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Biomedical subjects

D W Powell

Publications and source records attributed to D W Powell.

At least 55 records · Page 3Linked to original sources
PubMed1989

Serosal bicarbonate protects against acid injury to rabbit esophagus.

The role of serosal bicarbonate ions (HCO3-) in protection against acid injury was investigated in rabbit esophageal mucosa mounted in Ussing chambers. Luminal acidification reduced potential difference and resistance in tissues exposed serosally to HCO3- or (unbuffered) HCO3-free solution. Whereas resistance declined similarly in both groups, potential difference declined less in HCO3- solution. After washout, HCO3-bathed tissues also had a greater increase in resistance, lower permeability to mannitol, and less histologic damage. Furthermore, as protection by HCO3- was not blocked by pretreatment with either the anion exchange blocker, 4 acetamido-4'-isothiocyanatostilbene 2-2'-disulfonic acid, or the carbonic anhydrase inhibitor, acetazolamide, and replacement of HCO3- with N-2-hydroxyethylpiperazine-N'-2-ethane sulfonic acid, a buffer impermeant to cells, was protective, an extracellular site for protection by HCO3- was likely. Where in the extracellular space HCO3- buffers H+ is unclear, but the absence of change in luminal pH and the inability to prevent the acid-induced increase in permeability in HCO3-bathed tissues argue against a luminal (preepithelial) site. Also, rapid repair was not demonstrated, indicating that a luminal site for protection after surface cell damage was unlikely. We conclude that serosal HCO3- is important in esophageal protection against acid damage by buffering H+ within the intercellular compartment of the extracellular space.

4-Acetamido-4'-isothiocyanatostilbene-2,2'-disulfo↗
PubMed1989

Colonic and esophageal transepithelial potential difference in cystic fibrosis.

To evaluate differences in the expression of cystic fibrosis (CF) transport defects in the gastrointestinal tract of subjects with CF, in vivo measurements of colonic and esophageal transepithelial electrical potential difference (PD) were performed before and during amiloride superfusion in CF and healthy subjects. Esophageal PD before (-16 +/- 2 vs. -16 +/- 3 mV) and after (-14 +/- 2 vs. -15 +/- 0.3 mV) superfusion with amiloride were similar for CF and healthy subjects. Basal rectosigmoid colon PD was also similar (CF: mean -23 +/- 6 and maximal -37 +/- 9 mV; normal: mean -26 +/- 5 and maximal -45 +/- 11 mV) in both groups. However, with amiloride superfusion (10(-4) M) the colonic PD in CF subjects was almost abolished (95% +/- 15% inhibition), whereas the PD in healthy subjects was only partially reduced (42% +/- 6%) (p less than 0.05). The greater inhibition with amiloride in CF, which was evident in absolute terms (26 +/- 4 vs. 16 +/- 3 mV for controls, p less than 0.05) as well as relative terms, could not be ascribed to a difference in mineralocorticoid secretion rates, because 24-h urine excretion of aldosterone and 17 hydroxy and 17 ketosteroids were similar in both groups. Freshly excised colonic epithelia from 1 CF and 3 non-CF subjects were studied in Ussing chambers, and a similar difference in amiloride responsiveness noted: PD and short-circuit current declined 33% +/- 2% and 37% +/- 4%, respectively, in seven tissues from the colons of 3 patients without CF, whereas both PD and short-circuit current were fully inhibited (100%) in all three tissues from the CF patient. As the presence of an amiloride-insensitive component of short-circuit current in non-CF colon is largely due to electrogenic Cl- secretion, the demonstration that this component was absent both in vivo and in vitro in CF colon establishes the presence of a defect in electrolyte transport in CF colon, a defect consistent with recent reports of absent electrogenic Cl- secretion in CF intestine.

Adult↗
PubMed1989

Immune system control of rat and rabbit colonic electrolyte transport. Role of prostaglandins and enteric nervous system.

