Examination of somatostatin involvement in the inhibitory action of GIP, GLP-1, amylin and adrenomedullin on gastric acid release using a new SRIF antagonist analogue.
1. The effect of a new type 2 selective somatostatin (SRIF) receptor antagonist (DC-41-33) on somatostatin-induced inhibition of pentagastrin-stimulated gastric acid secretion in conscious, chronic gastric fistula equipped rats was studied. 2. Infused intravenously, DC-41-33 dose-dependently inhibits SRIF-induced inhibition of pentagastrin-stimulated gastric acid secretion with an IC50 of 31.6+/-1.2 nmol kg(-1) versus 10 nmol kg(-1) SRIF and blocks the inhibitory effects of SRIF when simultaneously co-infused. Its effectiveness provides additional evidence that SRIF-inhibition of gastric acid release is a SRIF type 2 receptor-mediated process. 3. DC-41-33 is able to completely reverse the inhibitory effect of glucose-dependent insulinotropic polypeptides, GIP and GIP-(1-30)NH2, and glucagon-like polypeptide, GLP-1(7-36)NH2, on pentagastrin-stimulated gastric acid secretion thus confirming that they exert these effects through stimulation of endogenous SRIF release. 4. DC-41-33 only partially blocks potent amylin and adrenomedullin-induced inhibition of gastric acid secretion, therefore suggesting that somatostatin may not function as a primary mediator in the action of these peptides. 5. Our results indicate that DC-41-33, is a potent in vivo inhibitor of exogenous and endogenous SRIF in rats. It represents a new class of SRIF analogues which should eventually provide excellent tools for further evaluating the many physiological roles of SRIF and its five receptor subtypes.
Rossowski
W J
WJ
Department of Medicine, Tulane University School of Medicine, New Orleans, Louisiana 70112-2699, USA.
Cheng
B L
BL
Jiang
N Y
NY
Coy
D H
DH
D053607:Adrenomedullin; D000682:Amyloid / Q000494:pharmacology; D000818:Animals; D004305:Dose-Response Relationship, Drug; D005744:Gastric Acid / Q000378:metabolism*; D005749:Gastric Inhibitory Polypeptide / Q000494:pharmacology; D005768:Gastrointestinal Hormones / Q000494:pharmacology; D005934:Glucagon / Q000494:pharmacology; D052216:Glucagon-Like Peptide 1; D058228:Islet Amyloid Polypeptide; D008297:Male; D010446:Peptide Fragments / Q000494:pharmacology; D010455:Peptides / Q000494:pharmacology; D011498:Protein Precursors / Q000494:pharmacology; D051381:Rats; D017481:Receptors, Somatostatin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013004:Somatostatin / Q000378:metabolism*
D000682:Amyloid; D005768:Gastrointestinal Hormones; D058228:Islet Amyloid Polypeptide; D010446:Peptide Fragments; D010455:Peptides; D011498:Protein Precursors; D017481:Receptors, Somatostatin; D053607:Adrenomedullin; D013004:Somatostatin; D005749:Gastric Inhibitory Polypeptide; D052216:Glucagon-Like Peptide 1; D005934:Glucagon; C093733:somatostatin receptor 2