Aspirin, ulcer, and intestinal bleeding: what do the data show?
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Aspirin↗
Biomedical subjects
W D Rees
Publications and source records attributed to W D Rees.
Evidence for negative cooperativity in human erythrocyte sugar transport.
1. When D-glucose exchange influx is measure over a wide range of concentrations then two affinity constants (2.27 and 26.0 mM) are evident. This is consistent with a transport model (the allosteric pore model) in which there is negative cooperativity between subunits of the transport protein. 2. The equations for the allosteric pore model interacting with two substrates (or a substrate and an inhibitor) have been derived and have been used to analyse data from exchange inhibition and for mixed infinite-trans uptake experiments. 3. The exchange inhibition of tracer 3-O-methyl-D-glucose, D-xylose and D-fructose uptake by D-glucose also shows evidence for negative cooperativity and for two inhibition constants which are approximately equal to the D-glucose equilibrium exchange affinity constants. 4. The uptake of D-glucose into infinite-trans D-glucose or 3-O-methyl-D-glucose gives Km values of 2.6 and 2.33 mM, respectively. The uptake of 3-O-methyl-D-glucose into infinite-trans D-glucose or 3-O-methyl-D-glucose gives Km values of 6.0 and 4.6 mM, respectively. V values are slightly higher when the internal sugar is 3-O-methyl-D-glucose. 5. In cells that are treated with fluorodinitrobenzene the apparent Ki value for D-glucose inhibition of tracer D-fructose uptake is lowered. It is proposed that this is due to a partially selective effect of FDNB on the internal subunit interface stability constant (the internal pore gate).
Biological Transport, Active↗
Spatial requirements for insulin-sensitive sugar transport in rat adipocytes.
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3-O-Methylglucose↗
Hydrogen bonding requirements for the insulin-sensitive sugar transport system of rat adipocytes.
(1) The t 1/2 for 1.3 mM D-allose uptake and efflux in insulin-stimulated adipocytes is 1.7 +/- 0.1 min. In the absence of insulin mediated uptake of D-allose is virtually eliminated and the uptake rate (t 1/2 = 75.8 +/- 4.99 min) is near that calculated for nonmediated transport. The kinetic parameters for D-allose zero-trans uptake in insulin-treated cells are Koizt = 271.3 +/- 34.2 mM, Voizt = 1.15 +/- 0.12 mM . s-1. (2) A kinetic analysis of the single-gate transporter (carrier) model interacting with two substrates (or substrate plus inhibitor) is presented. The analysis shows that the heteroexchange rates for two substrates interacting with the transporter are not unique and can be calculated from the kinetic parameters for each sugar acting alone with the transporter. This means that the equations for substrate analogue inhibition of the transport of a low affinity substrate such as D-allose can be simplified. It is shown that for the single gate transporter the Ki for a substrate analogue inhibitor should equal the equilibrium exchange Km for this analogue. (3) Analogues substituted at C-1 show a fused pyranose ring is accepted by the transporter. 1-Deoxy-D-glucose is transported but has low affinity for the transporter. High affinity can be restored by replacing a fluorine in the beta-position at C-1. The Ki for D-glucose = 8.62 mM; the Ki for beta-fluoro-D-glucose = 6.87 mM. Replacing the ring oxygen also results in a marked reduction in affinity. The Ki for 5-thio-D-glucose = 42.1 mM. (4) A hydroxyl in the gluco configuration at C-2 is not required as 2-deoxy-D-galactose (Ki = 20.75 mM) has a slightly higher affinity than D-galactose (Ki = 24.49 mM). A hydroxyl in the manno configuration at C-2 interferes with transport as D-talose (Ki = 35.4 mM) has a lower affinity than D-galactose. (5) D-Allose (Km = 271.3 mM) and 3-deoxy-D-glucose (Ki = 40.31 mM) have low affinity but high affinity is restored by substituting a fluorine in the gluco configuration at C-3. The Ki for 3-fluoro-D-glucose = 7.97 mM. (6) Analogues modified at C-4 and C-6 do not show large losses in affinity. However, 6-deoxy-D-glucose (Ki = 11.08 mM) has lower affinity than D-glucose and 6-deoxy-D-galactose (Ki = 33.97 mM) has lower affinity than D-galactose. Fluorine solution at C-6 of D-galactose restores high affinity. The Ki for 6-fluoro-D-galactose = 6.67 mM. Removal of the C-5 hydroxymethyl group results in a large affinity loss. The Ki for D-xylose = 45.5 mM. The Ki for L-arabinose = 49.69 mM. (7) These results indicate that the important hydrogen bonding positions involved in sugar interaction with the insulin-stimulated adipocytes transporter are the ring oxygen, C-1 and C-3. There may be a weaker hydrogen bond to C-6. Sugar hydroxyls in non-gluco configurations may sterically hinder transport.
