BENEFICIAL EFFECT OF H2−AGONISM AND H1−ANTAGONISM IN RAT ENDOTOXIC SHOCK

Abstract

Although histamine release is generally considered harmful in endotoxic shock, several data exist to doubt this view. Own previous studies in rats let us assume a possible beneficial effect only with H1-antagonists, however a detrimental effect on survival with H2-antagonists. Consequently H1- and H2-agonists and antagonists were studied to prove the hypothesis of a beneficial H2-agonistic and H1-antagonistic effect. Two randomized studies were performed in a standardized rat endotoxic shock model (45 mg of Escherichia coli endotoxin/kg body weight (b.w.)). In both, methylprednisolone (50 mg/kg b.w.) and saline were used as positive and negative controls, respectively. Study I compared the effects of H1- and H2-agonists (betahistine, .1 mg/kg/h, and impromidine, 100 micrograms/kg/h) with H1- and H2-antagonists (astemizole and famotidine both 1 mg/kg b.w.; 20 rats/dose). Study II was performed to estimate the dose-response relationship of a new, highly potent H2-agonist with additional H1-antagonistic features (BU-E 75: .01, .1, 1.0, 10, and 100 micrograms/kg/h; 20 rats/dose). Animals receiving impromidine or BU-E 75 all received omeprazole (1 mumol/kg b.w.) to suppress gastric acid secretion. In study I impromidine significantly increased the survival-time and -course compared to famotidine treated animals (p = .01 and p < .05). Study II showed a positive dose-response relationship of BU-E 75 with an increase in survival rates from 30% (.01 microgram/kg/h) to 70% (100 micrograms/kg/h). These data strongly support the hypothesis of a beneficial effect of H2-agonism and H1-antagonism on survival parameters in rat endotoxic shock.