Role of Gastrin/CCK-B Receptor in the Regulation of Gastric Acid Secretion in Rat

The aim of this study was to investigate whethergastrin regulates morphological changes andalpha-subunit gene expression in parietal cells throughthe gastrin/CCK-B receptor on enterochromaffin-likecells by histamine release. Treatment with 100 mg/kgof YM022, a potent and selective gastrin/CCK-B receptorantagonist, for one week in rats did not alter mRNAlevels of histidine decarboxylase or H⁺,K-ATPase. However, parietal cell morphology predominantlychanged to the resting form, although the serum gastrinconcentration was significantly increased. Additionaltreatment with YM022 and oral omeprazole, 100 mg/kg, for one week markedly suppressed theincreases of mRNA levels of histidine decarboxylase andH⁺, K-ATPase and completely blocked themorphological transformation of the parietal cells to astimulated form induced by treatment with omeprazolealone. This indicates that the morphologicaltransformation of parietal cells to an activated formwith a subsequent increase in H⁺, K-ATPasesynthesis caused by hypergastrinemia is mediated by increasedhistidine decarboxylase gene expression inenterochromaffin-like cells via gastrin/CCK-Breceptors.     

Famotidine,a histamine-2-receptor antagonist,inhibits the increase in rat gastric H+/K+-ATPase mRNA induced by intravenous infusion of gastrin 17 and histamine

We examined the effects of gastrin and histamine on rat gastric H⁺/K⁺-ATPase, the enzyme responsible for H⁺ secretion, gene expressionin vivo. Gastrin 17 (G 17) or histamine dihydrochloride (histamine) was continuously infused through the femoral vein of anesthetized rats. Gastric H⁺/K⁺-ATPase mRNA levels were measured using northern blot analysis. Infusion of G 17 and histamine increased the H⁺/K⁺-ATPase mRNA level significantly compared with basal control level or vehicle control level (P<0.01). However, pretreatment with famotidine, a potent histamine-2 (H₂)-receptor antagonist, inhibited the increase of rat gastric H⁺/K⁺-ATPase mRNA following G 17 and histamine infusion. These findings indicate that both histamine and G 17 increase expression of H⁺/K⁺-ATPase mRNA by activating H₂ receptor on the parietal cell.     

Regenerating gene protein may mediate gastric mucosal proliferation induced by hypergastrinemia in rats

Background & Aims: Regenerating gene (Reg) has been isolated from rat regenerating pancreatic islets, and Reg protein is mitogenic to islet cells. We have recently shown that Reg gene and Reg protein are expressed in gastric enterochromaffin-like (ECL) cells. This study aimed to clarify whether gastrin enhances Reg protein production in ECL cells and whether Reg protein is mitogenic to gastric mucosal cells. Methods:Reg gene expression in response to acute and chronic hypergastrinemia was investigated in rats. Immunohistochemical studies, Northern blotting, and in situ hybridization were performed to investigate the expression of Reg protein and Reg gene. The direct effect of gastrin on Reg gene expression was investigated using isolated ECL cells, and the trophic effect of Reg protein on cultured gastric epithelial cells was assessed by [³H]thymidine uptake. Results: Both chronic hypergastrinemia and short-term gastrin administration stimulated Reg gene expression and Reg protein production in fundic mucosa. Reg gene expression was also augmented in isolated ECL cells after incubation with rat gastrin. Reg protein was mitogenic to cultured rat gastric epithelial cells. Conclusions: Gastrin stimulates the production of Reg protein in gastric ECL cells, which may be involved in the gastrin-induced gastric mucosal cell growth.GASTROENTEROLOGY 1998;115:1483-1493     