Adipose Tissue↗
Effect of carbenoxolone on alkaline secretion by isolated amphibian gastric and duodenal mucosa.
The influence of carbenoxolone sodium on HCO-3 transport has been examined in spontaneously alkalinizing amphibian antral (Necturus and Rana catesbeiana) and proximal duodenal (Rana catesbeiana) mucosa and in cimetidine-treated fundic mucosa (Rana temporaria) in vivo. Low concentrations of carbenoxolone (10(-6)-10(-4) mol/l, serosal side and 10(-5) mol/l, luminal side) did not affect the secretory rate or electrical properties of these tissues. In the stomach a higher concentration of carbenoxolone (10(-3) mol/l, serosal side) caused an immediate fall in transmucosal potential difference (PD) and electrical resistance. There was an initial decrease in the rate of HCO-3 transport followed by an increase in titratable alkalinization due to passive permeation of base from the serosal bathing solution. The non-steroidal anti-inflammatory agent ibuprofen (3 x 10(-3) mol/l, serosal side) inhibited alkaline secretion while the bile salt sodium taurocholate (10(-4) mol/l, luminal side) converted net alkaline secretion to a titratable acidity in cimetidine-treated fundus. Pretreatment of the mucosa with carbenoxolone (10(-4) mol/l) did not influence the response to taurocholate but when added with ibuprofen it potentiated the inhibitory effect of this drug on fundic alkaline secretion. In contrast, prostaglandin E2 (10(-6) mol/l) markedly reduced the inhibition of fundic alkaline secretion caused by ibuprofen. The anti-ulcer properties of carbenoxolone do not appear to be related to effects on gastroduodenal HCO-3 transport.
Animals↗
Effect of sodium taurocholate on secretion by amphibian gastric mucosa in vitro.
Effects of sodium taurocholate on the electrical and secretory activity of amphibian gastric mucosa have been studied in vitro. Exposure of the luminal surface of fundic mucosa to high concentrations (5 X 10(-2) M) at low pH (2.0 and 3.0) produced a marked fall in potential difference and electrical resistance. At lower concentrations (10(-3) to 10(-4) M) and higher pH (7.4), taurocholate did not alter the electrical properties but significantly increased net acidification from 1.39 +/- 0.27 to 2.01 +/- 0.18 mueq . cm-2 . h-1 (means +/- SE; P less than 0.01). Pretreatment of fundic mucosa with cimetidine resulted in net alkaline secretion (0.27 +/- 0.07 mueq . cm-2 . h-1), and addition of taurocholate (10(-4) M) to the luminal surface at pH 7.4 converted net alkalinization to net acidification (0.94 +/- 0.28 mueq . cm-2 . h-1). This response was not inhibited by atropine (10(-5) M) or somatostatin (10(-6) M) but exhibited marked tachyphylaxis. Taurocholate (10(-4) M) inhibited alkaline secretion in thiocyanate-treated fundic mucosa (0.63 +/- 0.04 to 0.14 +/- 0.09 mueq . cm-2 . h-1; P less than 0.001) and in spontaneously alkaline-secreting antral mucosa (0.36 +/- 0.12 to 0.09 +/- 0.06 mueq . cm-2 . h-1; P less than 0.05), but acidification did not occur. Apparent stimulation of acid secretion and simultaneous inhibition of alkaline secretion of sodium taurocholate may play a role in the pathogenesis of mucosal damage by bile.
