Intragastric pH regulates conversion from net acid to net alkaline secretion by the rat stomach

Our previous report showed gastric mucosal surface pH was determined by alkali secretion at intragastric luminal pH 3 but by acid secretion at intragastric pH 5. Here, we question whether regulation of mucosal surface pH is due to the effect of luminal pH on net acid/base secretions of the whole stomach. Anesthetized rats with a gastric cannula were used, the stomach lumen was perfused with weakly buffered saline, and gastric secretion was detected in the gastric effluent with 1) a flow-through pH electrode and 2) a fluorescent pH-sensitive dye (Cl-NERF). During pH 5 luminal perfusion, both pH sensors reported the gastric effluent was acidic (pH 4.79). After perfusion was stopped transiently (stop-flow), net acid accumulation was observed in the effluent when perfusion was restarted (peak change to pH 4.1-4.3). During pH 3 luminal perfusion, both pH sensors reported gastric effluent was close to perfusate pH (3.0-3.1), but net alkali accumulation was detected at both pH sensors after stop-flow (peak pH 3.3). Buffering capacity of gastric effluents was used to calculate net acid/alkaline secretions. Omeprazole blocked acid secretion during pH 5 perfusion and amplified net alkali secretion during pH 3 perfusion. Pentagastrin elicited net acid secretion under both luminal pH conditions, an effect antagonized by somatostatin. We conclude that in the basal condition, the rat stomach was acid secretory at luminal pH 5 but alkaline secretory at luminal pH 3.     

Feedback control of pancreatic secretion in rats. Role of gastric acid secretion.

Pancreatic secretion in rats is regulated by feedback inhibition of cholecystokinin (CCK) release by proteases in the gut lumen, but little is known about the role of gastric acid in this regulation. This study, carried out on conscious rats with large gastric fistulas (GF) and pancreatic fistulas, shows that diversion of pancreatic juice results in the progressive stimulation of pancreatic secretion only in rats with the GF closed. When the GF was kept open, the diversion resulted in only small increment in pancreatic secretion and this was accompanied by progressive increase in gastric acid outputs. Similar amounts of HCl instilled into the duodenum in rats with the GF open fully reproduced the increase in pancreatic secretion observed after the diversion of pancreatic juice. Pretreatment with omeprazole (15 mumol/kg) to suppress gastric acid secretion or with L-364,718 (5 mumol/kg) to antagonize CCK receptors in the diverted state, resulted in the decline in pancreatic secretion similar to that observed after opening the GF. CCK given s.c. (20-320 pmol/kg) failed to cause any significant rise in the post-diversion pancreatic secretion in rats with the GF closed, but stimulated this secretion dose-dependently when the GF was open. Camostate (6-200 mg/kg) in rats with pancreatic juice returned to the duodenum caused dose-dependent increase in pancreatic secretion, but after opening the GF or after omeprazole this increase was reduced by about 75%. This study provides evidence that gastric acid plays a crucial role in the pancreatic response to diversion of pancreatic juice or inhibition of luminal proteases, and that factors that eliminate gastric acid secretion reduce this response.     

Capsaicin inhibits the pentagastrin-stimulated gastric acid secretion in anaesthetized rats with acute gastric fistula.

The effect of capsaicin on basal and pentagastrin-stimulated gastric acid secretion was investigated in the urethane anaesthetized acute gastric fistula rat. Gastric acid secretion was measured by flushing of the gastric lumen with saline every 15 min or by continuous gastric perfusion. Capsaicin given into the rat stomach at 120 ng x mL(-1) prior to pentagastrin (25 microg x kg(-1), iv) reduced gastric acid secretory response to pentagastrin by 24%. Intravenous (iv) capsaicin (0.5 microg x kg(-1)) did not reduce the pentagastrin-stimulated gastric acid secretion. After topical capsaicin desensitization (3 mg x mL(-1)), basal gastric acid secretion and that in response to pentagastrin (25 microg x kg(-1), intraperitonaeally) was unaltered compared with the control group. Data indicate that topical capsaicin inhibits gastric acid secretion stimulated with pentagastrin in anaesthetized rats.     

