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Biomedical subjects

G L Kauffman

Publications and source records attributed to G L Kauffman.

At least 73 records · Page 4Linked to original sources
PubMed1982

Endogenous gastric mucosal prostaglandins: their role in mucosal integrity.

These studies were designed to determine the role of endogenous gastric mucosal prostaglandins (PG) in maintaining mucosal integrity. Vagally denervated, separated pouches of gastric fundic mucosa in unanesthetized dogs were irrigated with either acetylsalicylic acid (ASA) or salicylic acid (SA) (0, 2.5, 5.0, 10.0, 20.0, and 40.0 mM) in 150 mM HCl. Transmucosal potential difference (PD) and net H+, Na+, and K+ flux were measured. Mucosal ex vivo generation of 6-oxo-PGF1 alpha, PGE2, and PGF2 alpha was measured by radioimmunoassay in mucosal biopsies taken after exposure to each agent. No difference in PD or net H+, Na+, or K+ flux was observed between pouch irrigation with ASA or SA at 2.5-20.0 mM concentrations. Net H+ and Na+ flux was significantly greater (P less than 0.01) after irrigation with 40 mM SA than with 40 mM ASA. No significant reduction in gastric mucosal ex vivo generation of 6-oxo-PGF1 alpha (range, 65-98 ng.g-.min-1), PGE2 (range, 250-326 ng.g-1.min-1), or PGF2 alpha (range, 115-156 ng.g-1.min-1) was observed after pouch irrigation with all concentrations of SA. In comparison, gastric mucosal ex vivo generation of 6-oxo-PGF1 alpha (range, 75-2 ng.g-1.min-1), PGE2 (range, 22-3 ng.g-1.min-1), and PGF2 alpha (range, 40-2 ng.g-1.min-1) was significantly reduced after irrigation with all concentrations of ASA. From these data, we conclude that the activity of endogenous gastric prostacyclin, PGE2 alpha, and PGF2 alpha is not a prerequisite for mucosal integrity as measured by PD and net cationic flux.

Animals↗
PubMed1982

Gastric vascular actions of prostanoids and the dual effect of arachidonic acid.

The effects of several prostanoids and arachidonic acid on gastric vascular perfusion pressure were studied in dogs. A chambered segment of gastric fundus in anesthetized, heparin-treated dogs was perfused at constant flow (10 ml.min-1) with femoral arterial blood. Changes in perfusion pressure were measured after intra-arterial injection of each agent, at a point from which it reached the stomach in 3 s. Prostacyclin, prostaglandin E2 (PGE2), and PGE1 (5-40 ng) reduced perfusion pressure by 10-35 mmHg and were equipotent. 6-oxo-PGE1, the endoperoxide PGH2, and two stable prostacyclin analogues carbacyclin and 6 beta-PGI1 were less potent vasodilators, whereas 6-oxo-PGF1a was inactive. The epoxymethano endoperoxide analogues (U-46619 and U-44069) were equipotent vasoconstrictors, doses of 10-100 ng causing increases in perfusion pressure of 10-35 mmHg. PGF2a and noradrenaline also had vasoconstrictor actions. PGD2 had inconsistent actions. The effect of arachidonic acid on perfusion pressure varied with the length of time in contact with blood. Close (3 s incubation) intra-arterial injection (25-200 micrograms) produced vasodilation, whereas distal intra-arterial injection, which allowed 30 s of contact with blood before reaching the stomach, produced vasoconstriction as evidenced by dose-related increases in perfusion pressure (10-65 mmHg). These observations suggest that arachidonic acid, given by close intraarterial injection, is converted in the stomach mainly to vasodilator substances, presumably PGI2 or PGE2, but is converted mainly to a vasoconstrictor substance, presumably thromboxane A2, when allowed to mix with blood for 30 s.

Adenosine Diphosphate↗
PubMed1982

Blood flow and gastric secretion.

