Protagonist: Early surgical intervention in ulcerative colitis.
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Colectomy↗
Biomedical subjects
R R Cima
Publications and source records attributed to R R Cima.
New developments in diverticular disease.
Colonic diverticular disease is common but surprisingly poorly understood. Recent advances in the field continue to focus on the introduction of new technology. Diagnosis and assessment of the severity of acute diverticulitis is improved with CT scanning. A specialized bleeding team employing advanced endoscopic techniques can control diverticular bleeding so that emergency surgical resection may be avoided. Selected patients undergoing laparoscopic sigmoid resection may benefit from this approach. The vast majority of reports are from retrospective studies and include few randomized, controlled trials.
Colectomy↗
Expression of an extracellular calcium-sensing receptor in rat stomach.
BACKGROUND & AIMS: Circulating levels of Ca2+ can influence secretory functions and myoelectrical properties of the stomach. A Ca2+-sensing receptor (CaR) has recently been identified in tissues that regulate systemic Ca2+ homeostasis. The aim of this study was to evaluate expression of CaR in the stomach of the rat. METHODS: In forestomach and glandular stomach, reverse-transcription polymerase chain reaction was used to amplify a 380-base pair product, which is 99% homologous with transcripts obtained in parathyroid and kidney. RESULTS: Northern analysis of gastric mucosal polyA+ RNA revealed 7. 5- and 4.1-kilobase transcripts, similar to those obtained in rat parathyroid and kidney. Immunohistochemistry revealed CaR expression in regions of the submucosal plexus and myenteric neurons. In sections of intact tissue, preparations of primary culture surface cells and surgically dissected gastric glands, staining was observed consistently in epithelial cells of the gastric glands and in gastric surface cells. In parietal cells in isolated gastric glands, intracellular levels of Ca2+ responded to conditions that are known to activate CaR. CONCLUSIONS: These are the first reported observations that CaR is expressed in different epithelial cells of mammalian gastric mucosa and its enteric nerve regions. The effects of extracellular Ca2+ on gastric function may be attributable to activation of CaR.
Animals↗
Identification and functional assay of an extracellular calcium-sensing receptor in Necturus gastric mucosa.
In mammals and amphibians, increases in extracellular Ca2+ can activate bicarbonate secretion and other protective functions of gastric mucosa. We hypothesized that the recently cloned extracellular Ca(2+)-sensing receptor (CaR) is functioning in the gastric mucosa. In Necturus maculosus gastric mucosa, reverse transcription-polymerase chain reaction using primers based on previously cloned CaR sequences amplified a 326-bp DNA fragment that had 84% nucleotide sequence identity with the rat kidney CaR. Immunohistochemical localization of the CaR using specific anti-CaR antiserum revealed its presence on the basal aspect of gastric epithelial cells. In microelectrode studies of Necturus antral mucosa, exposure to elevated Ca2+ (4.8 mM) and the CaR agonists NPS-467 and neomycin sulfate resulted in significant hyperpolarizations of basal membrane electrical potentials and increases in apical-to-basal membrane resistance ratios. Circuit analysis revealed that these changes reflected specific decreases in basolateral membrane resistance. Inhibition of prostaglandin synthesis using indomethacin significantly attenuated these effects. We conclude that the CaR is present and functioning in Necturus gastric antrum.
Amiloride↗
Effects of serosal-side acidosis on cell pH (pHi) and membrane electrical properties in gastric mucosa.
