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We investigated the effects of the sensory neuropeptide substance P (SP) on amylase and fluid secretion in the isolated vascularly perfused rat pancreas. SP inhibited CCK-induced amylase release and secretin-induced juice flow via the pancreatic duct in a dose-related fashion. Threshold inhibition occurred following addition of 10(-10) M SP to the perfusate, and maximal inhibition was seen with 10(-8) M SP. The effects of SP were partially blocked by both the neurokinin-1 (NK1) and neurokinin-2 (NK2) receptor antagonists. Atropine and TTX blocked SP-induced effects on both amylase secretion (26 and 63% blockade, respectively) and pancreatic juice flow (21 and 79% blockade, respectively). Excitation of pancreatic sensory nerves using capsaicin (in the absence of SP) inhibited both amylase and pancreatic juice flow via activation of the NK1 receptor. We conclude that SP inhibits exocrine secretion via an indirect neural mechanism.

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In adult gastric epithelium, gastrin and somatostatin regulate parietal cell acid secretion; however, their expression and function in the fetus are largely unknown. We defined the developmental expression of gastrin and somatostatin in the fetal rabbit stomach and determined their effects on fetal acid secretion. To define peptide expression, fetuses from 12 time-mated New Zealand white rabbit does were analyzed at successive ages during the third trimester (term is 31 days). Peptides were extracted from fetal gastric tissue by boiling in water and then in acetic acid. Amidated gastrin and somatostatin levels were measured by radioimmunoassay using antisera 1296 for gastrin and 8402 for somatostatin. To determine the effects of gastrin and somatostatin, pentagastrin (64 microg/kg/hr) or octreotide (35 microg/kg/hr) were infused intravenously in conscious pregnant rabbits at 28 days of gestation for 3 hr. Fetuses (n = 45) were harvested and gastric acid was titrated with 0.02 N NaOH. Gastrin and somatostatin tissue content were 12 +/- 3 and 51 +/- 6 pmol/g at gestational day 20, respectively, and increased to 146 +/- 10 and 162 +/- 5 pmole/g by day 30 (P < 0.05). Between days 24 and 26, when gastric acid was first detectable, the molar ratio of somatostatin to gastrin decreased from 5.0 +/- 1.0 to 1.1 +/- 0.1 (P < 0.05). Fetal gastric acid content (micromole) was 28.5 +/- 1.7 in controls, 27.5 +/- 1.9 with pentagastrin treatment, and 15.8 +/- 1.4 micromole with octreotide (P < 0.05). In summary, 1) In fetal gastric tissue, gastrin increased 12-fold and somatostatin increased 3-fold between days 20 and 30 of gestation. 2) The decreased ratio of somatostatin to gastrin between days 24 and 26 of gestation coincides with the onset of fetal gastric acid secretion in the fetal rabbit. 3) Maternal administration of octreotide inhibited fetal gastric acid content; however, pentagastrin had no effect. We conclude that, in the fetal rabbit stomach, the relative expression of gastrin and somatostatin may regulate the onset of parietal cell acid secretion.

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BACKGROUND: The parietal cell specific protein H+/K(+)-adenosine triphosphatase H+/K(+)-ATPase) is responsible for gastric acid secretion in adult mammals; however, its ontogeny and role in fetal acid secretion are unknown. The purpose of this study was twofold: (1) to determine the ontogeny of gastric acid secretion and parietal cell H+/K(+)-ATPase expression in the fetal rabbit and (2) to determine the role of H+K(+)-ATPase in fetal acid secretion. METHODS: For the ontogeny studies 88 fetuses from nine time-mated rabbits were studied at successive gestational ages. Gastric fluid and amniotic fluid pH were measured, and total gastric acid was determined by titration. Gastric microsomal protein was analyzed by Western blot analysis for H+/K(+)-ATPase expression by using a monoclonal antibody to the 94 kd alpha-catalytic subunit. To determine the role of H+/K(+)-ATPase in fetal acid secretion, 37 fetuses at day 26 from four time-mated rabbits were treated with (1) omeprazole (20 mg/kg) injection into the amniotic sac (n = 13), (2) carrier injection (n = 12), or (3) no injection (n = 12). Fetal gastric pH and titratable acid were measured at day 28. RESULTS: Amniotic fluid pH was neutral (7.44 to 7.64) throughout the third trimester. Gastric fluid pH was neutral (7.42 to 7.51) until day 25, when it decreased to 7.16 +/- 0.23 (p < 0.05) and subsequently fell to 5.37 +/- 0.05 by day 30. Titratable gastric acid (micromoles) increased from 0 at day 20 to 54.7 +/- 5.4 by day 30. By use of Western blot analysis and immunohistochemistry, gastric microsomal H+/K(+)-ATPase expression was absent from days 20 through 25 of gestation and first detectable at day 26, with qualitative increases to term. Omeprazole significantly inhibited pH (5.45 +/- 0.13 in controls, 5.56 +/- 0.12 with carrier injection, and 6.01 +/- 0.10 with omeprazole injection; p < 0.05). CONCLUSIONS: These data suggest that (1) gastric acid acid secretion begins at day 25 of gestation and increases to term, (2) gastric microsomal H+/K(+)-ATPase expression is first detectable at day 26 of gestation, and (3) omeprazole inhibits, but does not abolish, gastric acid secretion in the fetal rabbit. We conclude that gastric acid secretion is present before birth in the fetal rabbit and is mediated, in part, by omeprazole-sensitive H+/K(+)-ATPase.

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