Benign gastric polyps: morphological and functional origin

The most common types of benign gastric polyps are fundic gland polyps, hyperplastic polyps, and adenomas. The aim of this study was to determine on which morphological and functional background benign gastric polyps develop. The study includes 85 consecutive patients with gastric polyps and sex- and age-matched controls without polyps selected at random from a general population sample. The type of polyp was hyperplastic in 52 (61%), fundic gland in 18 (21%), adenoma in 10 (12%), carcinoid in 2 (2%), hamartoma in 2 (2%), and inflammatory fibroid in 1 (1%) of the cases. Routine biopsies from the gastric corpus and antrum were examined for presence of gastritis and H. pylori. Blood samples were analyzed for H. pylori antibodies, H⁺,K⁺-ATPase antibodies, gastrin, and pepsinogen I. Patients with hyperplastic polyps had increased P-gastrin concentrations and S-H⁺,K⁺-ATPase antibody titers and decreased S-pepsinogen I concentrations with a high prevalence of atrophic corpus gastritis or pangastritis. A similar pattern was observed among patients with adenomas, whereas patients with fundic gland polyps had normal serology and a lower prevalence of gastritis and H. pylori infection than controls. In conclusion, hyperplastic polyps and adenomas are generally associated with atrophic gastritis. Patients with fundic gland polyps seem to have a sounder mucosa than controls. Whereas the risk of malignant gastric neoplasia is increased in patients with hyperplastic polyps or adenomas, this does not seem to be the case in patients with fundic gland polyps.     

Role of Na+-H+-antiport in restitution of isolated guinea pig gastric epithelium after superficial injury

In addition to its pH_i regulatory function Na⁺-H⁺-antiport is also involved in volume regulation of epithelial cells, particularly in neutral conditions. It is also known that the antiport is activated after ligand binding following growth factor receptor activation. The aim of the present study was to evaluate the role of the antiport in restitution of gastric mucosa and whether its activity is dependent on the type of superficial injury. Therefore the fundic epithelium of guinea pig stomach was perfused in an Ussing chamber in neutral conditions. Na⁺-H⁺- and Cl^–-HCO ₃ ^– -antiports were inhibited with 1.0 mM amiloride, 1.0 mM SITS, or with HCO ₃ ^– removal and Na⁺-K⁺-2Cl^2–-cotransporter with 0.3 M furosemide during 4 hr of restitution after superficial injury induced either by 1.25 M NaCl or by 1.0% Triton. Luminal exposure of the epithelium to amiloride had no effect on restitution but serosal application abolished the process completely. The inhibitory effect of amiloride was similar after both NaCl and Triton injury. The inhibition of Cl^–-HCO ₃ ^– -antiport with SITS interfered with the process as well, while HCO ₃ ^– removal had no significant inhibitory effect, nor did the inhibition of Na⁺-K⁺-2Cl^–-cotransporter. The morphologic findings were in accordance with the electrophysiologic measurements in each pair of tissues. It is concluded that the Na⁺-H⁺-antiport is essential for the epithelial cells during restitution even in neutral conditions, but a functional Cl^–-HCO ₃ ^– -antiport is also required. The activity of Na⁺-H⁺-antiport is sensitive to basolateral amiloride and is necessary regardless of the type of chemical injury.This study was supported by grants from Astra Co., the Orion Corporation Research Foundation, the Sigrid Juselius Foundation, the Academy of Finland, the Research Foundation of Gastrointestinal Diseases, the Clinical Research Institute of Helsinki University Central Hospital, Helsinki, Finland.     

Serum Group I Pepsinogens and Gastrin in Relation to Gastric H+ and Pepsin Outputs before and after Subcutaneous Injection of Pentagastrin

A conventional pentagastrin test was carried out in 25 patients with dyspeptic complaints, and gastric H⁺ and pepsin outputs were determined. Blood was drawn before the intubation and 5 and 30 min after subcutaneous injection of pentagastrin, and serum group I pepsinogens (PG I) and serum gastrin were determined by radioimmunoassay methods. A significant correlation was found between serum PG I, on the one hand, and basal gastric pepsin output as well as pentagastrin-stimulated gastric H⁺ and pepsin outputs, on the other. Basal serum gastrin was also significantly correlated to pentagastrin-stimulated gastric pepsin output as well as to serum PG I. Pentagastrin failed to induce an increase in serum PG I during the first 30 min.     

