Significance of histamine formation and release in the development of endotoxic shock: proof of current concepts by randomized controlled studies in rats.

The significance of histamine in the initiation and progression of septic (endotoxic) shock is still uncertain. Increased new formation and increased release of histamine are the two hypotheses currently considered as the basis for a causal relationship. Both hypotheses were tested in a standardized rat model of endotoxic shock. Several randomized controlled studies were performed with inhibitors of histamine formation (histidine decarboxylase inhibitors) and of its action via receptors (H1 and H2 receptor antagonists). Two inhibitors of histamine formation (alpha-methylhistidine and alpha-fluoromethylhistidine) in a wide range of doses exerted no significant effects on survival curves for rats in endotoxic shock, despite enzyme inhibition in vitro and in homogenates of liver obtained from rats immediately after death. In addition, three H1 and three H2 receptor antagonists, which were selected on the basis of markedly different antihistaminic efficacies and of defined non-antihistaminic (nonspecific) efficacies, gave no indications of specific histamine-mediated effects on survival parameters in these studies when tested either singly or in various combinations. Thus, histamine cannot be shown to be a predominant factor in the lethal outcome of endotoxic shock in rats.