Beneficial effect of H2-agonism and H1-antagonism in rat endotoxic shock.

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.