Control of gastric acid secretion in somatostatin receptor 2 deficient mice: shift from endocrine/paracrine to neurocrine pathways

The gastrin-enterochromaffin-like (ECL) cell-parietal cell axis is known to play an important role in the regulation of gastric acid secretion. Somatostatin, acting on somatostatin receptor type 2 (SSTR(2)), interferes with this axis by suppressing the activity of the gastrin cells, ECL cells, and parietal cells. Surprisingly, however, freely fed SSTR(2) knockout mice seem to display normal circulating gastrin concentration and unchanged acid output. In the present study, we compared the control of acid secretion in these mutant mice with that in wild-type mice. In SSTR(2) knockout mice, the number of gastrin cells was unchanged; whereas the numbers of somatostatin cells were reduced in the antrum (-55%) and increased in the oxyntic mucosa (35%). The ECL cells displayed a reduced expression of histidine decarboxylase and vesicle monoamine transport type 2 (determined by immunohistochemistry), and an impaired transformation of the granules to secretory vesicles (determined by electron microscopic analysis), suggesting low activity of the ECL cells. These changes were accompanied by an increased expression of galanin receptor type 1 in the oxyntic mucosa. The parietal cells were found to respond to pentagastrin or to vagal stimulation (evoked by pylorus ligation) with increased acid production. In conclusion, the inhibitory galanin-galanin receptor type 1 pathway is up-regulated in the ECL cells, and the direct stimulatory action of gastrin and vagal excitation is enhanced on the parietal cells in SSTR(2) knockout mice. We suggest that there is a remodeling of the neuroendocrine mechanisms that regulate acid secretion in these mutant mice.     

Impairment of gastric secretion modulation in duodenal ulcer and in long-term PPI treatment: quantitative morphologic findings and pathophysiologic implications

Helicobacter pylori affects gastric secretion. This functional effect might have a morphometric counterpart. Therefore, the gastric cell secretory compartment was morphometrically assessed in different pathophysiologic conditions related to Helicobacter pylori infection. Nineteen Helicobacter pylori-positive nonduodenal ulcer subjects, 15 omeprazole chronically treated subjects, and 19 duodenal ulcer patients were studied against 19 controls. Somatostatin, gastrin, enterochromaffin-like, and parietal cell density was assessed in gastric biopsies. No differences in any cell type density were found between Helicobacter pylori-positive nonduodenal ulcer subjects and controls. On the contrary, differences were significant when comparing omeprazole and duodenal ulcer patients to controls (higher density of gastrin, enterochromaffin-like, and parietal cells, lower density of somatostatin cells). In duodenal ulcer a reversion to control values followed Helicobacter pylori eradication and ulcer healing. A direct linear correlation between enterochromaffin-like, gastrin, and parietal cell density was demonstrated. An almost complete map of mucosal cells involved in gastric secretion is provided by this study. The cell density pattern, identical to the omeprazole group, points to an impaired feedback control of secretion in duodenal ulcer. The reversion to control values after Helicobacter pylori eradication and ulcer healing demonstrates the pathogenetic role of Helicobacter pylori–host interaction in these changes.     

