CHARACTERIZATION OF SOMATOSTATIN RECEPTOR SUBTYPES CONTROLLING RAT GASTRIC-ACID AND PANCREATIC AMYLASE RELEASE

An examination of the binding characteristics of a large number of som atostatin analogues with respect to the five known somatostatin recept or subtypes has recently resulted in the discovery of several peptides with some selectivity for types 2, 3, and 4 and little affinity for t ype 1 or 5 receptor. A panel of these peptides has thus far implicated type 2 receptors in the inhibition of release of pituitary growth hor mone and type 4 receptors in inhibiting pancreatic insulin release. in the present article, we have examined the inhibitory effects of the s ame group of peptides on in vivo rat gastric acid and pancreatic amyla se release and binding to rat pancreatic acinar cells. The type 2-sele ctive ligand NC-8-12 was a potent inhibitor of gastric acid release (E C(50)s in the 1.5 nM region) whereas the type 4-selective ligand, DC-2 3-99, elicited little response. However, some involvement of type 3 re ceptors could not be ruled out because the type 3-selective analoueg, DC-25-20, exhibited inhibitory effects at higher dose levels (EC(50) > 10 nM). Conversely, the type 4 analogue was a potent inhibitor of amyl ase release (EC(50) 1.1 nM) whereas the type 3 analogue had no signifi cant effects at doses tested. DC-23-99 also bound with high affinity t o rat acinar cells (EC(50) 3.8 nM), whereas DC-25-20 exhibited more th an 10-fold less affinity. Thus, these two major biological functions o f somatostatin appear to be controlled by different receptors and, fur thermore, effects on both endocrine and exocrine pancreas appear to be type 4 receptor mediated.