Henrik Forssell

Continuous computerized determination of gastric bicarbonate secretion in man.

A method for continuous determination of gastric bicarbonate secretion in man has been developed. A computer-based system calculated the total bicarbonate secretion every 30 sec throughout the experiment on the basis of the continuously recorded pH and Pco2 measurements. A high gastric perfusion rate facilitated the identification of duodenogastric reflux, which was observed as rather short-lived spikes on the curves. The contribution of alkaline saliva to the measured gastric bicarbonate secretion was minimized by continuous salivary suction and was corrected for after determining amylase in the gastric aspirate. Validation of the measuring system, by introducing bicarbonate in the range of 50-400 mumol into the stomach, demonstrated a correlation value of 0.91 (p less than 0.001) between added and recovered bicarbonate. Basal gastric bicarbonate output in seven healthy subjects was 379 +/- 105 mumol/h (mean +/- SEM). Intragastric instillation of 16,16-dimethyl prostaglandin E2 in five subjects resulted in a fourfold increase in gastric bicarbonate output.

Structure and Function of the Dog Gastric Mucosa During and After a 1-Year Treatment with Omeprazole. I. Macro- and Microscopic Findings

In addition to its stimulatory action on acid secretion, gastrin also exerts trophic effects on the oxyntic mucosa. An increase in serum gastrin levels may be evoked by compounds that inhibit gastric acid secretion, and it is conceivable that this might bring about changes in the structure of the gastric mucosa. The aim of the present study was to investigate whether long-term treatment with omeprazole results in any morphological changes in the canine gastric mucosa. Two dose regimens were used; one at therapeutic levels (2 μmol/kg) and another at extremely high doses (80 μmol/kg) of omeprazole.

Effect of 7 Years’ Daily Oral Administration of Omeprazole to Beagle Dogs

Ten beagle dogs were given omeprazole orally at a dose of 0.17 mg/kg (0.5 mumol/kg) daily for 7 years. Six dogs served as controls. Regularly evaluated criteria were clinical signs, body weight, food consumption, rectal temperature, electrocardiography, hematology, blood chemistry, urinalysis, ophthalmoscopy, gastroscopic examination including gastric mucosal biopsy sampling for histological evaluation, pharmacokinetics of omeprazole, and plasma gastrin levels. After approximately 5 years, a quantitative gastric acid secretion test was performed. No treatment-related adverse clinical signs or effects were observed in the dogs, and all animals survived to term. The annual gastroscopy with histological examinations of gastric mucosa did not show any treatment-related changes. At all investigations and in all dogs, the parietal cells were morphologically normal, and there were no changes of pattern or any increase in the number of argyrophil enterochromaffin-like cells compared to the control animals. In the plasma samples collected 24 h after dosing, there were no significant differences in either basal or meal-stimulated gastrin levels between the controls and the omeprazole-treated animals. Peak plasma concentration of omeprazole occurred within 2 h of dosing. The area under the concentration curve (AUC) was not affected by dosing over 7 years and was in good agreement with the AUC in humans given a dose of 20 mg omeprazole daily. Acid secretion tests after 5 years of treatment showed that the mean inhibition of acid secretion by omeprazole 4-7 h after dosing was as expected--about 50%.(ABSTRACT TRUNCATED AT 250 WORDS)