Role of the Na~+/K~+/2Cl~- cotransporter NKCC1 in cell cycle progression in human esophageal squamous cell carcinoma

AIM:To investigate the role of Na+/K+/2Cl-cotransporter 1(NKCC1)in the regulation of genes involved in cell cycle progression and the clinicopathological significance of its expression in esophageal squamous cell carcinoma(ESCC).METHODS:An immunohistochemical analysis was performed on 68 primary tumor samples obtained from ESCC patients that underwent esophagectomy.NKCC1expression in human ESCC cell lines was analyzed by Western blotting.Knockdown experiments were conducted using NKCC1 small interfering RNA,and the effects on cell cycle progression were analyzed.The gene expression profiles of cells were analyzed by microarray analysis.RESULTS:Immunohistochemical staining showed that NKCC1 was primarily found in the cytoplasm of carcinoma cells and that its expression was related to the histological degree of differentiation of SCC.NKCC1 was highly expressed in KYSE170 cells.Depletion of NKCC1in these cells inhibited cell proliferation via G2/M phase arrest.Microarray analysis identified 2527 genes with altered expression levels in NKCC1depleted KYSE170.Pathway analysis showed that the top-ranked canonical pathway was the G2/M DNA damage checkpoint regulation pathway,which involves MAD2L1,DTL,BLM,CDC20,BRCA1,and E2F5.CONCLUSION:These results suggest that the expression of NKCC1 in ESCC may affect the G2/M checkpoint and may be related to the degree of histological differentiation of SCCs.We have provided a deeper understanding of the role of NKCC1 as a mediator and/or a biomarker in ESCC.     

The CCK-2 Receptor is Located on the ECL Cell,But Not on the Parietal Cell

Background: The interrelationship between histamine and gastrin in the physiological regulation of gastric acid secretion is still a matter of dispute. CCK-2 receptors are located on enterochromaffin-like (ECL) cells in corpus mucosa and gastrin stimulates acid production by releasing histamine from the ECL cells, which in turn stimulates the parietal cells. Whether parietal cells also possess gastrin receptors of physiological significance is unclear. The aim of the present study was to localize the CCK-2 receptor cellularly and concomitantly demonstrate a gastrin receptor response (histamine release). Methods: Fluorescein labelled cholecystokinin-8 (Fluo-CCK-8) was added to the arterial infusion to totally isolated, vascularly perfused rat stomachs to a final concentration of 130 pmol L -1 for 1 min, either alone or along with 520 nmol -1 CCK-8 after 10-min pre-perfusion with CCK-8. Immediately after the FluoCCK-8 had reached the oxyntic mucosa, biopsies were taken and the binding sites were localized by double immunohistochemistry combined with the tyramide signal amplification (TSA) technique. Venous histamine was measured before and during stimulation. Results: Fluo-CCK-8 (130 pM) evoked histamine release, and binding sites were found in the basal part of corpus mucosa, co-localized with histidine decarbocylase (HDC) immunoreactive ECL cells. No binding of Fluo-CCK was found in the midglandular region of corpus, dominated by parietal cells. Binding of Fluo-CCK-8 was abolished by concomitant perfusion with excess CCK-8. Conclusion: Fluo-CCK-8 given to isolated rat stomachs in a physiological concentration binds to CCK-2 receptors on ECL cells and causes histamine release, whereas no binding of Fluo-CCK-8 to parietal cells was found.     

The CCK-2 receptor is located on the ECL cell, but not on the parietal cell.

BACKGROUND: The interrelationship between histamine and gastrin in the physiological regulation of gastric acid secretion is still a matter of dispute. CCK-2 receptors are located on enterochromaffin-like (ECL) cells in corpus mucosa and gastrin stimulates acid production by releasing histamine from the ECL cells, which in turn stimulates the parietal cells. Whether parietal cells also possess gastrin receptors of physiological significance is unclear. The aim of the present study was to localize the CCK-2 receptor cellularly and concomitantly demonstrate a gastrin receptor response (histamine release). METHODS: Fluorescein labelled cholecystokinin-8 (Fluo-CCK-8) was added to the arterial infusion to totally isolated, vascularly perfused rat stomachs to a final concentration of 130 pmol L(-1) for 1 min, either alone or along with 520 nmol(-1) CCK-8 after 10-min pre-perfusion with CCK-8. Immediately after the Fluo-CCK-8 had reached the oxyntic mucosa, biopsies were taken and the binding sites were localized by double immunohistochemistry combined with the tyramide signal amplification (TSA) technique. Venous histamine was measured before and during stimulation. RESULTS: Fluo-CCK-8 (130 pM) evoked histamine release, and binding sites were found in the basal part of corpus mucosa, co-localized with histidine decarbocylase (HDC) immunoreactive ECL cells. No binding of Fluo-CCK was found in the mid-glandular region of corpus, dominated by parietal cells. Binding of Fluo-CCK-8 was abolished by concomitant perfusion with excess CCK-8. CONCLUSION: Fluo-CCK-8 given to isolated rat stomachs in a physiological concentration binds to CCK-2 receptors on ECL cells and causes histamine release, whereas no binding of Fluo-CCK-8 to parietal cells was found.     