The role of the immune system in controlling intestinal electrolyte transport was studied in rat and rabbit colon in Ussing chambers. A phagocyte stimulus, the chemotactic peptide FMLP, and a mast cell stimulus, sheep anti-rat IgE, caused a brief (less than 10 min) increase in short-circuit current (Isc). Products of immune system activation, platelet-activating factor (PAF) and reactive oxygen species (ROS), caused a sustained, biphasic increase in the Isc. Ion replacement and flux studies indicated that these agonists stimulated electrogenic Cl secretion and inhibited neutral NaCl absorption; responses that were variably inhibited by the cyclooxygenase blockers indomethacin and piroxicam. Lesser degrees of inhibition by nordihydroguaiaretic acid could be accounted for by decreased prostaglandin synthesis rather than by lipoxygenase blockade. Tetrodotoxin, hexamethonium, and atropine also inhibited immune agonist-stimulated Isc, but had no effect on immune agonist-stimulated production of PGE2 or PGI2. These results indicate that immune system agonists alter intestinal epithelial electrolyte transport through release of cyclooxygenase products from cells in the lamina propria with at least 50% of the response being due to cyclooxygenase product activation of the enteric nervous system. The immune system, like the enteric nervous system and the endocrine system, may be a major regulating system for intestinal water and electrolyte transport in health and disease.

Animals↗
PubMed1988

Effect of BW 942C, an enkephalinlike pentapeptide, on sodium and chloride transport in the rabbit ileum.

BW 942C is a novel enkephalinlike pentapeptide that has been shown to have antidiarrheal action in model systems. The effect of BW 942C on rabbit ileal electrolyte transport was studied to gain insight into the mechanism of the antidiarrheal action of opiate-like compounds. Multiple effects were observed, differing with the basal state of the tissue. BW 942C increased Na absorption in tissues that were not absorbing in the basal state, whereas it had little effect on Na absorption in tissues that were previously absorbing at moderate to high rates (greater than 1 microEq/h.cm2. It increased Cl absorption and caused a dose-related decrease in short-circuit current in all tissues. This effect was reversed or inhibited by naloxone (10(-5) M), suggesting that it is mediated by opiate receptors. No significant change in residual flux was noted. BW 942C was effective from both the serosal and mucosal side; however, it required a 2-log higher dose on the mucosal side (10(-4) M, maximal) to achieve a response similar to that observed with serosal application (10(-6) M, maximal). The ability of BW 942C to alter stimulated secretion was studied using theophylline, prostaglandin E2, vasoactive intestinal peptide, and bethanechol. There was significantly less Cl secretion in BW 942C-treated tissues than in control tissues after stimulation with prostaglandin E2 (10(-7) M). However, this effect was not apparent at higher doses of prostaglandin E2 and there was no inhibition of the short-circuit current response to any of the secretory stimuli by BW 942C. Loperamide was also found to be unable to inhibit the Cl secretion or change in short-circuit current stimulated by theophylline. Although opiates have been shown to be moderately effective antidiarrheal agents, their ability to influence mucosal electrolyte transport is weak and may only account for part of their antidiarrheal action.

Animals↗
PubMed1988

Altered intestinal chloride transport in cystic fibrosis.

Sodium ion and chloride transport was studied in vitro in small intestinal and colonic tissue from patients with cystic fibrosis (CF) and from non-CF control subjects matched as to age and sex. Normal histological appearance and substantial response to mucosal glucose (5 mM, ileum) or mucosal amiloride (10(-5) M, colon) indicated normal tissue viability in both control and CF tissues. Electroneutral NaCl absorption was demonstrated in the small intestine of control subjects and CF patients. Small intestinal and colonic tissues of control subjects responded to four secretagogues (theophylline, 5 mM; prostaglandin E2, 10(-6) M; calcium ionophore (A23187), 10(-5) M; bethanechol, 5 x 10(-5) M), with electrogenic chloride secretion. The tissues of CF patients, however, did not respond to any of the test secretagogues. These studies demonstrate that an abnormality in chloride transport is present in the small intestinal and colonic epithelia of CF patients. Unlike airway epithelia, which secrete chloride in response to Ca ionophore, the intestinal epithelia of CF patients do not respond to either cAMP- or Ca-mediated secretagogues. This abnormality in intestinal electrolyte transport may play a role in the pathogenesis of meconium impactions in CF patients.

Adult↗
PubMed1987

Mucosal protection by sucralfate and its components in acid-exposed rabbit esophagus.

