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Current Topics in Pharmacology   Volumes    Volume 7  Issue 1
Regulation of release of natriuretic peptides in the gastrointestinal tract
William R. Gower Jr., David L. Vesely
Pages: 133 - 142
Number of pages: 10
Current Topics in Pharmacology
Volume 7  Issue 1

Copyright © 2003 Research Trends. All rights reserved


Atrial natriuretic peptides (LANPs) are a family of at least six peptide hormones synthesized primarily in the atria of the heart but also in a variety of other tissues including the gastrointestinal tract.  Within the stomach, atrial natriuretic peptide (ANP) prohormone gene expression has been localized in the rat gastric antrum using immunohistochemistry and in situ hybridization to mucosal cells in the lower portion of the antropyloric glands.  Co-localization with serotonin in these cells indicates these cells are enterochromaffin cells.

The secretion of ANP from the antrum of the stomach is regulated by both cholinergic decrease ANP secretion) and non-cholinergic pituitary adenylate cyclase activating polypeptide (PACAP) neurons which increase ANP secretion.  Utilizing selective neural agonists and antagonists has revealed the following regarding the neural pathways regulating ANP secretion in the stomach: The nicotinic agonist, 1, 1-dimethyl-4-phenylpiperazinium (10 pM-10 µM; DMPP), causes a concentration-dependent increase in ANP secretion (EC50, 3 nM) that is abolished by the nicotinic antagonist, hexamethonium, but augmented two-fold by atropine.  The effect of atropine implies that DMPP activated concomitantly cholinergic neurons that inhibit ANP secretion and non-cholinergic neurons that stimulate ANP secretion; the effect of the latter predominating.  Consistent with this, methacholine (10 pM-1mM) caused a concentration-dependent decrease in ANP secretion (EC50, 5nM).  Potential non-cholinergic transmitters responsible for stimulation of ANP include bombesin/gastrin-releasing peptide (bombesin), vasoactive intestinal polypeptide (VIP), and pituitary adenylate cyclase activating polypeptide (PACAP).  Neither bombesin nor VIP, at concentrations of 10 pM to 0.1 µM, stimulated ANP secretion, whereas PACAP-27, PACAP-38, and the PACAP type 1 (PAC1) receptor agonist, maxadilan, each caused a concentration dependent increase in ANP secretion.  The PAC1 receptor antagonist, M65 (0.1 µM): (1) abolished PACAP-27 and PACAP-38-stimulated ANP secretion, (2) inhibited basal ANP secretion by 28±5% (P<0.01), implying that endogenous PACAP stimulates ANP secretion, and (3) converted the ANP response to DMPP (1 µM) from 109±21% above to 40±5% below basal (control) level (P<0.01), thus unmasking the cholinergic component and indicating that it is DMPP activated PACAP neurons that stimulate ANP secretion.  A combination of atropine and M65 restored DMPP-stimulated ANP secretion to control basal levels.  These studies indicate that antrum of the stomach is regulated by intramural cholinergic and PACAP neurons; with cholinergic neurons inhibiting and PACAP neurons stimulating ANP secretion.

In addition to neuronal control of ANP secretion in the stomach, hormone(s) help regulate ANP secretion in the stomach.  Somatostatin (1 pM to 1 µM) causes a concentration-dependent decrease in ANP secretion (EC50, 0.7 nM) that is abolished by addition of the somatostatin subtype 2 receptor (sst2) antagonist, PRL 1325.  Neuralization of ambient somatostatin with somatostatin antibody (final dilution 1:200) increases basal ANP secretion by 70±8% (P<0.01), implying that endogenous somatostatin inhibits ANP secretion.

ANP (0.1 pM to 0.1µM), in turn, causes a concentration-dependent increase in somatostatin secretion (EC50, 0.3 nM).  The somatostatin response to ANP is unaffected by the axonal blocker tetrodotoxin but abolished by addition of the selective natriuretic peptide (NPR)-A antagonist, anantin.  Anantin alone inhibited somatostatin secretion by 18±3% (P<0.005), implying that endogenous ANP, acting via the NPR-A receptor, stimulates somatostatin secretion.  These studies suggest that antral ANP and somatostatin secretion are linked by paracrine feedback pathways: endogenous ANP, acting via the NPR-A receptor, stimulating somatostatin secretion, and endogeneous somatostatin, acting via the sst2 receptor, inhibiting ANP secretion.  These studies taken in combination suggest that both hormonal and neuronal mechanisms regulate the secretion of ANP from the stomach.      
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