Action Potentials↗
Effect of compound 48/80 on canine gastric mucosa.
The effect of compound 48/80 on the mucosal barrier of the canine Heidenhain pouch and mast cell content of gastric mucosa has been studied. 48/80 was administered in increasing doses (0.5--2.0 mg/kg) over 5 days. 0.5 mg/kg produced signs of systemic histamine release and stimulation of acid secretion by the pouch; these effects being most marked on the 1st day and absent on the 5th. Subsequent exposure of the mucosa to sodium taurocholate produced damage to the barrier similar to that in untreated animals. Histological examination revealed no evidence of mucosal mast cell degranulation by 48/80. The results suggest that the effects of 48/80 on gastric mucosa are mediated by systemic release of histamine and that local mast cells are resistant to its action.
Animals↗
The role of histamine in changes which occur in the gastric mucosal barrier with bile damage.
H1 and H2 histamine receptor antagonists were used in dogs with Heidenhain pouches during experiments in which the mucosa was damaged with sodium taurocholate. In these experiments when both antagonists were used together the usual increase in hydrogen and sodium ion flux across the mucosa was not observed, but the usual fall in transmucosal potential difference occurred. The results suggest that mucosal histamine probably mediates the changes in ionic flux across gastric mucosa which follow exposure to bile. Attempts to establish the source of this histamine were made in both rats and dogs using compound 48/80 over a period to degranulate the mast cells. Treatment with this compound did not affect the change in ionic fluxes which followed exposure to bile acid, suggesting that the source of histamine mediating changes in ionic flux is probably from tissue sites other than mast cells.
Animals↗
Biochemical aspects of gastric secretion.
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Alkalies↗
Reappraisal of the effects of aspirin on the stomach.
In a survey of the published evidence linking aspirin ingestion to gastric mucosal damage an attempt has been made to assess the role of aspirin in the pathogenesis of acute and chronic gastric haemorrhage and peptic ulceration. It seems that aspirin ingestion rarely causes clinically significant gastric damage in normal subjects and then usually only with large or frequent doses. Even in these rare instances the specific role of aspirin remains uncertain.
Aspirin↗
Gastric motor abnormalities in diabetic and postvagotomy gastroparesis: effect of metoclopramide and bethanechol.
Gastroparesis is a relatively uncommon but clinically troublesome disorder that develops in some patients with diabetes mellitus or after gastric operations. Its pathogenesis remains obscure. We used a manometric technique to record pressure changes in fasting patients in the gastric fundus, distal stomach, and adjacent small bowel of patients with severe gastroparesis, asymptomatic diabetic patients, asymptomatic postsurgical patients, and healthy controls. Patients with gastroparesis had normal interdigestive motor cycles (phase III) in the intestine but not in the stomach. Sporadic motor activity in the stomach (phase II) also was markedly reduced. Metoclopramide and bethanecol significantly increased gastric motor activity in these patients, often triggering an intense burst of motor activity in the stomach, similar to phase III. These observations suggest that gastroparesis is a potentially reversible disorder and should encourage further attmpts for pharmacologic control of the syndrome.
Adult↗
Dyspepsia, antral motor dysfunction, and gastric stasis of solids.
Extensive gastric manometric and emptying studies were performed in a patient with postprandial dyspeptic symptoms which, for many years, had been diagnosed as functional complaints. After ingestion of a mixed, solid-liquid meal we observed marked gastric stasis of solids associated with a weak antral pressure response, whereas gastric emptying of fluids was normal. Fundic pressure activity, recorded separately, was also normal. This case may represent a pathophysiologic expression of the specific roles of the antrum in the emptying of solids (abnormal) and of the fundus in the emptying of liquids (normal) and shows that pathophysiologic abnormalities can sometimes be demonstrated in patients lumped under a "functional" category.
