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Biomedical subjects

G L Kauffman

Publications and source records attributed to G L Kauffman.

At least 55 records · Page 3Linked to original sources
PubMed1985

Intravenous histamine reduces bombesin-stimulated gastrin release in dogs.

The effect of histamine on gastrin release was studied in 7 conscious mongrel dogs with chronic gastric and duodenal fistulas. Histamine-2 HCl was infused in doses of 0 (control), 20, 40, 80, and 160 micrograms/kg per h for 2 h on separate days. During the second hour, bombesin 500 ng/kg per h was infused intravenously. Intragastric pH was constantly kept at 2.5 by intragastric titration during each test. Leakage of gastric contents into the duodenum was prevented by a prepyloric balloon passed retrograde through a duodenal fistula. Gastrin release, as expressed by the integrated response during the last 50 min of the bombesin infusion was significantly (P less than 0.05) decreased by all doses of histamine, compared to control. The infusion doses of histamine studied, 20, 40, 80, and 160 micrograms/kg per h reduced bombesin-stimulated gastrin release 16%, 19%, 19%, and 30%, respectively. This effect was blocked by a histamine H-2 but not an H-1 receptor antagonist. We conclude that by an H-2 mechanism, exogenous histamine reduces bombesin-stimulated gastrin release in dog.

Animals↗
PubMed1985

Somatostatin inhibits gastric acid secretion after gastric mucosal prostaglandin synthesis inhibition by indomethacin in man.

The inhibitory effect of indomethacin, 200 + 200 mg administered per os over 24 hours, on the prostaglandin E2 generative capacity of gastric mucosal tissue was determined in healthy male volunteers. The effect of prostaglandin synthesis inhibition on somatostatin induced suppression of food-stimulated acid secretion was tested. Peptone meal stimulated acid secretion was quantified in five healthy volunteers by intragastric titration with and without indomethacin pretreatment. Somatostatin doses of 200, 400, and 800 pmol/kg/h each significantly inhibited the peptone stimulated acid output. Indomethacin treatment, resulting in 90% inhibition of prostaglandin E2 synthesis, did not affect glucose- or peptone-stimulated acid output or modify the inhibitory action of somatostatin. Clinically, acid inhibition by somatostatin has been used to treat bleeding peptic ulcers. Ulcer haemorrhage may be preceded by an excessive use of drugs that inhibit prostaglandin synthesis such as aspirin or other non-steroidal anti-inflammatory agents. Recent observations in the rat indicate that prostaglandins mediate the inhibitory action of somatostatin on gastric acid secretion. The present results suggest that prostaglandins are not required for inhibition of gastric acid secretion by somatostatin in man.

Adult↗
PubMed1985

Salicylic acid blocks indomethacin-induced cyclooxygenase inhibition and lesion formation in rat gastric mucosa.

Salicylic acid has been shown to decrease gastric mucosal lesions induced by indomethacin in the rat. In vitro, it has also been shown to counteract the inhibitory effect of indomethacin and aspirin on the cyclooxygenase enzyme system in seminal vesicle microsomes and in platelets and vascular tissue. The hypothesis that the mechanism of salicylic acid "protection" against indomethacin-induced gastric lesions involves interference with indomethacin-induced mucosal cyclooxygenase inhibition was tested. Male, fasted rats were treated with intragastric salicylic acid in doses of 50, 100, 200, 300, or 400 mg/kg concomitantly with a sc injection of 20 mg/kg of indomethacin. Gastric mucosal lesions and mucosal cyclooxygenase activity (as measured by ex vivo prostaglandin F2 alpha synthesis) were examined 3 hr later. Intragastric salicylic acid, 200-400 mg/kg, significantly reduced indomethacin-induced lesion formation, while counteracting significantly indomethacin inhibition of prostaglandin synthesis. Salicylic acid alone did not significantly change cyclooxygenase activity. It is concluded that topical salicylic acid can decrease indomethacin-induced gastric mucosal lesion in the rat, in part, by counteracting the inhibitory effect of indomethacin at the cyclooxygenase level.

Animals↗
PubMed1984

16-16 dimethyl prostaglandin E2 reduces 5-fluorouracil-induced and mitomycin C-induced gastric mucosal injury in the dog.