Sucralfate has been reported to protect the esophageal epithelium of the rabbit and cat against acid injury. To determine the contribution of its components, aluminum hydroxide and sucrose octasulfate (SOS), rabbit esophageal epithelia were mounted in Ussing chambers to monitor changes in electrical resistance (R) upon exposure to HCl (pH 1.4-1.6). In untreated tissues, acidification of the luminal bath produced a progressive decline in R, indicating increased epithelial permeability. Sucralfate added to the luminal bath 45 min after acidification increased R to preexposure levels--an effect accompanied by increased luminal pH. Similar to sucralfate, aluminum hydroxide added to the acidified bath increased R and luminal pH. However, the effect of aluminum hydroxide could be abolished by titration with HCl to maintain pH similar to acid-treated control tissues. Tissues treated with sucralfate and whose luminal solutions were titrated with HCl to maintain pH similar to controls no longer exhibited an increase in R but, in contrast to aluminum hydroxide treatment, the acid-induced decline in R was prevented. This action of sucralfate was shown to be a property of its other component, SOS. Sucrose octasulfate, like acid-titrated sucralfate solutions, did not increase luminal bath pH, yet prevented the acid-induced decline in R. Confirmation of protection by SOS was shown by additional morphologic and flux studies. Thus 1 h after luminal bath acidification in the Ussing chamber, SOS-treated tissues demonstrated less damage (injury score 0.6 +/- 0.4 vs. 1.6 +/- 0.3, p less than 0.05) and lower permeability to mannitol (0.003 +/- 0.001 vs. 0.013 +/- 0.005 mumol/h X cm2, p less than 0.05) than untreated tissues. Similarly, 1 h of luminal perfusion with HCl in vivo produced less damage (injury score 1.3 +/- 0.5 vs. 3.5 +/- 0.4, p less than 0.05) and less H+ efflux from the lumen in SOS-treated than untreated tissues. These results indicate that sucralfate can protect against acid injury in esophagus and that this protection is mediated by (a) intraluminal pH buffering through its content of aluminum hydroxide and (b) enhancing mucosal defense against H+ entry and injury through its content of SOS.

Acids↗
PubMed1987

Development of a scoring system to predict mortality from upper gastrointestinal bleeding.

Despite the widespread application of endoscopy in acute upper gastrointestinal bleeding, there is little evidence of improved survival among those who undergo the procedure. To select high-risk patients who might benefit most from diagnostic and therapeutic endoscopy, the authors developed and validated a scoring system based on prognostic indicators of increased mortality. The scoring system was developed from the best clinical predictors of mortality, determined in a prospective study of consecutive bleeding patients. The model was then tested in a prospective validation phase at three hospitals. Three main factors in the model predict mortality: bleeding, including hematochezia, drop in hematocrit of 5%, short duration of bleeding, absence of melena, and hypotension; liver disease, manifested by prolonged prothrombin time and encephalopathy; and renal disease. Patients determined to be at high risk for death using the scoring system might be candidates for aggressive management and for therapeutic endoscopy.

Adolescent↗
PubMed1987

Bradykinin-stimulated eicosanoid synthesis and secretion by rabbit ileal components.

The eicosanoid profiles, sites of production, and response to bradykinin stimulation were determined in rabbit ileum and its various components by radioimmunoassay of various prostanoids and 5-lipoxygenase products in the incubation media. The profile of eicosanoid synthesis and secretion by the epithelial cell fraction was PGF2 alpha greater than 6-keto-PGF1 alpha greater than dihydro-keto-PCM = PGE2 greater than TxB2 much greater than 5-HETE greater than LTB4 and by the deepitheliated ileum was PGE2 = 6-keto-PGF1 alpha greater than PGF2 alpha greater than dihydro-keto-PGM greater than TxB2 much greater than LTB4 greater than 5-HETE. PGD2 was not sought in these studies. Rates of eicosanoid production by the deepitheliated ileum were over 200 times that of the epithelial cells. The epithelial cells accounted for 67% of the protein but only 0.2% of the PGE2 produced, while the lamina propria and submucosa contained only 12-30% of the protein but produced 80-90% of the PGE2. Bradykinin (1 microM), A23187 (10 microM), arachidonic acid (20 microM), and melittin (0.7 microM) stimulated PGE2 and 6-keto-PGF1 alpha production by 200% in deepitheliated (or subepithelial) ileum, but bradykinin failed to stimulate production of any eicosanoid by the epithelial cell fraction. Thus the subepithelium (predominantly the lamina propria) is the major eicosanoid producer of rabbit ileum and is the major site of bradykinin-stimulated eicosanoid synthesis and secretion. Eicosanoids released from subepithelial components may be important regulators of epithelial function.

