INTRACISTERNAL NEUTRAL ENDOPEPTIDASE-24.11 INHIBITORS PRODUCE INHIBITION IN GASTRIC-ACID OUTPUT - INDEPENDENCE FROM OPIATE, BOMBESIN, OR NEUROTENSIN-MEDIATED MECHANISMS

Intracisternal (ic) injection of the neutral endopeptidase-24.11 inhib itor phosphoramidon (1-100 nmol) produced a dose-dependent inhibition of gastric acid secretion in 2-h pylorus-ligated rats. The response re sulted from a reduction in acid concentration and volume. Likewise, ic injection of another neutral endopeptidase-24.11 inhibitor Zincov (20 0 nmol) produced a 63% inhibition in gastric acid output. In contrast, neither intravenous injection of phosphoramidon (100 nmol) nor ic inj ection of the aminopeptidase inhibitor amastatin (100 nmol) produced a ny change in gastric acid secretion. The inhibitory effect of ic phosp horamidon (10 nmol) was not reversed by a dose of naloxone sufficient to antagonize the acid inhibitory effects of ic [D-Ala2-D-Met5]enkepha linamide (8.5 nmol). Moreover, phosphoramidon-induced inhibition of ac id was not reduced by the centrally effective bombesin antagonist N-ac etyl-GRP(20-26)-O-CH3 or by reserpine pretreatment at a dose effective to antagonize ic neurotensin-induced inhibition in acid secretion. Th ese results suggest that an endogenous neutral endopeptidase-24.11 sen sitive substrate may act in the brain to inhibit gastric acid output b y mechanisms independent of CNS opiate, bombesin or neurotensin activi ty.