Gastric complications occur in 5% to 20% of patients treated with hepatic artery infusion of chemotherapeutic agents for hepatic metastatic lesions. Often these complications are due to catheter dislodgement from the common hepatic artery into the left gastric artery. These studies were designed to answer the following questions: (1) Will chronic infusion of 5-fluorouracil into the left gastric artery produce mucosal injury in dogs; and (2) if so, will 16-16 dimethyl prostaglandin E2 afford protection against such injury? Mongrel dogs, 20 kg, were prepared with a polyethylene catheter in the left gastric artery and a Thomas cannula in the antrum 5 days prior to the study. Daily intraarterial infusions of either 5-fluorouracil, 6.7 mgM-2 X h-1, (N = 5) or 5-fluorouracil + 16-16 dimethyl prostaglandin E2, 2 micrograms X kg-1 X h-1, (N = 5) were given 12 hours a day for 5 days. In 2 dogs, 0.15 M NaCl was infused for 12 hours a day for 5 days as controls. Daily endoscopic evaluation of the gastric mucosa was made through the Thomas cannula by an unbiased observer and scored 0 to +5 based on degree of erythema, edema, friability, exudate, and gross ulceration. Results of these studies demonstrated that this dose of 5-fluorouracil had no effect on histamine-stimulated acid output. This dose of 16-16 dimethyl prostaglandin E2 inhibited histamine-stimulated maximal acid output 65%. From the observations made it was concluded that infusion of this chemotherapeutic regimen into the left gastric artery produced significant mucosal injury, simultaneous intraarterial infusion of 16-16 dimethyl prostaglandin E2 provided significant protection against this damage, and, since 16-16 dimethyl prostaglandin E2, at this dose, inhibits stimulated gastric acid secretion, it cannot be determined whether this observed mucosal protection is due to its antisecretory effect or some other mechanism.

Animals↗
PubMed1984

Stimulation of gastric alkaline secretion by stable prostacyclin analogues in rat and dog.

The stimulation of gastric alkaline secretion in vivo following topical mucosal application of four stable anti-ulcer analogues of prostacyclin has been investigated in the rat and in the dog using intragastric pH-stat techniques. In the rat, basal alkaline secretion was significantly stimulated by the prostacyclin analogues 16-phenoxy-(5 alpha)-5,9-epoxy-PGF1 (16-phenoxy) and its methyl ester, when administered in the luminal perfusion fluid. The 16-phenoxy analogue (25 and 50 micrograms ml-1) increased basal alkaline secretion with its methyl ester being more potent. The methyl ester of 16,16-dimethyl PGI1 (25 and 50 micrograms ml-1) likewise stimulated alkaline secretion whereas its corresponding free acid was inactive at these concentrations. In further studies in the conscious dog with a Heidenhain gastric pouch, these four prostacyclin analogues administered intraluminally (1.25 micrograms ml-1) significantly increased gastric alkaline secretion. The present findings indicate that the stable 16-phenoxy and 16, 16-dimethyl analogues of prostacyclin, can stimulate gastric alkaline secretion in the dog and rat in vivo. As with the previously reported 16,16-dimethyl PGE2 analogue, this property of stimulating alkaline secretion may therefore contribute to the antiulcer activity of these prostacyclin analogues.

Alkalies↗
PubMed1984

Molecular heterogeneity of canine cholecystokinin in portal and peripheral plasma.

The release of molecular forms of cholecystokinin (CCK) into the portal and peripheral blood in response to an intraduodenal perfusion of sodium oleate (9 mmol X h-1) was studied in six conscious dogs with chronic portal vein catheters. Immunoreactive CCK as concentrated from 20 ml plasma by C18 SEP PAK cartridges and the pattern of molecular forms of CCK were studied by G50 gel filtration. CCK-like immunoreactivity (CCK-LI) was measured in the column eluates with antibody 5135, which measures gastrin and CCK equally and requires the intact carboxyl-terminus for full recognition. Gastrin was measured specifically with antibody 1611. Intraduodenal perfusion with oleate did not alter basal gastrin release. Release of CCK-LI by intraduodenal oleate was calculated by the increments of the integrated CCK-LI peaks over basal. Total CCK-like immunoreactivity (CCK-LI), calculated by integration of all CCK-LI peaks in gel filtration eluates, increased over basal by 12 fmol/ml in the portal and by 6 fmol/ml in the peripheral plasma after intraduodenal perfusion with sodium oleate. The main molecular forms eluted on gel filtration in positions of CCK33,39 and of CCK8. The pattern of CCK in the peripheral plasma was similar to that in the portal plasma except that in the peripheral plasma large molecular forms were more abundant than small forms. This finding was confirmed when CCK39 and CCK8 were infused either into the portal vein or into the peripheral vein and peripheral plasma CCK levels were measured. Elimination of CCK8 after portal vein infusion compared to peripheral vein infusion was about 3 times higher than that of CCK39. The abundance of large molecular forms of CCK in the circulating blood which are similar in potency to small forms, underlines their role in the physiology of CCK.

Animals↗
PubMed1984

Analysis of hydrogen ion concentration in the gastric gel mucus layer.