Histamine 3 receptor activation mediates inhibition of acid secretion during Helicobacter-induced gastritis

AIM: To test the hypothesis that histamine 3 receptor (H3R) activation during Helicobacter infection inhibits gastric acid secretion in vivo and in vitro.METHODS: Helicobacter felis (H. felis) infected and uninfected C57Bl/6 mice were infused with either PBS or the H3 receptor antagonist thioperamide (THIO) for 12 wk. After treatment, mice were analyzed for morphological changes and gastric acid content. Total RNA was prepared from the stomachs of each group and analyzed for changes in somatostatin and gastrin mRNA abundance by real time-polymerase chain reaction (RT-PCR). Location of H3 receptors in the stomach was analyzed by co-localization using antibodies specific for the H3 receptor and parietal cell marker H⁺, K⁺-ATPase β subunit.RESULTS: Inflammation and parietal cell atrophy was observed after 12 wk of H. felis infection. Interestingly, treatment with the H3R antagonist thioperamide (THIO) prior to and during infection prevented H. felis-induced inflammation and atrophy. Compared to the uninfected controls, infected mice also had significantly decreased gastric acid. After eradication of H. felis with THIO treatment, gastric acidity was restored. Compared to the control mice, somatostatin mRNA abundance was decreased while gastrin gene expression was elevated during infection. Despite elevated gastric acid levels, after eradication of H. felis with THIO, somatostatin mRNA was elevated whereas gastrin mRNA was suppressed. Immunofluorescence revealed the presence of H3 receptors on the parietal cells, somatostatin-secreting D-cells as well as the inflammatory cells.CONCLUSION: This study shows that during H. felis infection, gastric acidity is suppressed as a consequence of an inhibitory effect on the parietal cell by H3R activation. The stimulation of gastric mucosal H3Rs increases gastrin expression and release by inhibiting release of somatostatin.     

Influence of endothelin 1 on human atrial myocardium—myocardial function and subcellular pathways

The influence of endothelin 1 on isometrically contracting human atrial muscle strip preparations was investigated under physiological conditions (37°C, 1 Hz, Ca²⁺ 2.5 mM). Endothelin dose-dependently increased isometric tension from 3×10^–10M to 1×10^–7M. At 1×10^–7M the inotropic effect of endothelin was maximum with isometric tension being increased by 32±6% (n=11, p<0.05). At 1×10^–7M endothelin the positive inotropic effect was preceded by a transient negative inotropic effect with a decline in tension by –5±1% (n=11, p<0.05). Endothelin prolonged time from peak tension to 50% relaxation (RT50) by 29±5%. With BQ123 a competitive antagonist of the ET_A receptor positive inotropic effect and the prolongation of relaxation was significantly reduced and initial negative inotropic effect was abolished, indicating a ET_A receptor mediated effect. Preincubation with phorbolmyristateacetate (10^–5M) to downregulate proteinkinase C (PKC) eliminated the positive inotropic effect of endothelin. Similarly, N-5,5-dimethylamiloride (10^–5M) which inhibits Na⁺/H⁺-exchanger activity, abolished the positive inotropic effect of ET. However, with either PMA or DMA the initial transient negative inotropic effect was still present (–13±7%, n=9, p<0.05 and –3±1%, n=6, p<0.05). Furthermore, both substances did not abolish the prolongation of twitch time parameters observed under endothelin. After preincubation with PMA, endothelin prolonged RT50 by 18±6% and with DMA by 11±2%. Using the photoprotein aequorin as an indicator for intracellular calcium concentrations showed that the positive inotropic effect was mainly mediated by an increase of systolic intracellular calcium concentrations. Thus, the present data indicate that the positive inotropic effect of endothelin in human atrial myocardium results from activation of PKC with a subsequent activation of the Na⁺/H⁺-exchanger. However, the initial negative inotropic effects as well as the prolongation of relaxation seem to result from a different intracellular mechanism of endothelin.     

