Concurrent elevation of fundic somatostatin prevents gastrin stimulation by GRP

Gastrin-releasing peptide (GRP) can stimulate both gastrin and somatostatin (SOM) secretion, but, as gastrin increases SOM and SOM in turn inhibits gastrin, the overall endpoint in terms of gastrin output is variable. To examine the mechanisms involved, we compared the effects of GRP on gastrin secretion in normal sheep and sheep chronically immunized against SOM. In the normal animal, GRP had no effect on either plasma gastrin or SOM. However, in sheep immunized against SOM, GRP stimulated gastrin secretion, suggesting that the concurrent stimulation of SOM prevents the increase in gastrin secretion. To determine the local source of SOM, GRP was then infused into nonimmunized sheep with cannulas draining blood from the fundus and antrum. GRP stimulated fundic SOM output but inhibited antral SOM and gastrin secretion, demonstrating that the fundus was the source of the SOM. Because cholinergic interactions have a major influence on the effects of GRP, a cholinergic stimulus was administered, and we found that the responses were different: SOM output was inhibited in both the antrum and fundus, and antral gastrin secretion was increased. The present study demonstrates two further instances of the differential regulation of SOM from the antrum and fundus. GRP fails to stimulate gastrin because of an increase in fundic SOM, whereas gastrin levels increase following a cholinergic stimulus because of inhibition of both antral and fundic SOM secretion.