Effect of Intragastric Administration of Crude Aqueous Leaf Extract Of Anacardium occidentale on Gastric Acid Secretion in Rats

The effect of an aqueous leaf extract ofAnacardium occidentale on gastric acid secretion was tested in rats. Twenty (20) Wistar albino rats were used for the gastric acid assay experiment. The rats were divided into 2 groups of 10 each. Gastric acid output was determined by continuous perfusion of rat stomach in urethane anesthetized rats. Control gastric acid output was obtained using 0.9% sodium chloride as perfusate and extract induced gastric acid output was obtained by perfusion with 0.1% solution of Anacardium occidentale Intragastric administration of the extract caused significant increase in mean gastric output (P <0.05). Atropine (5μg/100g,) lM and Cimetidine (5mg/100g), IM. significantly inhibited the extract induced gastric acid secretion via muscarinic and histaminic receptors respectively. Our findings showed that the use of the plant extract as a single anti-gastric ulcer therapy may not involve lowering of acid secretions rather it may be due to its anti Helicobacter pylori effect.     

Gastric acid secretion in aquaporin-4 knockout mice

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.     

Heterogeneity of acid secretion induced by carbachol and histamine along the gastric gland axis and its relationship to [Ca2+]i

The gastric glands of the mammalian fundic mucosa are constituted by different cell types. Gastric fluid is a mixture of acid, alkali, ions, enzymes, and mucins secreted by parietal, chief, and mucous cells. We studied activation of acid secretion using LysoSensor Yellow/Blue in conjunction with fluo 3 to measure changes in pH and Ca(2+) in isolated rabbit gastric glands. We evidenced a spatial heterogeneity in the amplitude of acid response along the gland axis under histamine and cholinergic stimulation. Carbachol induced a transitory pH increase before acidification. This relative alkalinization may be related to granule release from other cell types. Omeprazole inhibited the acid component but not the rise in pH. Histamine stimulated acid secretion without increase of lumen pH. We studied the relationship between Ca(2+) release and/or entry and H(+) secretion in glands stimulated by carbachol. Ca(2+) release was associated with a fast and transient components of H(+) secretion. We found a linear relationship between Ca(2+) release and H(+) secretion. Ca(2+) entry was associated with a second slow and larger component of acid secretion. The fast component may be the result of activation of Cl(-) and K(+) channels and hence H(+)/K(+) pumps already present in the membrane, whereas the slow component might be associated with translocation of H(+)/K(+) pumps to the canaliculi. In conclusion, with cholinergic stimulation, gastric glands secrete a mixture of acid and other product(s) with a pH above 4.2, both triggered by Ca(2+) release. Maintenance of acid secretion depends on Ca(2+) entry and perhaps membrane fusion.     

HCO3- secretion in the esophageal submucosal glands

The mammalian esophagus has the capacity to secrete a HCO(3)(-) and mucin-rich fluid in the esophageal lumen. These secretions originate from the submucosal glands (SMG) and can contribute to esophageal protection against refluxed gastric acid. The cellular mechanisms by which glandular cells achieve these secretions are largely unknown. To study this phenomenon, we used the pH-stat technique to measure luminal alkali secretion in an isolated, perfused pig esophagus preparation. Immunohistochemistry was used to localize receptors and transporters involved in HCO(3)(-) transport. The SMG-bearing esophagus was found to have significant basal alkali secretion, predominantly HCO(3)(-), which averaged 0.21 +/- 0.04 microeq.h(-1).cm(-2). This basal secretion was doubled when stimulated by carbachol but abolished by HCO(3)(-) or Cl(-) removal. Basal- and carbachol-stimulated secretions were also blocked by serosal application of atropine, pirenzipine, DIDS, methazolamide, and ethoxzolamide. The membrane-impermeable carbonic anhydrase inhibitor benzolamide, applied to the serosal bath, partially inhibited basal HCO(3)(-) secretion and blocked the stimulation by carbachol. Immunohistochemistry using antibodies to M(1) cholinergic receptor or carbonic anhydrase-II enzyme showed intense labeling of duct cells and serous demilunes but no labeling of mucous cells. Labeling with an antibody to Na(+)-(HCO(3)(-))(n) (rat kidney NBC) was positive in ducts and serous cells, whereas labeling for Cl(-)/HCO(3)(-) exchanger (AE2) was positive in duct cells but less pronounced in serous cells. These data indicate that duct cells and serous demilunes of SMG play a role in HCO(3)(-) secretion, a process that involves M(1) cholinergic receptor stimulation. HCO(3)(-) transport in these cells is dependent on cytosolic and serosal membrane-bound carbonic anhydrase. HCO(3)(-) secretion is also dependent on serosal Cl(-) and is mediated by DIDS-sensitive transporters, possibly NBC and AE2.     