Acute gastric mucosal injury and bleeding occur in the settings of both respiratory acidosis or metabolic acidosis secondary to systemic sepsis or shock. Respiratory acidosis, however, is more predictably associated with acute injury than metabolic acidosis. We hypothesized that the gastric surface epithelial cells are more susceptible to acute increases in PCO2 than to acute decreases in HCO3-, even for the same level of extracellular acidification. To evaluate this hypothesis, we used intracellular microelectrodes to measure pHi, cell membrane potential (Vc), as well as ion conductances of the apical (Ga) and basolateral (Gb) membranes and the paracellular pathway (Gs) in gastric mucosal cells during acute changes in serosal PCO2 or HCO3-. Necturus antral mucosae were mounted in Ussing chambers, perfused on both sides by Ringer solution (40 mmHg PCO2, 18 mM HCO3-, pH 7.3). Measurements were performed before and during increases in PCO2 (80 mmHg, pH 7.0) or decreases in HCO3- (7.2 mM, pH 6.8 or 2.4 mM, pH 6.4). Both forms of acidosis acidified pHi, depolarized membrane potentials, and decreased ion conductances across apical and basolateral membranes, but not the paracellular pathways. For the same level of extracellular acidification, increases in PCO2 were more effective than acute decreases in HCO3- in acidifying pHi and eliciting disturbances in voltage-generating and ion permeability properties of the cell membranes. These findings suggest that pH-buffering mechanisms in gastric surface cells respond less effectively to high PCO2 than low HCO3.
Acidosis↗
Pentagastrin selectively modulates levels of mRNAs encoding apical H/K adenosine triphosphatase and basolateral Na-K-Cl cotransporter in rat gastric fundic mucosa.
BACKGROUND: Gastrin regulates gastric acid secretion and gastric mucosal cell proliferation. We hypothesized that pentagastrin administration would affect mRNA levels of two membrane proteins that are important during stimulated states of HCl secretion, the basolateral Na-K-Cl cotransporter (BSC) and the apical H/K adenosine triphosphatase (H/K). METHODS: Two groups of Fischer rats received intraperitoneal injections of pentagastrin (2.5 or 25 micrograms/kg) every 8 hours for three doses. A third group served as controls. An additional group received pentagastrin plus the gastrin receptor antagonist (GRA) L740,093. Fundic mucosae were subjected to semiquantitative Northern analysis of mRNAs encoding H/K and BSC. The mRNA for Na/K adenosine triphosphatase (Na/K), a transport protein not involved directly in acid secretion, also was evaluated. RESULTS: Administration of pentagastrin caused dose-dependent increases in levels of mRNAs encoding H/K and BSC but had no significant effect on levels of Na/K mRNA. Administration of GRA prevented the pentagastrin-induced changes in mRNA levels for these transporters. CONCLUSIONS: Pentagastrin administration selectively up-regulates levels of mRNA encoding membrane proteins involved in acid secretion. The up-regulation of the mRNAs encoding BSC during pentagastrin stimulation indicates that regulation of basolateral Cl- movement may be as important as the regulation of apical H+ movement under stimulated states.
Acids↗
Evidence for Cl(-)-independent HCO3- transport in basolateral membranes of Necturus oxyntopeptic cells.
Luminal H+ secretion by gastric mucosa is accompanied by basolateral HCO3- release. A basolateral Cl-/HCO3- exchanger is known to mediate HCO3- extrusion from oxyntopeptic cells during resting and secretagogue-induced apical HCl secretion. From recent work, we hypothesized that there might be a Cl(-)-independent pathway for basolateral HCO3- exit in Necturus oxyntopeptic cells. In this study, we used a fluorescent pH indicator [2',7'-bis(2-carboxyethyl)-5(6)-carboxyfluorescein] to evaluate Cl(-)-independent HCO3- transport across the basolateral membranes of intact oxyntopeptic cells. Removal of serosal Cl- increased intracellular pH (pHi) (7.05 to 7.25), consistent with Cl(-)-dependent HCO3- extrusion. Removal of serosal Na+ in the absence of Cl- resulted in significant acidification of pHi (7.10 to 6.89), but studies involving amiloride, 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS), and 0 HCO3(-)-N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid-buffered solutions suggest that Na(+)-dependent changes in pHi are due to Na+/H+ exchange. Our studies demonstrate a marked concentration-dependent alkalinization when tissues are exposed to increases in serosal K+. A substantial part of this alkalinization in response to increases in serosal K+ (pHi 7.00 to 7.46) appears to be a HCO3- exit pathway that is independent of both Na+ and Cl-, unaffected by bumetanide or amiloride, but sensitive to DIDS. We propose the presence of a Cl(-)- and Na(+)-independent K(+)-dependent HCO3- cotransporter in Necturus oxyntopeptic cell basolateral membranes.
