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Peripheral PACAP inhibits gastric acid secretion through somatostatin release in mice.

ABSTRACT: 1. Studies in rats suggest that PACAP modulates gastric acid secretion through the release of both histamine and somatostatin. 2. We characterized the effects of exogenous PACAP on gastric acid secretion in urethane-anesthetized mice implanted with a gastric cannula and in conscious 2-h pylorus ligated mice, and determined the involvement of somatostatin and somatostatin receptor type 2 (SSTR2) by using somatostatin immunoneutralization, the SSTR2 antagonist, PRL-2903, and SSTR2 knockout mice. 3. Urethane-anesthetized wild-type mice had low basal acid secretion (0.10+/-0.01 micromol (10 min)(-1)) compared with SSTR2 knockout mice (0.93+/-0.07 micromol (10 min)(-1)). Somatostatin antibody and PRL-2903 increased basal secretion in wild-type mice but not in SSTR2 knockout animals. 4. In wild-type urethane-anesthetized mice, PACAP-38 (3-270 microg kg(-1) h(-1)) did not affect the low basal acid secretion, but inhibited the acid response to pentagastrin, histamine, and bethanechol. 5. In wild-type urethane-anesthetized mice pretreated with somatostatin antibody or PRL-2903 and in SSTR2 knockout mice, peripheral infusion of PACAP-38 or somatostatin-14 did not inhibit the increased basal gastric acid secretion. 6. In conscious wild-type mice, but not in SSTR2 knockout mice, PACAP-38 inhibited gastric acid secretion induced by 2-h pylorus ligation. The antisecretory effect of PACAP-38 was prevented by immunoneutralization of somatostatin. 7. These results indicate that, in mice, peripheral PACAP inhibits gastric acid secretion through the release of somatostatin and the activation of SSTR2 receptors. There is no evidence for stimulatory effects of PACAP on acid secretion in mice.

SUBMITTER: Piqueras L

PROVIDER: S-EPMC1574929 | biostudies-other | 2004 May

REPOSITORIES: biostudies-other

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Project description:Background & aimsHypochlorhydria during Helicobacter pylori infection inhibits gastric Sonic Hedgehog (Shh) expression. We investigated whether acid-secretory mechanisms regulate Shh gene expression through intracellular calcium (Ca2(+)(i))-dependent protein kinase C (PKC) or cyclic adenosine monophosphate (cAMP)-dependent protein kinase A (PKA) activation.MethodsWe blocked Hedgehog signaling by transgenically overexpressing a secreted form of the Hedgehog interacting protein-1, a natural inhibitor of hedgehog ligands, which induced hypochlorhydria. Gadolinium, ethylene glycol-bis(β-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA) + 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA), PKC-overexpressing adenoviruses, and PKC inhibitors were used to modulate Ca(2+)(i)-release, PKC activity, and Shh gene expression in primary gastric cell, organ, and AGS cell line cultures. PKA hyperactivity was induced in the H(+)/K(+)-β-cholera-toxin-overexpressing mice.ResultsMice that expressed secreted hedgehog-interacting protein-1 had lower levels of gastric acid (hypochlorhydria), reduced production of somatostatin, and increased gastrin gene expression. Hypochlorhydria in these mice repressed Shh gene expression, similar to the levels obtained with omeprazole treatment of wild-type mice. However, Shh expression also was repressed in the hyperchlorhydric H(+)/K(+)-β-cholera-toxin model with increased cAMP, suggesting that the regulation of Shh was not solely acid-dependent, but pertained to specific acid-stimulatory signaling pathways. Based on previous reports that Ca(2+)(i) release also stimulates acid secretion in parietal cells, we showed that gadolinium-, thapsigargin-, and carbachol-mediated release of Ca(2+)(i) induced Shh expression. Ca(2+)-chelation with BAPTA + EGTA reduced Shh expression. Overexpression of PKC-α, -β, and -δ (but not PKC-ϵ) induced an Shh gene expression. In addition, phorbol esters induced a Shh-regulated reporter gene.ConclusionsSecretagogues that stimulate gastric acid secretion induce Shh gene expression through increased Ca(2+)(i)-release and PKC activation. Shh might be the ligand transducing changes in gastric acidity to the regulation of G-cell secretion of gastrin.

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Peripheral PACAP inhibits gastric acid secretion through somatostatin release in mice.

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