The importance of gastric secretion in the feedback control of interdigestive and postprandial pancreatic secretion in rats.

Previous studies demonstrated that pancreatic enzyme secretion in rats is stimulated by the diversion of pancreatic juice from the duodenum or by the inhibition of pancreatic proteinases in the intestinal lumen but little attention has been paid to the role of gastric secretion in this stimulation. This study, carried out on conscious rats with large gastric (GF) and pancreatic fistulas, confirms that diversion of pancreatic juice in rats with the GF closed results in the progressive stimulation of pancreatic secretion reaching the maximum similar to that induced by exogenous CCK. When the GF was kept open, the diversion resulted in only small increment in pancreatic secretion and this was accompanied by progressive increase in gastric acid outputs. Similar amounts of HCl (25-400 mumol/h) instilled intraduodenally (i.d.) in rats with the GF open fully reproduced the increase in pancreatic secretion observed after the diversion of pancreatic juice and this effect was completely abolished by the pretreatment with L-364,718, a specific CCK receptor antagonist. Pretreatment with omeprazole to suppress completely gastric acid secretion in the diverted state resulted in a decline in pancreatic secretion similar to that observed after opening the GF. Camostate given in graded doses (6-200 mg/kg) either i.d. or s.c. in rats with pancreatic juice returned to the duodenum caused a dose-dependent increase in pancreatic secretion, but after opening the GF or after omeprazole this increase was reduced by about 50% while after L-364,718 it was abolished. This study provides evidence that gastric secretion plays an important role in the pancreatic response to diversion of pancreatic juice or inhibition of luminal proteinases (but not to feeding) and the elimination of gastric acid reduces this response.     

Acute adaptive cellular base uptake in rat duodenal epithelium

We studied the role of duodenal cellular ion transport in epithelial defense mechanisms in response to rapid shifts of luminal pH. We used in vivo microscopy to measure duodenal epithelial cell intracellular pH (pH(i)), mucus gel thickness, blood flow, and HCO secretion in anesthetized rats with or without the Na(+)/H(+) exchange inhibitor 5-(N,N-dimethyl)-amiloride (DMA) or the anion transport inhibitor DIDS. During acid perfusion pH(i) decreased, whereas mucus gel thickness and blood flow increased, with pH(i) increasing to over baseline (overshoot) and blood flow and gel thickness returning to basal levels during subsequent neutral solution perfusion. During a second brief acid challenge, pH(i) decrease was lessened (adaptation). These are best explained by augmented cellular HCO uptake in response to perfused acid. DIDS, but not DMA, abolished the overshoot and pH(i) adaptation and decreased acid-enhanced HCO secretion. In perfused duodenum, effluent total CO(2) output was not increased by acid perfusion, despite a massive increase of titratable alkalinity, consistent with substantial acid back diffusion and modest CO(2) back diffusion during acid perfusions. Rapid shifts of luminal pH increased duodenal epithelial buffering power, which protected the cells from perfused acid, presumably by activation of Na(+)-HCO cotransport. This adaptation may be a novel, important, and early duodenal protective mechanism against rapid physiological shifts of luminal acidity.     

Histamine in stress ulcer prophylaxis in rats.

