Reversal of Enterotoxic Diarrhoea by Anaesthetic and Membrane‐stabilizing Agents

Abstract

The effect of membrane‐stabilizing and sedative drugs on enterotoxic diarrhoea was studied in mice. Fluid secretion was induced in ligated loops of the small intestine by challenge with cholera toxin (CT), heatlabile enterotoxin (LT) from Escherichia coli or dibuturyl‐cyclic AMP (dB‐cAMP). Chlorpromazine, melperone, diazepam, mebumal, ketamine and ethanol all inhibited CT‐induced hypersecretion, ED50 being 1.5, 4, 4, 35, 70 and 1500 mg/kg, respectively. The drugs also blocked CT‐stimulation of adenylate cyclase, which mediates the action of CT. Concomitant with the antisecretory effect a sedative effect was induced, as judged by the motility and righting reflex of the animals. Hypersecretion by E. coli and LT was also totally blocked by chlorpromazine, diazepam, ketamine and ethanol. In contrast, the secretion by dB‐cAMP which bypasses adenylate cyclase in its action, was not affected by diazepam and was only partly reversed by chlorpromazine, ketamine and ethanol. The reversal of dB‐cAMP‐secretion is probably due to enhanced absorption, rather than inhibition of adenylate‐cyclase. The use of membrane‐stabilizing drugs may represent a new principle for pharmacological treatment of diarrhoea.

INTERNALIZATION IN VIVO OF CHOLERA TOXIN IN THE SMALL INTESTINAL EPITHELIUM OF THE RAT

“…Chlorpromazine, on the other hand, completely quenched CT-induced fluid secretion, apparently without affecting the distribution of CT in intestinal cells. This agrees with previous results (7, 10) suggesting that chlorpromazine interferes specifically by direct interaction with adenylate cyclase.…”