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Naloxone-reversible inhibition of gall-bladder mucosal fluid secretion in experimental cholecystitis in the cat by acetorphan, an enkephalinase inhibitor.

1. Enkephalin immunoreactive nerve fibres have been demonstrated in the gall bladder of various mammals including man. In various tissues, enkephalins are partly degraded by a membrane metallo-endopeptidase, enkephalinase (EC 3.4.24.11). 2. Using 3H-labelled [D-Ala2,Leu5]enkephalin as a substrate, enkephalinase activity, immunoprecipitated by a monoclonal antibody directed against the rabbit kidney enzyme, was demonstrated in the feline gall bladder. Using the same antibody in 125I-labelled form, the peptidase was immunolocalized by autoradiography, mainly in the epithelium. 3. In experimental cholecystitis, elicited by implantation of human gall-stones into the cat gall bladder, the continuous fluid secretion into the lumen was inhibited by exogenous enkephalins. 4. Acetorphan, an enkephalinase inhibitor, was found to block fluid secretion by the inflamed gall bladder via a naloxone-sensitive mechanism, but not to affect fluid transport in the normal gall bladder. The drug also transiently contracted the gall bladder and increased bile outflow from the liver. 5. It is suggested that acetorphan, by reducing the degradation of endogenous enkephalins in the inflamed gall bladder, decreases fluid secretion by the epithelium and that enkephalinase inhibitors may find clinical applications in acute cholecystitis.