BACKGROUND: Gastrin and its analogues increase the gastric acid secretion, but also enhance mucosal defense mechanisms. On the other hand, increased formation of histamine leading to an increase in gastric acid secretion is accompanied with gastroprotection and acceleration of gastric ulcer healing. AIM: Of this study was to examine the effect of histamine on stress induced gastric ulcers in rats. METHODS: Male Wistar rats were exposed to water immersion and restrain stress (WRS) for 3.5 h at 23 degrees C. Before WRS rats were pretreated with saline, histamine, ranitidine or omeprazole. RESULTS: WRS produces gastric lesions which were strongly reduced by ranitidine or omeprazole. Also treatment with histamine markedly reduced ulcer area evoked by WRS. Addition of histamine to ranitidine or omeprazole caused an additional reduction in ulcer area. Gastroprotective effect of histamine was accompanied with the increase in gastric blood flow (GBF). Administration of omeprazole or ranitidine alone was without significant effect on GBF. Histamine caused an slight decrease in gastric luminal pH, whereas ranitidine or omeprazole significantly increased gastric luminal pH. Plasma interleukin-1beta was significantly reduced after administration of omeprazole, ranitidine, or histamine, however, the effect of histamine was less pronounced. DNA synthesis was increased after administration of omeprazole, ranitidine or histamine when compared with WRS alone. Administration of histamine in combination with ranitidine or omeprazole caused an additional increase in DNA synthesis. CONCLUSIONS: Histamine exhibits protective effect and increases gastroprotective effect of ranitidine and omeprazole against stress-induced gastric lesions. This effect of histamine seems to be independent on gastric acid secretion but related to the increase in gastric blood flow and the reduction in activation of cytokine cascade.     

Effect of Histalog,Insulin and Reserpine on Gastric Emptying and Secretion in Man

Four different groups of subjects were given Histalog, insulin or reserpine or acted as controls. Changes were noted in gastric emptying, acid, chloride, parietal and non-parietal secretions and neutral chloride. Gastric emptying and secretion were measured by the Hunt and Spurrell test meal as modified by us for drug testing.Histalog stimulated gastric secretion but not emptying. Insulin stimulated both secretion and emptying. Reserpine stimulated secretion but it stimulated emptying only in one-half of the subjects.After Histalog and reserpine the rise in hydrogen and chloride secretion was equal, so the neutral chloride did not increase. After insulin the rise of chloride was proportionately greater than the rise of hydrogen, so that neutral chloride was increased.     

Active sulfate secretion by the intestine of winter flounder is through exchange for luminal chloride

SO4(2-) transport by winter flounder intestine in Ussing chambers was characterized. With 50 mM SO4(2-) (physiological level) bathing the lumen, net absorption (lumen to blood) dominated. Under short-circuited conditions, 1 mM SO4(2-) on both sides, net active SO4(2-) secretion occurred (8.55 +/- 0.96 nmol. cm(-2). h(-1)). NaCN (10 mM), ouabain (10(-4) M), and luminal DIDS (0.2 mM) inhibited net secretion. Removal of luminal Cl- and HCO3- together (Cl--HCO3-) or Cl- alone blocked net secretion, whereas removal of luminal HCO3- alone increased net secretion. SO4(2-) uptake into foregut brush-border membrane vesicles was stimulated by a trans-Cl- gradient (in > out) and unaffected by a trans-HCO3- gradient (in > out). Short-circuiting with K+ (in = out) and valinomycin had no effect on Cl--stimulated SO4(2-) uptake, suggesting electroneutral exchange. Satiety (i.e., full stomach) stimulated the unidirectional absorptive flux, eliminating net secretion. It was concluded that the intestine is a site of SO4(2-) absorption in marine teleosts and that active SO4(2-) secretion is in exchange for luminal Cl-.     

A gastric acid secretion model.