Effects of Ranitidine on Gastric Vesicles Containing H+, K+-Adenosine Triphosphatase in Rats

Background: To ascertain the mechanism for rebound acid hypersecretion after treatment with an H₂-receptor blocker, we investigated the effects of ranitidine on gastric H⁺, K⁺-adenosine triphosphatase (ATPase) in rats, Methods: Male Wistar rats received ranitidine (1-50mg/kg body weight intraperito-neally twice a day for 5 days). The rats were starved for 15 h after the last treatment and then killed, and gastric vesicles containing H⁺, K⁺-ATPase were prepared. Results: Treatment with ranitidine dose-dependently increased protein content in the gastric vesicular fraction purified from the gastric mucosa without changing total protein content. Ranitidine also increased the content of a 94,000-dalton protein, the catalytic subunit of H⁺, K⁺-ATPase. On the other hand, ranitidine did not affect the specific activity of the enzyme (μmol/min/mg of the gastric vesicular protein). Since gastric vesicles in the fasting state mainly consist of the tubulovesicular membrane, these results suggest that ranitidine administration increases total tubulovesicular H⁺, K⁺-ATPase content (μmol/min/rat) by increasing the number of tubulovesicles per parietal cell. The ranitidine-induced increase in total tubulovesicular H⁺, K⁺-ATPase activity was still evident 1 week after treatment and returned to control level 1 month later. Conclusions: All these findings suggest that the increased content and total activity of tubulovesicular H⁺, K⁺-ATPase after ranitidine treatment may contribute to the mechanism for acid rebound after H₂-blocker therapy.     

Effects of baicalin in CD4 + CD29 + T cell subsets of ulcerative colitis patients

AIM: To evaluate the role of baicalin in ulcerative colitis (UC) with regard to the CD4⁺CD29⁺ T helper cell, its surface markers and serum inflammatory cytokines.METHODS: Flow cytometry was used to detect the percentage of CD4⁺CD29⁺ cells in patients with UC. Real time polymerase chain reaction was used to detect expression of GATA-3, forkhead box P3, T-box expressed in T cells (T-bet), and retinoic acid-related orphan nuclear hormone receptor C (RORC). Western blotting was used to analyze expression of nuclear factor-κB (NF-κB) p65, phosphorylation of NF-κB (p-NF-κB) p65, STAT4, p-STAT4, STAT6 and p-STAT6. The concentrations of interferon-γ (IFN-γ), interleukin (IL)-4, IL-5, IL-6, IL-10 and TGF-β in serum were determined by ELISA assay.RESULTS: The percentages of CD4⁺CD29⁺ T cells were lower in treatment with 40 and 20 μmol/L baicalin than in the treatment of no baicalin. Treatment with 40 or 20 μmol/L baicalin significantly upregulated expression of IL-4, TGF-β1 and IL-10, increased p-STAT6/STAT6 ratio, but downregulated expression of IFN-γ, IL-5, IL-6, RORC, Foxp3 and T-bet, and decreased ratios of T-bet/GATA-3, p-STAT4/STAT4 and p-NF-κB/NF-κB compared to the treatment of no baicalin.CONCLUSION: The results indicate that baicalin regulates immune balance and relieves the ulcerative colitis-induced inflammation reaction by promoting proliferation of CD4⁺CD29⁺ cells and modulating immunosuppressive pathways.     