Gastric Mucosal Defence Mechanisms: A Brief Review

In the stomach several mucosal defence mechanisms protect the stomach against hydrochloric acid and noxious agents. The pre-epithelial protection is made up by the mucus-bicarbonate barrier. Mucus and bicarbonate, secreted by mucus cells, create a pH gradient maintaining the epithelial cell surface at near neutral pH. In humans, secretion of bicarbonate is an active process and is activated by vagal stimulation and fundic distension. Several mechanisms at the epithelial cell level contribute to an intact mucosal barrier. Surfactants in apical cell membranes prevent water-soluble agents in the gastric lumen from reaching and damaging the epithelium. Nonprotein sulphydryls in the epithelium are capable of binding reactive free radicals. Rapid cell turn-over and the process of restitution contribute to an intact epithelial lining. In subepithelial protection, mucosal blood flow is essential in supplying the epithelium with nutrients and oxygen and for disposal of hydrogen ions and noxious agents permeating the mucosa. Prostaglandins may maintain blood flow and prevent vascular endothelial injury caused by ethanol. Several agents have been established as protective for the gastric mucosa. Prostaglandins possess direct cytoprotective actions, whilst sucralfate, aluminium containing antacids, carbenoxolone and bismuth are mild irritants that induce liberation of endogenous prostaglandins of the mucosa.

Effect of Fundic Distension on Gastric Bicarbonate Secretion in Man

Human gastric mucosa secretes small amounts of bicarbonate into the mucus layer to maintain the pH at the cell surface as close to neutrality as possible. We have measured gastric bicarbonate secretion continuously with a computer-based system, using recordings of pH and PCO2. The formula of Henderson and Hasselbalch was used in the calculations. Graded fundic distension of the stomach with a balloon in six healthy subjects increased the gastric bicarbonate output by 46% (p less than 0.05), 28% (NS), and 84% (p less than 0.05) during 1 h of distension to 150 ml, 300 ml, and 600 ml, respectively. Continuous fundic distension during 2 1/2 h with a volume of 300 ml elicited a response that peaked after 45 min and vanished after 90 min. The rather short duration of gastric bicarbonate secretion response to fundic distension may be due to a fading caused by a volume adaptation or, alternatively, to an activation of inhibitory mechanisms. Seven duodenal ulcer patients who had undergone proximal gastric vagotomy showed virtually the same gastric bicarbonate secretion response to graded fundic distension. The anticholinergic drug benzilonium bromide totally inhibited the gastric bicarbonate response to 30 min of fundic distension to 150 ml, whereas indomethacin did not significantly affect the response to distension. These studies indicate that the gastric bicarbonate response to fundic distension is mainly mediated by short intramural neural cholinergic pathways and is independent of mucosal production of prostaglandins.

A criterion for completeness of vagotomy based on basal and vagally stimulated gastric acid secretion after esophagectomy or proximal gastric vagotomy.

The variation in basal acid secretion was determined in 10 patients after resection of the esophagus, an operation resulting in a total transection of all vagal nerves to the abdomen. After recording basal acid secretion over a 3-h period, a 15-min modified sham feeding procedure was performed, and the acid output was studied for an additional hour. The mean basal acid output +2 SD was 0.27 mmol/15 min. The difference between the highest and lowest recorded 15-min output--that is, the oscillation of basal acid output--was calculated for each patient. The mean oscillation of basal acid output +2 SD was 0.58 mmol/15 min. Vagal stimulation accomplished by sham feeding produced no significant increase in acid output above this level. The variation in basal acid secretion was also investigated in 20 duodenal ulcer patients after proximal gastric vagotomy. These patients were insulin-negative and remained asymptomatic during a 7- to 10-year follow-up study. Shortly after the vagotomy, measurement of basal acid secretion over 3 h showed a mean basal acid output +2 SD of 0.58 mmol/15 min. The mean oscillation of basal acid output +2 SD was 0.66 mmol/15 min. On the basis of the oscillation in basal acid secretion after complete vagotomy we propose a new criterion for completeness of vagotomy, namely a response to physiologic vagal stimulation which does not exceed the lowest basal level by more than 0.6 mmol/15 min.

Simultaneous measurement of gastric acid and bicarbonate secretion in man.