Animals↗
Luminal osmolarity downregulates gene expression of Na+/H+ exchanger (NHE3) in rat colon mucosa.
Water-coupled Na&sup+ absorption in the colon is mediated principally by Na+/H+ exchange (isoforms NHE2 and NHE3). To determine whether luminal ion composition or osmolarity influences NHE expression in colon mucosa, two groups (n = 6 in each) of adult male Sprague-Dawley rats underwent sham laparotomy or loop ileostomy. In these studies, diversion did not markedly alter mRNA levels for NHE2, NHE3, or Na+/K+, at 8 or 21 days, indicating that loss of luminal volume does not alter NHE gene expression. To evaluate the effects of specific luminal components, we infused equal volumes of half-normal (154 mOsm) or iso-osmolar (308 mOsm) solutions of saline and mannitol into the diverted colon. All solutions elicited significant (45% to 60%; P <0.05) decreases in mRNA levels for NHE3, with iso-osmolar mannitol eliciting the greatest changes. Decreases in NHE2 and Na+/K+ mRNA levels were observed following these infusions but were not as marked as the changes for NHE3. These findings suggest that (1) loss of luminal Na+ is not, in itself, a signal that regulates NHE expression and (2) infusion of any solute, including Na+ itself, provides a signal to downregulate expression of NHE3 in colon mucosa.
Animals↗
Selective increase in gastric mucosal mRNA encoding basolateral Na-K-2C1 cotransporter following ileostomy in the rat.
Results of previous studies suggest that major surgical resections or reconstructions of the distal small intestine can alter morphologic and functional properties of the stomach. Little is known about the effect of lesser surgical alterations such as construction of an ileostomy, on the morphology and transport properties of the gastric mucosa. To evaluate the effects of ileostomy, Sprague-Dawley rats underwent sham laparotomy (n = 10) or loop ileostomy construction (n = 10). After body weights had stabilized ( approximately 21 days) the animals were killed. Gastric mucosal scrapings were prepared for Northern blot analysis of messenger RNA levels for (1) H/K ATPase, found in parietal cells; (2) Na-K-2C1 cotransporter, found in both parietal and surface cells; and (3)Na/K ATPase, found in all gastric mucosal cells. Gastric mucosa from ileostomy animals was visibly hypertrophied compared to sham-operated animals. There was a 145% increase in the mRNA levels of the Na-K-2Cl cotransporter in gastric mucosa of the ileostomy group but no significant changes in H/K ATPase or Na/K ATPase mRNA levels. Construction of an ileostomy selectively enhances expression of the Na-K-C1 cotransporter in the gastric mucosa. Further studies are required to understand the neurohumoral stimuli underlying this selective response.
Animals↗
Selective decreases in levels of mRNA encoding a water channel (AQP3) in ileal mucosa after ileostomy in the rat.
Water channels (aquaporins) provide pathways for water permeation in a variety of epithelia. Aquaporin-3 (AQP3) has been localized to the basolateral membranes of epithelial cells in the small intestine, but mechanisms that regulate its expression and function have not been explored. To determine whether luminal content may influence intestinal AQP3 gene expression, adult Sprague-Dawley rats underwent sham laparotomy (N = 11) or loop ileostomy (N = 9) and were killed 8 days after procedures. Northern blot analysis was used to measure messenger RNA (mRNA) levels for AQP3 and the Na(+)/K(+) ATPase, a housekeeping transporter that regulates cellular levels of Na(+) and K(+). At sacrifice, histologic examination revealed only minimal changes in mucosal morphology. In sham animals, Na/K mRNA levels increased moderately in distal regions of the small intestine. Ileostomy did not alter these levels in any region. In contrast, in sham animals, AQP3 mRNA levels increased along the length of the intestine and were markedly higher in the distal ileum. Diversion of luminal contents decreased AQP3 mRNA levels in the postileostomy region by 30% to 50%. These findings indicate regional variations in expression of the AQP3 water channel in mucosa of the small intestine. In addition, they suggest that AQP3 gene expression may depend on the presence of luminal contents.
Analysis of Variance↗