Cell Volume Regulation During Hyperosmotic Shrinkage Is Mediated by Na+/K+-ATPase and Na+–K+–2Cl− Cotransporter in Necturus Gastrics Surface Epithelial Cells

Cell volume regulation was investigated in gastric surface epithelial cells during hypertonic conditions. Isolated Necturus antral mucosa was perfused on the serosal side with Ringer's solution (pH 7.25, 95%O₂/5%CO₂) and on the mucosal side successively with 150–500 mM NaCl. Amiloride, ouabain, and bumetanide were used to experimentally inhibit Na⁺/H⁺, Na⁺/K⁺ ATPase or Na⁺–K⁺–2Cl^– ion transporters. Intracellular sodium activity and cell volume changes were measured with liquid sensor microelectrodes. The increase in intracellular sodium activity caused by luminal hyperosmolar exposure was mainly due to cell shrinkage. Inhibition of Na⁺/K⁺ ATPase or Na⁺–K⁺–2Cl^– cotransporter increased hyperosmotic cell shrinkage (−52 ± 5%, −85 ± 19%, and −77 ± 9% for control, ouabain, and bumetanide, respectively). Inhibition of Na⁺/K⁺ ATPase increased intracellular sodium activity (from 18 ± 4 to 52 ± 12 mM). Cell volume regulation in gastric epithelial surface cells during mucosal hyperosmolar exposure is maintained by the basolateral Na⁺–K⁺–2Cl^– cotransporter, while Na⁺/K⁺ ATPase maintains sodium balance, but Na⁺/H⁺ antiport seems to have a less important role. This work was supported by the Research Foundation of Helsinki University Central Hospital (EVO), Academy of Finland, Antti and Jenny Wihuri Foundation, and Biomedicum Research Foundation, Helsinki, Finland. The authors thank Mrs Paula Kokko for excellent technical assistance.     

Altered Gastrin Regulation in Mice Infected with Helicobacter felis

Altered gastrin expression associated with Helicobacter pylori infection may contribute to the pathogenesis of peptic ulcer disease or gastric cancer in man, but gastrin has not been investigated in a murine model of Helicobacter infection. C57BL/6 mice were inoculated with Helicobacter felis and examined after 4–21 weeks for G and D cell numbers, antral gastrin and somatostatin mRNA, and luminal pH. In H. felis-infected mice, gastrin mRNA declined at four and six weeks after infection to 57% and 23%, respectively, of uninfected control values. Concurrently, somatostatin mRNA showed no change at four weeks and a modest 25% decrease at six weeks after infection. Similar reductions were noted in G and D cell numbers, resulting in a decrease in the G/D cell ratio after mice were infected with H. felis. Infected animals also showed a loss of parietal and chief cells, and an increased gastric pH. H. felis infection in C57BL/6 mice leads to an early suppression of G cell number and gastrin mRNA. These changes precede an alteration in somatostatin cell number and mRNA and, coupled with reductions in parietal and chief cells, may contribute both to severe impairment of gastric acid output and the potential for carcinogenic processes.     

