EFFECT OF SHORT-TERM TREATMENT WITH GASTRIN AND RELATED PEPTIDES ON GASTROINTESTINAL HISTAMINE-H(2)-RECEPTORS

The effects of short-term, 7-day, treatment with synthetic 15-leucine human gastrin 1, pentagastrin or sulfated cholecystokinin-8 on the activity of histamine (HA)-stimulated adenylate cyclase in membranes isolated from guinea pig gastric mucosa and H-2-receptor-mediated contractions of isolated ilea were evaluated. Treatment with each of the peptides produced a decrease in the maximal rate of HA-stimulated adenylate cyclase. The decreases in the maximal rate occurred without any effect on the potency of HA or any effect on basal rates of activity. In animals treated with pentagastrin, but not with cholecystokinin octapeptide sulfate, the contractile activity of dimaprit, a selective H-2-agonist, was decreased. In animals treated with pentagastrin, the contractile actions of pentagastrin on isolated ileal preparations were increased. A 7-day treatment with the H-2-antagonist, tiotidine, did not alter the potency of or the maximal response for HA-stimulated adenylate cyclase activity. Co-treatment with tiotidine prevented the effects of pentagastrin on gastric mucosal HA-stimulated adenylate cyclase. Treatment with pentagastrin did not alter the sensitivity of the gastric mucosal H-2-receptor to inhibition by tiotidine. The effects of treatment with gastrin on NaF-stimulated adenylate cyclase activity also were determined. Treatment with gastrin did not after the actions of NaF, suggesting that the coupling between the G(s) subunit and the catalytic subunit of adenylate cyclase was not altered. These results suggest that the decrease in the maximal response for HA-stimulated adenylate cyclase activity might be due to either a direct action of the peptides or due to a desensitization or down-regulation of gastric mucosal H-2-receptors that is produced by HA released by the peptides.