1-Methyl-3-isobutylxanthine↗
PubMed1987

Cytoprotection by sucralfate: role of sulfate ions.

Sucralfate and its component, sucrose octasulfate, are both SO4(2-)-containing compounds shown to protect against acid-peptic injury in rabbit and/or cat esophagi. To determine if sulfate ions (SO4(2-) contributed to this protection, a series of in vitro and in vivo experiments were performed in acid-exposed rabbit esophagi. In the Ussing chamber SO4(2-)-containing solutions significantly reduced the acid-induced decline in electrical resistance (R) observed in controls. This effect was unrelated to buffering of H+, accompanying cation or changes in luminal solution osmolality. Protection by SO4(2-) was specific since other divalent (HPO4(2-] or impermeant anions (gluconate-) failed to reduce the acid-induced decline in R. Protection was confirmed in vivo by showing that acid-perfused esophagi exposed to SO4(2-) had less morphologic damage, higher R and lower permeability to 14C-mannitol and H+ than controls. These results indicate that SO4(2-) have a unique protective action against acid injury to esophageal epithelia, and this action appears to explain the cytoprotective properties of sucralfate.

Animals↗
PubMed1986

Effect of cigarette smoke on esophageal epithelium of the rabbit.

Cigarette smoking is a recognized risk factor for esophageal mucosal disease. For this reason we investigated the effects of smoke on esophageal epithelial electrolyte transport and barrier function in the rabbit. Studies were performed using an extract of cigarette smoke (EOCS) prepared from high-tar, high-nicotine cigarettes. Epithelia were exposed to EOCS in vivo or in vitro in the Ussing chamber. Acute in vivo exposure to EOCS lowered in vivo esophageal potential difference by 61%, and in vitro studies established that this was due to inhibition of active Na transport from mucosa to serosa. Exposure to an EOCS had no effect on net Cl transport or epithelial permeability, the latter reflected by the absence of change in electrical resistance or mannitol flux. The ability of an EOCS to lower potential difference (and inhibit Na transport) was dose-related and equally effective whether contact occurred with the luminal or serosal surface of the tissue. Similar studies performed with an EOCS prepared from filtered smoke established that the component(s) in EOCS responsible for the effects on transport resided in the particulate phase of smoke (i.e., nicotine and "tars"). However, nicotine only inhibited Na transport from the serosal side of the tissue, thus indicating that one or more tars either cause or contribute to the effect of an EOCS on transport. The inhibition by smoke of ion transport in esophageal epithelium may well be an early deleterious link in the pathophysiological chain between cigarette smoking and esophageal mucosal disease.

Animals↗
PubMed1986

Prostaglandin synthesis by enterocyte microsomes of rabbit small intestine.

We studied the prostaglandin (PG) synthetic capacity of microsomes of a relatively pure population of rabbit enterocytes and determined ideal conditions for product synthesis. The epithelial cells were freed from the basement membrane by a combination of calcium chelation and mechanical vibration, and 100,000 X g microsomes were prepared. These microsomes were found to synthesize PG from exogenously added arachidonic acid. The ideal conditions for the reaction were a microsomal protein concentration of 1.0 mg/ml, an arachidonic acid concentration of 33 uM, a reaction mixture pH of 8.0-9.5 and with epinephrine 1.5 mM added as a cofactor. The product yields increased linearly with time up to 30 min. of incubation and were inhibited by 100 uM indomethacin. Under the above ideal conditions enterocyte microsomes yielded the following products expressed as pmole/mg protein/20 min. incubation: PGF2 alpha 98 +/- 7, PGE2 48 +/- 9, PGD2 28 +/- 7, TxB2 40 +/- 5, 6 Keto PGF1 alpha 15 +/- 6.

Animals↗
PubMed1986

Cytoprotective effect of sulfate ions in acid-exposed rabbit esophagus.