Kinetics of Red Cell Na+ and K+ Transport in Prague Hypertensive Rats

Kinetics of ouabain-sensitive, furosemide-sensitive (FS), bumetanide-sensitive (BS) and -resistant Na⁺ and K⁺ transport were studied in erythrocytes of Prague hypertensive rats (PHR) and Prague normotensive rats (PNR). Maximal transport rates (V_max) and apparent affinities for either intracellular Na⁺ or extracellular K⁺ (replaced by Rb⁺) were determined in red cells in which Na⁺ content varied around the physiological range and that were incubated in Na⁺ media. No major differences between PHR and PNR were disclosed in the kinetics of ion transport mediated by the Na⁺-K⁺ pump or BS inward Na⁺-K⁺ cotransport. FS Rb⁺ uptake was higher (due to a greater V_max) in red cells of PHR as compared to PNR. In cells with a lowered Na⁺ content this elevation of FS Rb⁺ uptake was largely due to an augmented K⁺-Cl^? cotransport which exhibits a low affinity for Rb⁺_o and is blocked by 1 mM furosemide but not by 10 μM bumetanide. Red cells of PHR and PNR strains did not differ in either Na⁺ or Rb⁺ leaks. A slight increase of red cell Na⁺ content in PHR was evaluated in terms of the pump-leak concept. The present study did not reveal any obvious kinetic abnormalities of red cell cation transport the presence of which in tissues involved in blood pressure regulation would favor the development or the maintenance of genetic hypertension in PHR.     

Gastric H+, K+-ATPase as a therapeutic target in peptic ulcer disease

The presence of unbuffered acid appears to be an essential contributory factor in the pathogenesis of peptic ulcer disease. Treatment has concentrated therefore on the reduction of acidity, and the last decade has seen the widespread and effective use of H₂ antagonists. They are, at low doses, more successful in improving the natural history of duodenal ulcer disease than of gastric or esophageal ulceration. The H₂ receptor plays a central role in activation of parietal cell acid secretion, and antagonists at this receptor block most (but not all) of the acid secretion due to even gastrinergic or muscarinic (vagal) stimulation. In hypergastrinemic states such as Zollinger-Ellison syndrome, or where acid secretion has to be inhibited by more than 20% over a 24-hr period, such as for treatment of esophagitis, NSAID damage, or gastric ulcers, the dose and frequency of administration of the currently available antagonists must be increased to achieve reliable therapy. This has led to a search for an alternative target for acid inhibitory drugs, such as the gastric acid pump, the H⁺,K⁺-ATPase. This article focuses on the function of this ATPase and suggests that inhibition of this pump will provide a more efficacious means of reduction of acid secretion by the stomach, hence improving and simplifying therapy of acid related diseases.This work was supported in part by grants from NIH and the USVA.     

Decrease in myocardial Na+-K+-ATPase activity and ouabain binding sites in hypercholesterolemic rabbits

Objectives The purpose of this study was to explore the effect of high dietary cholesterol on the lipid composition, Na⁺–K⁺-ATPase activity and ouabain receptor property of the myocardial sarcolemma.Methods Male New Zealand white rabbits were fed with standard chow or standard chow supplemented with 0.5% (w/w) cholesterol and 10% (w/w) coconut oil to induce hypercholesterolemia. After 8 weeks, the rabbits were sacrificed; a myocardial sarcolemma fraction was then prepared from the left ventricular myocardium and analyzed for lipid composition. Assay of Na⁺–K⁺-ATPase activity and³H-ouabain binding studies were performed in the myocardial sarcolemma from the control and cholesterol-fed rabbits.Results The cholesterol content, but not the phospholipid content, of the sarcolemma was significantly greater in the cholesterol-fed group, thus, resulting in an increased cholesterol/phospholipid molar ratio in the cholesterol-fed group. In addition, a decrease in Na⁺–K⁺-ATPase activity was also found in this group. The decrease in Na⁺–K⁺-ATPase activity was selective, since the Mg⁺⁺-ATPase and 5-nucleotidase activities remained unchanged. In the³H-ouabain binding study, a decrease in the number of maximum binding sites, but not the binding affinity, for³H-ouabain was foundie the cholesterol-fed group.Conclusions High dietary cholesterol induces higher levels of cholesterol not only in the plasma, but also in the myocardial sarcolemma. These changes result in decreased myocardial Na⁺–K⁺-ATPase activity mediated by a reduction in the maximum number of binding sites for ouabain but not a change in binding affinity.