical situations. Adult male rats were prepared with vascular access, hemodynamic and temperature monitors, and gastric strain gauge transducers. After an overnight fast, rats received a 4-hr infusion of saline (0.5 ml/hr), endotoxin (12.5 mg/kg/hr), PAF (36 μg/kg/hr, or 600 ng/kg/min), or endotoxin plus the PAF inhibitor CV 3988 (1 mg/kg/hr, after an initial pretreatment of 1 mg/kg). Rats were killed, stomachs were harvested, and contents were analyzed at the end of the infusions. Blood pressure was not affected by any treatment, but all treated groups developed diarrhea and vasodilatation. Endotoxin and PAF infusions decreased heart rate and body temperature to a similar extent, although the PAF effect on temperature was delayed. The PAF inhibitor did not prevent the body temperature effect, but did reverse it. Gastric secretions were affected by PAF to a lesser extent than by endotoxin, and the PAF inhibitor did not decrease endotoxin's gastric secretory effects. PAF has similar systemic and gastric effects to endotoxin in conscious, unrestrained, normotensive animals. The systemic effects of endotoxin at 12.5 mg/kg/hr were prevented or reversed by the PAF inhibitor CV-3988 at 1 mg/kg/hr, but not the gastric secretory effects.