The relationship between gastric blood flow and acid secretion has been studied by using a number of secretory stimulants and inhibitors and different techniques that measure gastric blood flow. Although there are conflicting data, there appears to be a consensus regarding the main aspects of this relationship. Agents that stimulate gastric acid secretion such as histamine, gastrin, cholinergic agents, and vagal stimulators also increase gastric blood flow. Other agents such as isoproterenol, epinephrine, and prostaglandins, which at low doses increase gastric blood flow, reduce gastric acid secretion at higher doses. Norepinephrine, vasopressin, and shock reduce gastric blood flow and thereby cause a decrease in secretion. Histamine H2-receptor antagonists reduce stimulated acid secretion and gastric blood flow. Histamine, gastrin, and acetylcholine have been shown to stimulate acid secretion in vitro. Therefore, these observations suggest that although blood flow is not a prerequisite for initiation of stimulated acid secretion, it can become rate-limiting at higher rates of secretion. Although the literature is replete with studies that attempt to characterize the relationship between gastric blood flow and acid secretion, conclusions have varied. Much of the difficulty has arisen because of the differences in technique used to measure gastric blood flow and the differences between anesthetized and unanesthetized animal preparations. Under some specific conditions, the different blood flow techniques give comparable results and this relationship can be defined.

Animals↗
PubMed1982

Salicylic acid blocks indomethacin- and aspirin-induced cyclo-oxygenase inhibition in rat gastric mucosa.

Salicylic acid reduces gastric mucosal lesions induced by aspirin and indomethacin. Aspirin and indomethacin reduce gastric mucosal cyclo-oxygenase activity. These studies were designed to determine whether or not salicylic acid interacts with gastric mucosal cyclo-oxygenase, decreasing the inhibitory effect of aspirin and indomethacin as has been observed in platelets and vascular tissue. The interaction between salicylic acid and two cyclo-oxygenase inhibitors, indomethacin and aspirin, was assessed on ex vivo prostaglandin generation in the rat gastric mucosa. Salicylic acid (100 mg/kg) was administered orally 30 min before the subcutaneous injection of either indomethacin (0.5-10 mg/kg) or aspirin (5.0-20 mg/kg). Pretreatment produced a shift of the mean 50% inhibitory dose for PGF2 alpha formation from 0.92 to 7.6 mg/kg for indomethacin and from 7.8 to 20 mg/kg for aspirin. Similar results were achieved with ex vivo prostacyclin synthesis as measured by the level of 6-keto-PGF 1 alpha. These data are consistent with competitive enzyme kinetics, and may, in part, explain the protective effect of salicylic acid against the ulcerogenicity of aspirin and indomethacin on the gastric mucosa.

Animals↗
PubMed1981

The role of prostaglandins in the regulation of gastric mucosal blood flow.

It has been postulated that endogenous gastric prostaglandin activity contributes to the maintenance of non-stimulated gastric mucosal blood flow. Prostacyclin and PGE2 increase mucosal blood flow in the non-stimulated canine stomach. Inhibition of prostaglandin synthesis by aspirin or indomethacin causes a reduction of 30% to 50% in nonstimulated gastric mucosal blood flow in dog and rat. These observations are consistent with the hypothesis that endogenous prostaglandin activity within the gastric mucosa contributes to the maintenance of its blood flow. Also it has been postulated that endogenous prostaglandins may, in part, mediate the vasodilation associated with stimulated gastric acid secretion. Exogenous prostacyclin and PGE2 inhibit stimulated acid secretion while increasing mucosal blood flow. Indomethacin and aspirin-inhibited endogenous prostaglandin synthesis has been reported to increase stimulated acid secretion and reduce mucosal blood flow in anesthetized rat and dog. In gastric secretory fluid, prostaglandins have been detected during gastrin stimulated by some investigators and a dose response relationship between rate of secretion and fluid prostaglandin output has been observed. These observations may, in part, contribute to the regulation of mucosal blood flow during stimulated acid secretion. Further studies, directly measuring specific endogenous prostaglandin and their metabolic products within the gastric mucosa during stimulated and inhibited acid secretion will be necessary to prove or disprove this hypothesis.

Animals↗
PubMed1981

Role of the small intestine and gastric antrum in pancreatic polypeptide release.

Gastrointestinal peptides have been proposed to play an important role in the pancreatic polypeptide response to a meal. These studies examine the role of the small intestine and gastric antrum in pancreatic polypeptide release in unanesthetized dogs. Intestinal perfusion with 5% liver extract in seven dogs resulted in a significant increase (P less than 0.05) in serum pancreatic polypeptide concentration (mean delta PP = 35.0 +/- 10.5 pM). Antrectomy without truncal vagotomy in four of these dogs significantly inhibited (P less than 0.05) this response. In five other dogs, antrectomy inhibited the pancreatic polypeptide response to an ingested meat meal by 81.9 +/- 4.5% (P less than 0.01). To further delineate the mechanism by which antrectomy inhibits pancreatic polypeptide release, the pancreatic polypeptide response to a meal was measured in four dogs before and after selective antral denervation. Antral denervation inhibited pancreatic polypeptide release to a degree similar (81.5 +/- 13.4%) to that previously observed after antrectomy. These studies have demonstrated an intestinal phase of pancreatic polypeptide release. They also suggest that antrectomy exerts its inhibitory effect on pancreatic polypeptide release by partially denervating the pancreas.

