Characterization of somatostatin receptor subtypes mediating inhibition of nutrient-stimulated gastric acid and gastrin in dogs

Five somatostatin receptor subtypes (SSTR) have been cloned and characterized in various tissues, including the gastrointestinal tract. This study examined which receptor subtypes mediate the inhibitory actions of somatostatin on gastric acid secretion and gastrin release in conscious dogs. Peptide agonists with relatively high specificity for SSTR1-5 (somatostatin-14), SSTR2 (MK-678), SSTR3 (L-362823), and SSTR5 (L-362855) were infused i.v. after nutrient-stimulated gastric acid secretion and gastrin release with intraduodenal perfusions of 8% peptone and after secretagogue-stimulated acid secretion with gastrin (75 pmol kg-1 h-1) or histamine (20 micrograms kg-1 h-1). At 1000 pmol kg-1 h-1, the SSTR2 agonist inhibited peptone-stimulated acid output to baseline (P < 0.001), whereas the SSTR3 agonist decreased acid output by 58 +/- 6% (P < 0.01): the SSTR5 agonist was without effect. The SSTR2 agonist at 100 pmol kg-1 h-1 also abolished the rise of plasma gastrin. At 50 pmol kg-1 h-1 i.v. infusions of S-14, to simulate circulating S-14 rises after nutrients, decreased peptone-stimulated acid secretion by 58 +/- 8% (P < 0.01), whereas the SSTR2 agonist inhibited gastric acid by 96 +/- 2% (P < 0.001); the SSTR3 agonist was without effect. S-14 or the agonists at 50 pmol kg-1 h-1 did not alter elevations of plasma gastrin. S-14 and the SSTR2 agonist at 50 pmol kg-1 h-1 decreased gastrin-stimulated acid secretion by 42 +/- 8% (P < 0.01) and 78 +/- 4% (P < 0.001), respectively but the SSTR3 and SSTR5 agonists were without effect. In contrast, histamine-stimulated acid secretion was not altered by 1000 pmol kg-1 h-1 S-14 or the agonists. These results in conscious dogs suggest that the inhibitory actions of circulating S-14 on nutrient and gastrin-stimulated acid secretion include activation of the SSTR-2 subtype. Regulation of gastrin release by S-14 may also occur via SSTR-2, but not through an endocrine mechanism. Factors in addition to gastrin and histamine modulate intestinal protein-stimulated acid secretion yet include peripheral S-14 inhibition via SSTR2 activation.