Experiments were performed to validate the computerized pH/PCO2 technique for measurement of HCO3 secretion at a physiologic pH in the human stomach. In bench-side experiments the system detected 103 +/- 2% (mean +/- SE, n = 66) of boluses or infusions of NaHCO3. The standard curve was linear in the physiologic concentration range, and in the pH interval from 1.8 to 6.9 the recovery rate of added HCO3 was independent of the pH of the aspirate. In vivo the recovery rate of an exogenous NaHCO3 infusion (240 mumol/15 min) was 95 +/- 5% (n = 9), and there was no significant correlation between basal gastric pH and recovery rate. The results support that our computerized gastric perfusion method can be used for quantification of gastric bicarbonate secretion also at a physiologic acid pH.

Attenuation of gastric sham feeding response during reflex sympathetic activation in man.

In six human volunteers we studied the effects of hypovolemia on the secretory activity of the gastric mucosa. The secretion of acid and HCO3 from the stomach was calculated from continuous measurements of pH and Pco2 in gastric effluent. Gastric secretion was stimulated by sham feeding (SF), and cardiac filling pressure was decreased by pooling blood in the lower extremities (lower body negative pressure (LBNP]. LBNP at -20 mmHg had no significant effects on systemic arterial pressure or heart rate but increased plasma norepinephrine concentration by 48 +/- 6% (p less than 0.001). Both the acid and the alkaline responses to SF were significantly attenuated during LBNP (-38 +/- 8%, p less than 0.01, and -55 +/- 14%, p less than 0.05, respectively). Analysis of the relationship between acid and HCO3 secretion in individual experiments suggested a relatively more pronounced inhibition of HCO3 secretion. The results imply that a decreased responsiveness of the gastric mucosa may be one component of the cardiovascular reflex adaptation to hypovolemia. A downregulation of active secretion will lead to smaller metabolic demands from the secreting cells and may thereby help to maintain a vasoconstriction in the gastric mucosa.

Pitfalls in postoperative testing of the completeness of vagotomy

The gastric acid response to insulin hypoglycemia represents an effect of several stimulatory and inhibitory mechanisms. In the intact stomach the direct vagal excitation of the acid secreting glands is the predominant mechanism. After vagotomy, however, the balance between the stimulatory and inhibitory mechanisms is unpredictable. Some stimulatory and inhibitory mechanisms are non-vagal, and may after vagotomy result in a false conception of remaining vagal fibers and complete vagotomy, respectively. Sham feeding may be a safer and more reliable test of completeness of vagotomy. A study of the spontaneous variation of basal acid secretion over several hours after vagotomy in 22 patients showed in 15-min samples a maximal range of 0.49 and 0.65 mmol with a P value of 0.05 and 0.01, respectively. A higher range may thus indicate a true acid response to a given stimulus. In 3 patients with an acid response to sham feeding but no acid response to insulin in a dose of 0.2 IU/kg after vagotomy, a repeated test with a lower dose of insulin resulted in an unequivocal acid response. In 4 patients with no acid response to sham feeding and a substantial acid response to insulin after vagotomy, the acid response to insulin was abolished after pretreatment with an adrenergic blocker. The insulin test may thus give false negative and positive information about the completeness of vagotomy.

Basal and Stimulated Human Gastric Bicarbonate Secretion

The mucus-bicarbonate barrier on the gastric mucosa is regarded as a first-line of defence against acid. Both mucus and bicarbonate originate from the mucus cells in the gastric mucosa. Bicarbonate is secreted actively by Cl-/HCO3- exchange at the luminal cell membrane. A computer based system with continuous measurement of pH and PCO2 in a gastric perfusion system was used to determine human gastric bicarbonate secretion. The rate of basal gastric bicarbonate secretion in 24 healthy subjects was 386 +/- 31 mumol/h (mean +/- SEM). The 95% confidence interval for basal bicarbonate output was 103-669 mumol/h. Vagal stimulation by sham feeding increased the bicarbonate output by 63% and instillation of 16,16 dimethyl prostaglandin E2 increased the bicarbonate output by 214%. The response to vagal stimulation was independent of intragastric pH. The sham feeding response was abolished by premedication with anticholinergics. Basal and vagally stimulated bicarbonate secretion was unaffected by prostaglandin biosynthesis blockade.