A theory of gastric acid production and self-protection is formulated mathematically and examined for clinical and experimental correlations, implications, and predictions using analytic and numerical techniques. In our model, gastric acid secretion in the stomach, as represented by an archetypal gastron, consists of two chambers, circulatory and luminal, connected by two different regions of ion exchange. The capillary circulation of the gastric mucosa is arranged in arterial-venous arcades which pass from the gastric glands up to the surface epithelial lining of the lumen; therefore the upstream region of the capillary chamber communicates with oxyntic cells, while the downstream region communicates with epithelial cells. Both cell types abut the gastric lumen. Ion currents across the upstream region are calculated from a steady-state oxyntic cell model with active ion transport, while the downstream ion fluxes are (facilitated) diffusion driven or secondarily active. Water transport is considered iso-osmotic. The steady-state model is solved in closed form for low gastric lumen pH. A wide variety of previously performed static and dynamic experiments on ion and CO2 transport in the gastric lumen and gastric blood supply are for the first time correlated with each other for an (at least) semiquantitative test of current concepts of gastric acid secretion and for the purpose of model verification. Agreement with the data is reported with a few outstanding and instructive exceptions. Model predictions and implications are also discussed.     

Intestinal serotonin acts as paracrine substance to mediate pancreatic secretion stimulated by luminal factors

We recently demonstrated that luminal factors such as osmolality, disaccharides, and mechanical stimulation evoke pancreatic secretion by activating 5-hydroxytryptamine subtype 3 (serotonin-3, 5-HT3) receptors on mucosal vagal afferent fibers in the intestine. We hypothesized that 5-HT released by luminal stimuli acts as a paracrine substance, activating the mucosal vagal afferent fibers to stimulate pancreatic secretion. In the in vivo rat model, luminal perfusion of maltose or hypertonic NaCl increased 5-HT level threefold in intestinal effluent perfusates. Similar levels were observed after intraluminal 10(-5) M 5-HT perfusion. These treatments did not affect 5-HT blood levels. In a separate study, intraduodenal, but not intraileal, 5-HT application induced a dose-dependent increase in pancreatic protein secretion, which was not blocked by the CCK-A antagonist CR-1409. Acute vagotomy, methscopolamine, or perivagal or intestinal mucosal application of capsaicin abolished 5-HT-induced pancreatic secretion. In conscious rats, luminal 10(-5) M 5-HT administration produced a 90% increase in pancreatic protein output, which was markedly inhibited by the 5-HT3 antagonist ondansetron. In conclusion, luminal stimuli induce 5-HT release, which in turn activates 5-HT3 receptors on mucosal vagal afferent terminals. In this manner, 5-HT acts as a paracrine substance to stimulate pancreatic secretion via a vagal cholinergic pathway.     

Cholinergically stimulated gastric acid secretion is mediated by M(3) and M(5) but not M(1) muscarinic acetylcholine receptors in mice

Muscarinic acetylcholine receptors play an important role in the regulation of gastric acid secretion stimulated by acetylcholine; nonetheless, the precise role of each receptor subtype (M(1)-M(5)) remains unclear. This study examined the involvement of M(1), M(3), and M(5) receptors in cholinergic regulation of acid secretion using muscarinic receptor knockout (KO) mice. Gastric acid secretion was measured in both mice subjected to acute gastric fistula production under urethane anesthesia and conscious mice that had previously undergone pylorus ligation. M(3) KO mice exhibited impaired gastric acid secretion in response to carbachol. Unexpectedly, M(1) KO mice exhibited normal intragastric pH, serum gastrin and mucosal histamine levels, and gastric acid secretion stimulated by carbachol, histamine, and gastrin. Pirenzepine, known as an M(1)-receptor antagonist, inhibited carbachol-stimulated gastric acid secretion in a dose-dependent manner in M(1) KO mice as well as in wild-type (WT) mice, suggesting that the inhibitory effect of pirenzepine on gastric acid secretion is independent of M(1)-receptor antagonism. Notably, M(5) KO mice exhibited both significantly lower carbachol-stimulated gastric acid secretion and histamine-secretory responses to carbachol compared with WT mice. RT-PCR analysis revealed M(5)-mRNA expression in the stomach, but not in either the fundic or antral mucosa. Consequently, cholinergic stimulation of gastric acid secretion is clearly mediated by M(3) (on parietal cells) and M(5) receptors (conceivably in the submucosal plexus), but not M(1) receptors.     