Sodium sulfate significantly inhibited the decline in epithelial electrical resistance (R) produced by mucosal acidification (pH 1.4) of rabbit esophagus mounted in the Ussing chamber. This protective effect was not due to the cation, to sodium loading, hyperosmolality, or pH change of the mucosal solution. Protection was specific for sulfate ions (SO2-4), since other divalent (HPO2-4) or impermeant anions (gluconate-) failed to prevent the acid-induced decline in R. In vivo studies in HCl-perfused rabbit esophagi confirmed protection by SO2-4. Tissues exposed to SO2-4 and HCl had higher R, lower permeability to H+ and mannitol, and less morphologic damage than controls exposed to HCl. These results suggest that SO2-4 have a unique protective action against acid injury to esophageal epithelia, and this action appears to explain the cytoprotective properties of sucralfate, a clinically effective agent for treating acid-peptic disease in humans.

Animals↗
PubMed1985

Regulation of water and ion movement in intestine.

The direction of net fluid transport in the gut is determined by the algebraic sum of Na+ absorption and Cl- secretion. Na+ absorption by small intestinal villous cells and colonic surface cells is controlled primarily by electrically neutral (NaCl) and electrogenic (Na+-glucose, Na+-amino acid, amiloride-insensitive, and amiloride-sensitive Na+ conductance) entry processes in the apical membrane. Neutral NaCl entry appears to be the result of parallel Na+:H- and Cl-:HCO3- exchangers operating at equal stoichiometry. Uncoupled exchangers operating at different stoichiometry may result in net HCO3- absorption (jejunum), net HCO3- secretion (ileum and proximal colon) or HCO3-:Cl- exchange (distal colon). Increases in intracellular cyclic nucleotides and/or ionized Ca2+ inhibit NaCl entry and, in vivo, promote HCO3- and Cl- secretion. Cl- secretion by crypt cells is the result of cyclic nucleotide-mediated or Ca2+-mediated Cl- conductance channels in the apical membrane which allow Cl- to exit down an electrochemical gradient created by a basolateral NaKCl2 entry process. Cyclic nucleotides may act via specific A and G protein kinases. They also release Ca2+ from intracellular stores and thus could alter transport via Ca2+ (and calmodulin)-activated kinases. Ca2+-dependent secretory agents initiate phospholipid hydrolysis and stimulate secretion via the resulting hydrolytic products: arachidonic acid metabolites when bradykinin is the stimulus or diacylglycerol and/or inositol trisphosphate when acetylcholine is the stimulus. The arachidonic acid metabolites may then stimulate cyclic nucleotide production, while diacylglycerol activates a specific Ca2+/phospholipid-dependent protein kinase (C kinase), and inositol trisphosphate releases Ca2+ from the endoplasmic reticulum. The interrelationships between these intracellular messengers and their exact modes of action remain to be clarified.

Arachidonic Acid↗
PubMed1985

Granulomatous enterocolitis induced in rats by purified bacterial cell wall fragments.

This study was designed to determine if poorly biodegradable bacterial cell wall components can produce chronic intestinal inflammation. A sterile aqueous suspension of sonically disrupted group A or group D streptococcal cell wall fragments was injected intramurally into the small intestine and cecum of 100 rats. Gross findings in rats killed at intervals of 1 day to 6 mo included intestinal thickening, adhesions, and mesenteric contraction. Acute histologic inflammation subsided by 2 wk, but chronic granulomatous inflammation persisted for 6 mo in the rats injected with group A streptococcal cell wall fragments and 3 mo in the rats injected with group D streptococcal cell wall fragments. Ninety-six control rats identically injected with human serum albumin or phosphate-buffered saline demonstrated mild acute inflammation that resolved, with only 1 rat having chronic intestinal inflammation. Granulomas in the intestine, mesentery, and mesenteric lymph nodes developed in 46% of the rats injected with group A fragments and 45% of the rats injected with group D streptococcal cell wall fragments, compared with 20% of the controls injected with albumin and 4% of the controls injected with phosphate-buffered saline. Group A streptococcal antigen was detected by immunofluorescence at the site of inflammation for 4 mo, and possible reactivation of acute inflammation was seen up to 6 mo after injection. We conclude that bacterial cell wall fragments are capable of producing chronic granulomatous inflammation in the intestinal wall if present in appropriate particle size and concentration. We speculate that cell walls from the enteric microflora may leak across a permeable mucosa in chronic inflammatory bowel disease to initiate and sustain local and systemic inflammation.

