Somatostatin inhibits pancreatic exocrine secretion via a neural mechanism

Abstract

The mechanism of inhibition of pancreatic exocrine secretion by somatostatin is unknown. We hypothesized that somatostatin acts indirectly, via intrinsic pancreatic neurons, to inhibit pancreatic exocrine secretion. To test this hypothesis, amylase and volume outputs in response to secretin (10 −8 mol/L) and cholecystokinin octapeptide (CCK) (10 −8 mol/L) were studied in the rat isolated, perfused, pancreas model. Somatostatin (10 −7 mol/L) significantly inhibited amylase output by 48% compared with control ( 352 ± 57 v 676 ± 85 U 30 min , P < .05 by ANOVA). Blockade of axonal neuronal transmission by tetrodotoxin (10 −7 mol/L) completely abolished the inhibitory effect of somatostatin ( 992 ± 53 U 30 min ). Similar effects were seen on volume output. The inhibitory effect of somatostatin on amylase output was not affected by cholinergic receptor blockade with atropine ( 328 ± 65 U 30 min ) or by sympathetic ganglionic blockade with hexamethonium ( 360 ± 68 U 30 min ). This suggests that the intrinsic pancreatic neurons responsible for the inhibitory effect of somatostatin are peptidergic. The possibility that somatostatin acts directly on the acinar cell to inhibit exocrine secretion was tested by incubating varying doses of somatostatin (10 −12 to 10 −7 mol/L) with isolated pancreatic acini in the presence of graded concentrations of CCK (10 −12 to 10 −10 mol/L). In this model, CCK alone is a potent stimulant of amylase release, with a Km of 6 × 10 −12 mol/L and a V max of 22 ± 3% total amylase. In this model, somatostatin had no inhibitory effect. The possibility that somatostatin releases a secondary inhibitory mediator from the pancreas was tested by perfusing rat pancreata arterially with 10 −7 mol/L somatostatin and collecting portal venous effuent. Aliquots of unconcentrated and 60-fold concentrated portal venous effluent were tested for inhibitory activity in the isolated acinar preparation in the presence of graded concentrations of CCK. As control, portal venous effluent was collected from pancreata perfused arterially with buffer alone. No inhibitory activity was identified in these perfusated suggesting that somatostatin does not release a secondary inhibitory substance to modulate pancreatic inhibition. We conclude that the mechanism of inhibition of pancrestic exocrine secretion by somatostatin is indirect, via intrinsic, inhibitory pancreatic neurons. These neurons are likely peptidergic.