Pentagastrin-stimulated gastric acid secretion by the isolated perfused rat stomach

The purpose of this present study was to develop a method for stimulation of acid secretion by the isolated perfused rat stomach. Rat stomachs were perfused $\text{in}$$\text{situ}$ via the abdominal aorta and celiac axis with Krebs-Ringer bicarbonate buffer in the presence or absence of 10% ovine erythrocytes. The gastric lumen was perfused with distilled water and gastric contents were collected at frequent intervals through a catheter at the pylorus. Sixty minute gastric acid output in response to various concentrations of pentagastrin was determined by titration of gastric contents with 0.01 N NaOH to pH 7.0. During arterial perfusion with Krebs-Ringer bicarbonate buffer in the absence of ovine erythrocytes gastric acid output was 2.50±0.58 SEM μEq H⁺/h, which did not increase in response to perfusion with Krebs-Ringer bicarbonate buffer containing pentagastrin. However, inclusion of 10% ovine erythrocytes in the arterial perfusate resulted in substantial stimulation of gastric acid by pentagastrin: maximal acid output, achieved with a pentagastrin dose of 0.6 μg/kg/h, was 23.5±3.73 μEq H⁺/h (p<0.01). The results of the present study demonstrate the capacity of the isolated vascularly perfused rat stomach to secrete acid and provide a model for studying interactions of gastrointestinal regulatory peptides and their physiologic roles in the regulation of gastric acid secretion.     

Effect of vasoactive intestinal peptide, peptide histidine isoleucine and growth hormone-releasing factor-40 on bombesin-like immunoreactivity, somatostatin and gastrin release from the perfused rat stomach

Bombesin-like immunoreactivity (BLI) has been demonstrated in neurons of the gastrointestinal tract and gastric BLI secretion can be demonstrated in response to the classical neurotransmitter acetylcholine. Since structurally related peptides VIP, PHI and GRF have to be considered as peptidergic neurotransmitters it was of interest to determine their effect on gastric BLI secretion. Additionally, somatostatin (SLI) and gastrin secretion was examined. The isolated stomach of overnight fasted rats was perfused with Krebs-Ringer buffer via the celiac artery and the effluent was collected via the portal vein. The gastric lumen was perfused with isotonic saline at pH7 or pH2. All four peptides were tested at a dose of 10(-11) M and 10(-8) M at both pH levels and in addition the effect of VIP and PHI was examined at 10(-14) M and 10(-12) M during luminal pH2. At luminal pH7 VIP and PHI stimulated SLI release at 10(-8) M but had no effect on BLI or gastrin secretion. rGRF and hpGRF were both ineffective on SLI and gastrin release while rGRF inhibited and hpGRF stimulated BLI secretion. This effect was not dose related. At luminal pH2 all four peptides stimulated BLI secretion. Stimulation by PHI was already observed at a dose of 10(-14) M while VIP elicited a stimulatory effect at 10(-12) M. PHI at the two lowest concentrations of 10(-14) and 10(-12) M elicited a stimulation of SLI and gastrin release while the same doses of VIP and the higher doses of all four peptides had no effect on SLI and gastrin secretion at an acidic intraluminal pH.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of inhibition gastric acid secretion on arterial acid-base status during digestion in the toad Bufo marinus

