Search

The neurotoxicity of the histamine H2 agonist dimaprit was characterized. Dimaprit (100 micrograms administered into the lateral cerebral ventricle) induced a large area of brain necrosis 1-3 days later which was uniformly lethal. Lower doses caused dose - related effects on survival, gross brain pathology and body weight. Experiments with other H2 agonists and H2 antagonists, together with studies by others demonstrating a similar toxicity of the congener homodimaprit suggest that the neurotoxicity of dimaprit is independent of brain H2 receptors. Although dimaprit is a useful tool for the characterization of H2 receptor responses, the present results show that this agent must be used with caution, if at all, in classifying brain H2-receptor mediated events.

The Dimaprit analog, S-[4-(N,N-dimethylamino)-butyl]isothiurea (SKF Compound 91488), which is a noncompetitive inhibitor (Ki, 0.9 microM) of histamine-N-methyltransferase in vitro, inhibited the methylation of labeled histamine in mice. When administered in combination with the diamine oxidase inhibitor, aminoguanidine, an almost complete block of histamine metabolism was observed. The inhibition was dependent on dose of drug and was apparent with doses of 50 mg/kg and greater. Since Compound 91488 is reported to have no agonist activity of its own, the drug may help to identify the actions of histamine released from endogenous stores in response to physiological and pathological stimuli.

Although the factors involved in the induction of gastric pathology have long been studied, the exact roles of the two histamine receptors in this process are still obscure. The aim of this study was to evaluate the consequences of the activation of histamine H1- and/or H2-receptors in the pathogenesis of gastric damage and antagonism of these pathological developments by specific antagonists. The following agents were used: histamine as H1- and H2H2-agonist; 2-pyridylethylamine (PEA) and mepyramine as H1-agonist and antagonist; dimaprit and ranitidine as H2-agonist and antagonist. Intravenous administration of the agonists caused definite gastric damage in rats. Both the antagonists inhibited histamine-induced gastric lesions, but the PEA and dimaprit-induced erosions could be prevented only by giving the specific H1- or H2-antagonist. In conclusion, activation of either H1- or H2-receptors can play a crucial role in the pathogenesis of histamine-induced gastric damage in rats.