Animals↗
PubMed1981

Drug therapy for peptic ulcer: drugs that act on the gastric mucosa.

Antacids, cimetidine, carbenoxolone, colloidal bismuth, and prostaglandins promote healing of gastric and duodenal ulcer at a rate nearly twice that of healing during placebo administration. These short-term, 4-12 week healing rates are nearly the same for each agent, with a 65 to 85% range. Drugs that appear to produce more sustained healing are carbenoxolone and colloidal bismuth, observations that must be confirmed. Carbenoxolone has the greatest frequency of side effects and the most potentially serious ones. The mechanism(s) of any action, beyond inhibition of acid secretion by cimetidine and prostaglandins, is not well understood. At present, only antacids and cimetidine are approved for long-term treatment of peptic ulcer in the United States. Colloidal bismuth and carbenoxolone are used in Europe, but have not been approved for use in the United States. Prostaglandins remain experimental with several studies being conducted.

Antacids↗
PubMed1981

Gastric gel mucus thickness: effect of distention, 16,16-dimethyl prostaglandin e2, and carbenoxolone.

We made direct measurements of the thickness of the layer of insoluble gel mucus lying on the gastric mucosa by using a slit lamp and an image-splitting system known as a pachymeter. Under nonstimulated conditions, the thickness (mean +/- SE) of the gastric gel mucus on fundic mucosa was 166 +/- 10 micrometers in the rat, 234 +/- 9 micrometers in the guinea pig, 429 +/- 17 micrometers in the dog, and 576 +/- 81 micrometers in human stomach. Using a pylorus-ligation rat model, the effects of distention and of topical application of acid, 16,16-dimethyl prostaglandin E2 and carbenoxolone, on mucus gel thickness were studied. Distention of the stomach produced an increase in gel mucus thickness that was correlated with the degree of distention. This distention effect was not affected by pretreatment with methscopolamine or indomethacin. Topical application of 0.1 M HCl had no demonstrable effect on gel mucus thickness when compared with phosphate buffer, pH 7.4. 16,16-Dimethyl prostaglandin E2 applied to the mucosa in concentrations of 1 microgram . ml-1 and 10 microgram . ml-1 caused an increase in gel mucus thickness of 81% and 140%, respectively, and carbenoxolone, 2.5 mg . ml-1, an increase of 78%. These studies suggest that thickness of gel mucus overlying the gastric mucosa is dynamic, being subject to increase or decrease under certain physiologic and drug-treatment conditions.

16,16-Dimethylprostaglandin E2↗
PubMed1981

Gastric mucus and bicarbonate secretion in relation to mucosal protection.

Gastric mucus, a viscous gel that coats the entire gastric mucosa, is produced by and secreted from the surface epithelial cells. Although 95% water by weight, gel mucus is a polymer of four equal-sized subunits joined by disulfide bridges. Carbohydrate side chains include N-acetylglucosamine, N-acetylgalactosamine, galactose, fucose, neuraminic acid, and sialic acid. At a concentration of about 20 mg/ml, the viscosity begins to rise, and a gel is formed. The thickness of the gel mucus layer is dynamic, and a function of release from surface epithelial cells and mechanical and proteolytic degradation within the lumen. An increase in luminal fluid glycoprotein output has been observed in response to splanchnic and vagal nerve stimulation, topical acetylcholine, prostaglandins, carbenoxolone, and parenteral secretin. Topical prostaglandins and carbenoxolone have been observed to increase mucus gel thickness. Gastric bicarbonate secretion is also thought to be a function of the surface epithelial cell. The magnitude of stimulated gastric bicarbonate secretion is 5 to 10% of maximal acid secretion for a given surface area of mucosa. Stimulants of gastric bicarbonate secretion are carbachol, Ca++, c-GMP, 16-16 dimethyl PGE2, and PGF2 alpha. Inhibitors of gastric bicarbonate secretion include atropine, metabolic inhibitors, acetazolamide, alpha-adrenergic agents, and inhibitors of prostaglandin synthesis. Taken together, these observations lend credence to the hypothesis that an unstirred layer of mucus, rich in bicarbonate, may offer significant protection against acid-peptic mucosal injury by neutralizing luminal acid and thereby providing the apical membrane of the surface epithelial cell with a near neutral pH milieu.