Animals↗
PubMed1984

Major gastrointestinal hemorrhage from peripancreatic blood vessels in pancreatitis. Treatment by embolotherapy.

Seven cases of gastrointestinal bleeding originating from peripancreatic blood vessels seen between 1977 and 1982 are presented. The bleeding originated either from true aneurysms, formed when the pancreatic inflammatory processes weaken the walls of peripancreatic blood vessels, from pseudoaneurysms which occurred after vascular leakage into pancreatic pseudocyst, or from veins. Gastrointestinal bleeding occurs when these entities rupture into gastrointestinal viscera. Hemorrhage of this nature must be considered in the clinical setting of patients who have a history of alcoholism, chronic relapsing pancreatitis, and known pseudocysts. Endoscopy, bleeding scans, and barium contrast studies are only occasionally helpful in diagnosis. Selective visceral angiography during acute hemorrhage is often diagnostic and concomitant arterial embolization techniques may offer a temporizing or permanent modality for hemostasis. This technique may be especially useful in the unstable, acutely ill patient with alcoholic hepatitis, sepsis, or an immature pseudocyst who poses a poor operative risk.

Adult↗
PubMed1984

Mechanisms of H+ injury in rabbit esophageal epithelium.

We previously postulated that active Na transport by the esophageal stratified squamous epithelium is important for maintenance of its barrier function. To investigate this further we studied the effects of HCl on the in vivo esophageal potential difference (PD), on in vitro Na transport, and on esophageal Na-K-ATPase activity. In vivo esophageal perfusion with low concentrations of HCl (20 or 40 mM) increased the PD and a high concentration (120 mM) decreased it. An intermediate concentration (80 mM) caused a biphasic response with an initial increase in PD followed by a progressive decrease in PD. In vitro transport studies were performed to explain the increased in vivo PD. In the presence of luminal H+ the increased PD resulted from H+ diffusion from lumen to blood, whereas after H+ exposure the increased PD was due largely to increased net Na transport from lumen to blood through an amiloride-sensitive mechanism. In tissues with prolonged exposure to 80 mM HCl (PD decreased 80-100%), Na-K-ATPase activity was significantly inhibited (1.94 +/- 0.32 vs. 5.12 +/- 0.73 mumol P X mg prot-1 X h-1). Thus, HCl initially increases the in vivo esophageal PD by H+ transport from lumen to blood, a process replaced by stimulated net Na transport when H+ is replaced by Na. Prolonged acid exposure ultimately decreases Na exit from cells by inhibiting Na-K-ATPase activity. This sequence suggests that alterations in Na transport could result in cell edema and necrosis via loss of cell volume regulation.

Animals↗
PubMed1984

Coupled NaCl transport: cotransport or parallel ion exchange?

In recent years it has become apparent that at least part of the transcellular movements of Na and Cl are linked by a process or processes which couple the entry of Na to Cl across the apical cell membrane of the intestinal cell. In some tissues, eg, gallbladder and renal tubule, this coupled transport of Na and Cl may be the predominant electrolyte-transporting mechanism. Studies in rabbit ileal brush-border membrane vesicles present evidence for a coupled NaCl process that has the same ionic specificities and similar kinetics as the processes demonstrated by influx techniques across the apical membrane of the intact epithelium. However, the vesicles also exhibit Na:H and Cl:HCO3 exchange processes and the inhibitors thought to be specific for either the NaCl cotransport system (loop diuretics), for the Na:H exchange (high-dose amiloride), or for the Cl:HCO3 exchange (disulfonic stilbenes such as SITS or DIDS), do not prove to be so. It is possible that all three processes could be present in intestinal brush-border membranes. Furthermore, the techniques of isolating vesicles could uncouple or otherwise inhibit the coupled NaCl process. Nonetheless, the preponderance of evidence at this time indicates that parallel ion exchangers of Na:H and Cl:HCO3, as initially suggested by Turnberg et al [4], account for coupled NaCl transport in rabbit ileum. Additional studies will be necessary to determine if this is the only mechanism in the intestinal apical membrane and whether this conclusion applies to other tissues such as gallbladder and renal tubule.

Animals↗