Selective release of somatostatin by calcitonin gene-related peptide and influence on pancreatic secretion.
Calcitonin gene-related peptide is a potent inhibitor of stimulated pancreatic exocrine secretion in vivo. The mechanism of this inhibitory action was studied in dogs and rats. The questions examined were: (1) is the inhibitory action of CGRP on pancreatic secretion mediated by somatostatin? (2) is the inhibition direct, via action on acinar cells, or indirect? and (3) is a neuronal mechanism involved, and, if so, by what pathway? In dogs with chronic pancreatic fistulae, CGRP caused significant inhibition of the outputs of pancreatic protein (63-68%) and of pancreatic bicarbonate (74-89%) and a simultaneous dose-related rise (40-102 fmol/ml) in plasma somatostatin-like immunoreactivity. A similar degree of inhibition was found when exogenous somatostatin was infused to achieve similar levels of plasma somatostatin-like immunoreactivity. More direct evidence of somatostatin mediation of CGRP action was sought in conscious rats with pancreatic fistulae using a potent and specific monoclonal antibody to somatostatin. The latter studies suggest that CGRP has both a somatostatin-dependent and a somatostatin-independent mechanism of action. In isolated rat acini, CGRP did not inhibit CCK-stimulated amylase release, suggesting that its in vivo action is indirect. In the isolated vascularly perfused rat pancreas, CGRP (10(-10)-10(-7) M) inhibited in a dose-dependent manner volume and protein output stimulated by a mixture of CCK-8 and secretin. The inhibitory action of CGRP was blocked by tetrodotoxin (10(-7) M) and by atropine (10(-7) M), but not by hexamethonium (10(-7) M). We conclude that CGRP action: (1) is partly explained by release of somatostatin; (2) is indirect; (3) is neurally mediated; and (4) involves cholinergic muscarinic neurons within the pancreas.
Debas
H T
HT
Department of Surgery, University of California, San Francisco 94143.
Nelson
M T
MT
Bunnett
N W
NW
Mulvihill
S J
SJ
D000681:Amylases / Q000378:metabolism*; D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000494:pharmacology*; D004285:Dogs; D006801:Humans; D066298:In Vitro Techniques; D010179:Pancreas / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D051381:Rats; D012844:Sincalide / Q000494:pharmacology; D013004:Somatostatin / Q000097:blood / Q000378:metabolism*
D013004:Somatostatin; D000681:Amylases; D015740:Calcitonin Gene-Related Peptide; D012844:Sincalide