Aged↗
Treating irritable bowel syndrome with peppermint oil.
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Chronic Disease↗
Simultaneous measurement of antroduodenal motility, gastric emptying, and duodenogastric reflux in man.
In six healthy individuals, the relationship between antroduodenal motor activity, duodenogastric reflux, and gastric emptying were simultaneously examined by combined use of multiple marker perfusion and miniature strain gauge transducers. An interdigestive pattern of motor activity was observed during the fasting period;duodenogastric reflux was of variable magnitude, but reproducible in each individual. Fasting reflux was significantly reduced during phase III of the interdigestive complex. Administration of 0.15 M sodium chloride into the stomach resulted in minor and inconsistent changes in antroduodenal motility, despite the rapid and similar pattern of gastric emptying in the six subjects. This study supports the concept that motor activity in the antroduodenal region does not affect gastric emptying of inert, isotonic fluids but may be involved in the regulation of duodenogastric reflux.
Adolescent↗
Effect of deglycyrrhizinated liquorice on gastric mucosal damage by aspirin.
Gastric mucosal damage induced by giving 60 mg aspirin orally to rats was reduced by simultaneous administration of 100-500 mg deglycyrrhizinated liquorice. Human faecal blood loss induced by 975 mg aspirin orally three times a day was less when 350 mg deglycyrrhizinated liquorice was given with each dose of aspirin.
Adult↗
Antroduodenal motor response to solid-liquid and homogenized meals.
The effect of the physical state of food on antroduodenal motor activity and the pattern of the emptying of an aqueous phase marker were examined in 6 healthy volunteers using an intestinal perfusion technique and intraluminal pressure transducers. Ingestion of a solid-liquid meal produced marked phasic changes in pressure in the distal antrum, lasting 92 +/- 10 min (mean +/- SE), while, in contrast, ingestion of the same nutrients in a homogenized state resulted in complete absence of distal antral changes in pressure lasting 133 +/- 12 min. The motor responses of the proximal antrum and duodenum were similar for the two meals. Both meals emptied during a 3-hr period, the pattern of emptying of the aqueous phase marker being similar for the two meals except for the first 40 min, when emptying was more rapid after the solid-liquid meal. The homogenized meal emptied despite the absence of changes in distal antral pressure. The gastrin response was similar for the two meals and is therefore not responsible for the different patterns of antral motility and gastric emptying.
Adult↗
Pesticide-induced changes in hepatic microsomal enzyme systems: further studies on the effects of 1,1,-di(p-chlorophenyl)-2-chloroethylene (DDMU) in the Japanese quail.
Changes in the liver resulting from the low level dietary administration of 1,1-di(p-chlorophenyl)-2-chloroethylene (DDMU),p,p'-DDT, o,p'-DDT, p,p'-DDD and p,p'-DDE to Japanese Quail have been monitored. DDMU was exceptional in causing substantial increases in relative liver wt. and hepatic glucose-6-phosphatase after feeding at 100 ppm for 28 days. The time course of liver enzyme induction by DDMU has also been studied in Japanese Quail after periods of dietary administration ranging from 1--28 days with particular reference to changes in hepatic cytochrome P-450 and relative liver wt. Structural changes in the liver have been followed by reference to protein and lipid components. The hepatic response to DDMU appears to be biphasic. Initially there are substantial increases in hepatic cytochrome P-450 and relative liver wt., but the latter is largely due to accumulation of triglycerides. After approximately 20 days the level of hepatic cytochrome P-450 remain at a high 'plateau' level. This secondary phase of liver induction probably involves cell proliferation. It is concluded that DDMU causes major changes in the avian liver and either directly or through a metabolite causes pronounced microsomal enzyme induction.
Animals↗