Animals↗
PubMed1980

Gastric bicarbonate secretion: an update.

In vitro and in vivo studies have demonstrated that gastric fundic and antral mucosa secretes a bicarbonate (HCO3-)-rich fluid under a variety of experimental conditions. Bicarbonate secretion appears to be an active, energy requiring process which is thought to occur at the surface epithelial cell. Transmembrane HCO3- transport, isotopic (H14CO3) flux, pH stat titration and pCO2 measurement has been used to indicate HCO3- secretion. Bicarbonate secretion is stimulated by cholinergic agents, dibutyryl-cGMP, calcium, and 16-16-dimethyl prostaglandin E2. Atropine inhibits carbachol-stimulated HCO3- secretion but has no effect on basal HCO3- secretion. Agents which have been shown to inhibit HCO3- secretion are acetazolamide, O2 deprivation, noradrenalin, aspirin and indomethacin. It is plausible to suppose that HCO3- secretion may play a role in protection of the gastric mucosal epithelium. Although for a given area of gastric mucosa, the amount of HCO3- secreted is only about 5 to 10% of the maximal acid output, the neutralizing capability of the HCO3- rich fluid may be significantly greater at the apical cell membrane of the surface epithelial cells.

Animals↗
PubMed1980

Intravenous indomethacin and aspirin reduce basal gastric mucosal blood flow in dogs.

The effect of two known inhibitors of prostaglandin synthesis, indomethacin and aspirin, on blood flow was studied in six Heidenhain pouch and three antral pouch dogs. The unstimulated gastric mucosa was bathed with 0.15 M HCl and clearance of [14C]-aminopyrine was used as an index of changes in mucosal blood flow. [14C]aminopyrine clearance was measured during three 15-min predrug periods and five 15 min-postdrug periods. Either indomethacin (10 mg . kg-1), aspirin (100 mg . kg-1), or 0.15 M NaCl were given intravenously as a bolus. Indomethacin reduced mucosal blood flow in the Heidenhain pouch 52% (P less than 0.05) and in the antral pouch 52% (P less than 0.05). Aspirin reduced Heidenhain pouch mucosal blood flow 31% (P less than 0.05). Indomethacin caused no significant change in electrical potential difference or in net flux of H+ or Na+ in Heidenhain pouches. Indomethacin (10 mg . kg-1 iv) produced no change in mean arterial pressure. We conclude that indomethacin and aspirin reduce unstimulated gastric mucosal blood flow, suggesting that endogenous prostaglandin may contribute to its maintenance.

Animals↗
PubMed1980

Gastric bicarbonate secretion: effect of topical and intravenous 16,16-dimethyl prostaglandin E2.

These studies were designed to compare intravenous and topical 16,16-dimethyl prostaglandin E2 (dmPGE2) as stimulants of gastric mucosal HCO3- secretion. In six Heidenhain pouch (HP) dogs, basal acid secretion was inhibited by cimetidine. With 100 ml 0.15 M NaCl as the fluid circulating through the HP, intrapouch titration to pH 6.0 was performed with 0.5 M HCl as titrant. After measuring basal HCO-3 secretion for 30 min, dmPGE2 was given intravenously or the fluid circulating in the HP was replaced by one containing dmPGE2. Intravenous dmPGE2 at infusion rates of 0, 0.5, 1.0, and 2.0 microgram . kg-1 . h-1 produced alkaline secretion rates of 34 +/- 9, 52 +/- 20, 72 +/- 21, and 70 +/- 20 (SE) mu mol . h-1, respectively. Topical dmPGE2 at concentrations of 0, 0.05, 1.25, and 2.50 microgram . ml-1 produced alkaline secretion rates of 22 +/- 7, 74 +/- 16, 134 +/- 28, and 144 +/- 35 mu mol . h-1, respectively (P less than 0,05 for each concentration). Glucosamine output, as an index of mucus secretion, increased significantly with HCO-3 secretion. We conclude that intragastric titration is a valid method for recording HCO-3 secretion from an HP, that topical dmPGE2 stimulates HCO3- secretion more effectively than intravenous dmPGE2, and that topical dmPGE2 stimulates mucus secretion as well as HCO-3 secretion,

Administration, Topical↗