Secretion of HCO-3 by the gastric epithelium has been thought to lower the concentration of H+ in the gastric mucus layer. This has been analyzed mathematically to include the HCO-3-H+ reaction, bulk water flow, diffusion, ion-ion electrical interaction, and ion-fixed charge interaction. The reaction-electrodiffusion problem is solved by use of singular perturbation theory. We show that there is a very thin layer for the reaction, equivalent to a sink of H+. In this layer there is negligible HCO-3 accumulation. A steady-state model is satisfactory if gastric mixing motions are more frequent than every 3 min. H+ concentration at the epithelium decreases with increased bicarbonate secretion, increased volume flow associated with bicarbonate secretion, increased thickness of the mucus layer, increased fixed negative charge of the mucus, and decreased cation flux into the lumen. The resultant lowering of H+ concentration may be as small as 5 mM but is probably considerably larger. Determining the actual drop will depend on more precise experimental measurements of the parameters of the problem.

Electrophysiology↗
PubMed1984

Lack of correlation between mucus gel thickness and gastric cytoprotection in rats.

The effect of various cytoprotective agents on the thickness of gastric mucus gel layer in rats was studied. It was hypothesized that an increase in the mucus gel layer might be involved in cytoprotection. The results show that this is not the case. Neither prostaglandin E2, 16,16-dimethyl prostaglandin E2, nor mild irritants (20% ethanol, 0.35 M HCl, 20% glucose, 20% mannitol), all given orally, altered the thickness of the mucus gel layer, although these agents were found to be cytoprotective, i.e., inhibiting the formation of gastric mucosal necrotic lesions caused by oral administration of absolute ethanol. The only agents that significantly increased the thickness of the mucus gel layer were a hypertonic solution (4% NaCl) and sodium salicylate. We conclude that if mucus plays a role in cytoprotection, it is not by virtue of an increase in thickness of the gel layer adherent to the gastric mucosa.

Animals↗
PubMed1984

Regional gastric mucosal blood flow measurements by hydrogen gas clearance in the anesthetized rat and rabbit.

Hydrogen gas clearance using 3% hydrogen in air and platinum contact electrodes was employed for measuring antral and corpus mucosal blood flow in anesthetized animals. Significantly greater antral than corpus mucosal blood flow was consistently demonstrated. Corpus but not antral mucosal blood flow showed a significant dose-related increase with intravenous pentagastrin. Vasopressin induced a significant dose-related decrease in both antral and corpus mucosal blood flow. Simultaneous measurement of basal corpus mucosal blood flow by hydrogen gas clearance and of gastric mucosal blood flow by aminopyrine clearance gave similar values, but the changes with intravenous pentagastrin or vasopressin measured by aminopyrine clearance were of a much higher order of magnitude. Hydrogen gas clearance, however, reflected changes in left gastric artery blood flow much more closely than did aminopyrine clearance. Therefore, we conclude that the hydrogen gas clearance technique as described is valid for measuring regional gastric mucosal blood flow. It is safe and has potential application in human studies.

Aminopyrine↗
PubMed1983

Gastric bicarbonate appearance with ethanol ingestion. Mechanism and significance.

Increasing quantities of HCO3- appeared in the stomach and in gastric pouches of conscious dogs with gastric infusion of increasing concentrations of ethanol. HCO3- appearance was closely correlated with gains of K+ and of glucose to the contents and with reductions in transmucosal potential differences, each of which is associated with increased mucosal permeability. We concluded that increased diffusion of HCO3- through a more permeable mucosa accounted for the appearance of HCO3- with the lower concentrations of ethanol we used (5-20%) and that bulk movement of the interstitial fluid into the contents added to HCO3- entry with the most damaging, desquamating, concentration (40%). With the gastric contents at 100 mM HCl, an unstirred layer of mucus gel over the mucosa would need to be of greater depth than previous estimates to produce mucosal surface neutrality at the rates of HCO3- appearance we observed. However, faster rates of HCO3- production combined with an unstirred layer could provide significant protection to the gastric mucosa.

Animals↗
PubMed1983

Aspirin can inhibit gastric mucosal cyclo-oxygenase without causing lesions in rat.

Dose-response relationships between aspirin-induced cyclo-oxygenase inhibition and gastric mucosal injury were studied in rats. Oral or parenteral aspirin, 25 mg/kg, inhibited prostaglandin generation by 87%-95% at 1, 3, and 6 h with no lesion formation. Aspirin, 100 mg/kg, inhibited prostaglandin generation by 95%-98% at 1, 3, and 6 h, but lesions were observed only when aspirin was given orally. Three-hour pretreatment with intraperitoneal aspirin, 12.5 mg/kg, did not enhance the mucosal injury caused by 10 mM acidified taurocholate, although prostaglandin generation was inhibited by 80%. Pretreatment with 25 mg/kg aspirin inhibited prostaglandin generation by 89% and was associated with significant mucosal injury by acidified taurocholate. We conclude that aspirin-induced 95% inhibition of gastric mucosal cyclo-oxygenase is not, by itself, sufficient to produce lesions and inhibition by greater than 80% is required to predispose the gastric mucosa to injury by otherwise mild irritants.