Digestion affects acid-base status, because the net transfer of HCl from the blood to the stomach lumen leads to an increase in HCO3(-) levels in both extra- and intracellular compartments. The increase in plasma [HCO3(-)], the alkaline tide, is particularly pronounced in amphibians and reptiles, but is not associated with an increased arterial pH, because of a concomitant rise in arterial PCO2 caused by a relative hypoventilation. In this study, we investigate whether the postprandial increase in PaCO2 of the toad Bufo marinus represents a compensatory response to the increased plasma [HCO3(-)] or a state-dependent change in the control of pulmonary ventilation. To this end, we successfully prevented the alkaline tide, by inhibiting gastric acid secretion with omeprazole, and compared the response to that of untreated toads determined in our laboratory during the same period. In addition, we used vascular infusions of bicarbonate to mimic the alkaline tide in fasting animals. Omeprazole did not affect blood gases, acid-base and haematological parameters in fasting toads, but abolished the postprandial increase in plasma [HCO3(-)] and the rise in arterial PCO2 that normally peaks 48 h into the digestive period. Vascular infusion of HCO3(-), that mimicked the postprandial rise in plasma [HCO3(-)], led to a progressive respiratory compensation of arterial pH through increased arterial PCO2. Thus, irrespective of whether the metabolic alkalosis is caused by gastric acid secretion in response to a meal or experimental infusion of bicarbonate, arterial pH is being maintained by an increased arterial PCO2. It seems, therefore, that the elevated PCO2, occuring during the postprandial period, constitutes of a regulated response to maintain pH rather than a state-dependent change in ventilatory control.     

Role of Na-K-2Cl cotransporter-1 in gastric secretion of nonacidic fluid and pepsinogen

Na-K-2Cl cotransporter-1 (NKCC) has been detected at exceptionally high levels in the gastric mucosa of several species, prompting speculation that it plays important roles in gastric secretion. To investigate this possibility, we 1) immunolocalized NKCC protein in the mouse gastric mucosa, 2) compared the volume and composition of gastric fluid from NKCC-deficient mice and their normal littermates, and 3) measured acid secretion and electrogenic ion transport by chambered mouse gastric mucosa. NKCC was localized to the basolateral margin of parietal cells, mucous neck cells, and antral base cells. In NKCC-deficient mice, gastric secretions of Na+, K+, Cl-, fluid, and pepsinogen were markedly impaired, whereas secretion of acid was normal. After stimulation with forskolin or 8-bromo-cAMP, chambered corpus mucosa vigorously secreted acid, and this was accompanied by an increase in transmucosal electrical current. Inhibition of NKCC with bumetanide reduced current to resting levels but had no effect on acid output. Although prominent pathways for basolateral Cl- uptake (NKCC) and apical Cl- exit [cystic fibrosis transmembrane conductance regulator (CFTR)] were found in antral base cells, no impairment in gastric secretion was detected in CFTR-deficient mice. Our results establish that NKCC contributes importantly to secretions of Na+, K+, Cl-, fluid, and pepsinogen by the gastric mucosa through a process that is electrogenic in character and independent of acid secretion. The probable source of the NKCC-dependent nonacidic electrogenic fluid secretion is the parietal cell. The observed dependence of pepsinogen secretion on NKCC supports the concept that a nonacidic secretory stream elaborated from parietal cells facilitates flushing of the proenzyme from the gastric gland lumen.     

Luminal glucose sensing in the rat intestine has characteristics of a sodium-glucose cotransporter

The presence of glucose in the intestinal lumen elicits a number of changes in gastrointestinal function, including inhibition of gastric emptying and food intake and stimulation of pancreatic and intestinal secretion. The present study tested the hypothesis that Na(+)-glucose cotransporter (SGLT)-3, a member of the SGLT family of transport proteins, is involved in detection of luminal glucose in the intestine. Gastric emptying, measured in awake rats, was significantly inhibited by perfusion of the intestine with glucose (60 and 90 mg); this effect was mimicked by alpha-methyl glucose (nonmetabolizable substrate of SGLT-1 and -3) but not 2-deoxy-d-glucose (substrate for GLUT-2) or isoosmotic mannitol. Gastric motility and intestinal fluid secretion, measured in anesthetised rats, were significantly inhibited and stimulated, respectively, by duodenal glucose but not galactose, which has a much lower affinity for SGLT-3 than glucose. Duodenal glucose but not galactose stimulated the release of 5-HT into mesenteric lymph and stimulated the discharge of duodenal vagal afferent fibers. mRNA for SGLT-3 was identified in the duodenal mucosa. Together these data suggest that detection of glucose in the intestine may involve SGLT-3, possibly expressed by enterochromaffin cells in the intestinal mucosa, and release of 5-HT.