ABSTRACT
The aquaporin-4 (AQP4) water channel has been proposed to play a role in gastric acid secretion. Immunocytochemistry using anti-AQP4 antibodies showed strong AQP4 protein expression at the basolateral membrane of gastric parietal cells in wild-type (+/+) mice. AQP4 involvement in gastric acid secretion was studied using transgenic null (-/-) mice deficient in AQP4 protein. -/- Mice had grossly normal growth and appearance and showed no differences in gastric morphology by light microscopy. Gastric acid secretion was measured in anesthetized mice in which the stomach was luminally perfused (0. 3 ml/min) with 0.9% NaCl containing [(14)C]polyethylene glycol ([(14)C]PEG) as a volume marker. Collected effluent was assayed for titratable acid content and [(14)C]PEG radioactivity. After 45-min baseline perfusion, acid secretion was stimulated by pentagastrin (200 microg. kg(-1). h(-1) iv) for 1 h or histamine (0.23 mg/kg iv) + intraluminal carbachol (20 mg/l). Baseline gastric acid secretion (means +/- SE, n = 25) was 0.06 +/- 0.03 and 0.03 +/- 0.02 microeq/15 min in +/+ and -/- mice, respectively. Pentagastrin-stimulated acid secretion was 0.59 +/- 0.14 and 0.70 +/- 0.15 microeq/15 min in +/+ and -/- mice, respectively. Histamine plus carbachol-stimulated acid secretion was 7.0 +/- 1.9 and 8.0 +/- 1.8 microeq/15 min in +/+ and -/- mice, respectively. In addition, AQP4 deletion did not affect gastric fluid secretion, gastric pH, or fasting serum gastrin concentrations. These results provide direct evidence against a role of AQP4 in gastric acid secretion.
Subject(s)
Aquaporins/genetics , Gastric Acid/metabolism , Gastric Mucosa/metabolism , Animals , Antibodies , Aquaporin 4 , Aquaporins/analysis , Aquaporins/immunology , Carbachol/pharmacology , Cholinergic Agents/pharmacology , Gastrins/metabolism , Gene Expression Regulation, Enzymologic , H(+)-K(+)-Exchanging ATPase/genetics , Histamine/pharmacology , Hydrogen-Ion Concentration , Mice , Mice, Transgenic , Parietal Cells, Gastric/chemistry , Parietal Cells, Gastric/drug effects , Parietal Cells, Gastric/enzymology , Pentagastrin/blood , Pentagastrin/pharmacology , Stomach/chemistry , Stomach/cytology , Water/metabolismABSTRACT
The time course of the plasma level metapramine following infusion at three different rates (1.18, 2.36 and 4.71 mg/h) has been studied in six healthy volunteers. The correlation coefficient of drug concentration and rate of infusion was 0.974 (alpha less than 0.001, n = 18). Plasma clearance, estimated from the steady-state level, varied from 68 to 1071/h. 3 subjects also received 35 mg of drug by i.v. bolus injection and plasma concentrations were determined at set times for up to 24 h. The plasma level of metapramine decreased tri-exponentially, with a terminal half-life of about 7.4 h. The plasma clearance after i.v. injection was in good agreement with that observed during the infusion study. Apparent volumes of distribution ranged from 41.9 to 90.31.