Administration, Oral↗
PubMed1983

Measurement of prostaglandin E2 in interstitial fluid from the dog stomach after feeding and indomethacin.

The purpose of the study was to develop a method for collecting interstitial fluid bathing the stomach tissues in which prostaglandins could be measured. Hollow dialysis fibers attached at the ends to Silastic tubes were surgically implanted into the submucosa of the gastric fundus and antrum of dogs. The Silastic tubes were exteriorized through the body wall. After full recovery from surgery, the fibers were filled with 5% bovine serum albumin in isotonic saline that was replaced at 5-min intervals. Prostaglandin E2 was measured in the dialysate by radioimmunoassay. In 6 dogs, feeding significantly stimulated the release of prostaglandin E2 into the fundic interstitial fluid from 5.3 +/- 0.6 ng X ml-1 to 12.1 +/- 1.6 ng X ml-1 (p less than 0.01) but had no effect on antral levels. In 4 dogs, indomethacin (0.01, 0.1, 1.0, and 10.0 ng X kg-1, i.v.) caused a dose-dependent depression in prostaglandin E2 levels in interstitial fluid of the fundus and antrum. In 4 other dogs, indomethacin depressed the ex vivo generation of prostaglandin E2 in biopsy specimens of the fundus and antrum. These results validate the technique of interstitial fluid dialysis and suggest that it is a powerful method for examining the secretion of locally acting substances in the stomach of conscious animals.

Animal Feed↗
PubMed1983

Pathological acid secretion not due to gastrinoma.

There are few detailed studies of patients with pathological hypergastrinaemia of antral origin. We have identified four patients with severe acid hypersecretion associated with peptic ulcer disease and in whom no evidence for gastrinoma or isolated retained antrum could be found. Three of these patients also had hypergastrinaemia. In two patients, one with gastric ulcers and one with duodenal ulcer disease, the hypergastrinaemia appeared to be due to antral gastrin cell hyperfunction and there was also evidence for mild antral gastrin cell hyperplasia. In the other hypergastrinaemic patient, a primary intestinal gastrin cell hyperfunction syndrome was suspected, but a hidden gastrinoma could not be excluded. The remaining patient had nearly fatal hypersecretory ulcer disease and cimetidine failed to control the hypersecretory state. In this patient the hypersecretion responded to a more potent H2 antagonist with resolution of a metabolic encephalopathy. No general pathophysiological mechanism could be identified in these patients or in larger groups of patients with gastric or duodenal ulcer disease.

Adult↗
PubMed1982

The demonstration of histamine release in clinical conditions: a review of past and present assay procedures.

Topics related to the measurement of histamine in human plasma and other body fluids are reviewed. These include (1) an overview of the data obtained by the biological, fluorometric and radioenzymatic assays over the past 45 years; (2) the various modifications of the radioenzymatic isotopic assay of histamine and the development of a single extraction step assay; (3) a compilation of values obtained in our laboratory by the radioenzymatic assay of histamine levels in various body fluids in disease states associated with abnormal histamine production or release; and (4) factors that affect histamine levels in plasma and some experimental considerations for monitoring changes in free histamine levels. The last topic includes a discussion of the halflife of histamine in the circulation, its clearance across various vascular beds, and the fact that capillary endothelial cells are one site of inactivation of circulating histamine.

Animals↗
PubMed1982

Time-dependent effects of vagotomy on pancreatic polypeptide release.

It has been suggested that the pancreatic polypeptide response to a meal is inhibited by truncal vagotomy but returns towards normal with time. We have examined this hypothesis by measuring the pancreatic polypeptide response to a meal in five dogs before and 1 and 6 months after truncal vagotomy. Pancreatic polypeptide responses to food were significantly inhibited (P less than 0.01) in both postoperative studies. However, comparison of the 1- and 6-month responses revealed a significant increase (P less than 0.05) in the magnitude of the second hour response from 2.3 +/- 1.5% of the preoperative response at 1 month to 21.3 +/- 9.6% at 6 months. The pancreatic content of pancreatic polypeptide in four vagotomized dogs (1.06 +/- 0.06 nmol/g) was not significantly different from normal (1.30 +/- 0.33 nmol/g). These studies have shown that truncal vagotomy permanently inhibits the early phase of pancreatic polypeptide release but that the magnitude of the late phase response increases with time. Whether the response would ever return to that observed before vagotomy is uncertain.

Animals↗