Protection of rats from compound 48/80-induced lethality. A simple test for inhibitors of mast cell-mediated shock

Abstract

The dose of 0.5 mg/kg i.v. of compound 48/80 was lethal in 97.2% of the injected rats. Observations before death and at autopsy were in accordance with the basic effect of compound 48/80 in rats i.e. the sustained release of mast cell mediators, whose action on the cardiovascular system leads to circulatory collapse. The administration of drugs with various pharmacological effects before the intravenous challenge with compound 48/80 allowed us to conclude that the following effects are not sufficient to prevent the lethal shock: inhibition of prostaglandin biosynthesis; H2-histamine antagonism; cholinergic, alpha- or beta-adrenergic blockade; beta-adrenergic stimulation; CNS-effects of antidepressants, hypnotics, sedatives, neuroleptics or narcotic analgesics; ganglion blockade; glucocorticoid or cromoglycate-like activity. Dose-dependent protection from the lethal reaction was obtained with compounds known to exert a single or several actions of the following types: oxatomide-like inhibition of mast cell mediator release; h1-histamine antagonism; serotonin antagonism. Quantitatively, however, when measured in in vitro systems these effects are poorly related to the protection from lethal compound 48/80 challenge. The new test offers the advantage of a simple, comprehensive measure of the potency of a compound to prevent mast cell-mediated shock.