The effect of the calcium antagonist verapamil on gastric acid secretion in humans

Studies on isolated gastric glands and parietal cells suggest that calcium plays a role in the stimulus-secretion coupling of acid secretion. To determine which stimulants of human gastric secretion depend on calcium-mediated receptors, the effect of the calcium antagonist verapamil on gastric secretion was studied. Gastric secretion was stimulated by intravenous infusion of 50 micrograms/kg/h bethanechol, 10 micrograms/kg/h impromidine, 0.5 micrograms/kg/h pentagastrin, 4 mg/kg/h Ca++, or by sham feeding. Each type of stimulation was tested twice in six healthy subjects, alone and together with verapamil. Verapamil was administered as an intravenous bolus of 200 micrograms/kg followed by an infusion of 150 micrograms/kg/h. Six subjects had 2 step tests in which 4 doses of pentagastrin were administered consecutively in increasing dosage. Pentagastrin was given either alone or superimposed on a verapamil bolus followed by an intravenous infusion. Verapamil left gastric secretion stimulated by bethanechol, impromidine, or sham feeding unaffected. During Ca++ infusion verapamil caused a significant drop in volume, but not acid output. Pentagastrin-stimulated acid and volume output were significantly inhibited by intravenous verapamil, the inhibition resembling an uncompetitive pattern. Pentagastrin-stimulated gastric secretion was also inhibited by the calcium antagonist diltiazem. The results confirm earlier reports that calcium is involved in the stimulus-secretion coupling of the human gastric mucosa. Calcium appears to mediate the stimulation of acid secretion by gastrin.     

Effect of proximal gastric vagotomy and anticholinergics on the acid and gastrin responses to sham feeding in duodenal ulcer patients.

Plasma gastrin concentrations and gastric acid output after modified sham feeding were determined in 20 duodenal ulcer patients. Sham feeding produced an acid response corresponding to 40-68% of the maximal acid output after pentagastrin stimulation, with no significant increase of plasma gastrin concentrations. In eight patients proximal gastric vagotomy almost abolished the acid responses to both insulin hypoglycaemia and sham feeding. Sham feeding in the vagotomised patients did not change the gastrin concentrations in plasma. After pretreatment with benzilonium, an anticholinergic with minimal central nervous effects, plasma gastrin concentrations increased after sham feeding. The study confirms that sham feeding is a poor stimulus for gastrin release in duodenal ulcer patients and supports a cholinergic inhibition of gastrin release. Intravenous injection of benzilonium bromide in a dose close to 70 micrograms/kg, and atropine in the low dose of 30 micrograms/kg inhibited the acid response to sham feeding by about 65%. Atropine in a dose of 50 micrograms/kg virtually abolished the acid sham feeding response, possibly owing to ganglionic or central nervous blockade. Vagal activation of the acid secretory glands does not seem to involve a purely cholinergic neurotransmission.     

Luminal gastric somatostatin-like immunoreactivity in response to various stimuli in man

This study investigates release of somatostatin-like immunoreactivity (SLI) into the gastric lumen of five healthy human subjects in response to pharmacological stimuli (pentagastrin and secretin) and physiological stimuli (sham feeding and intrajejunal perfusion of elemental diet). Basal and poststimulation gastric juice aspirates were collected at 15-min intervals, extracted with acetone, and SLI determined by radioimmunoassay, with these results: (1) A considerable amount of SLI was secreted during the basal period. (2) Pentagastrin stimulated SLI release quickly and was associated with increased acid secretion. (3) Both secretin and sham feeding increased SLI only slightly. (4) During intrajejunal perfusion of the elemental diet, SLI increased significantly, was associated with decreased acid secretion, and rapidly returned to basal level when elemental diet was replaced by saline. Basal levels of gastric luminal SLI thus showed distinct changes in response to each stimulus. Although the physiological action of luminal SLI remains to be studied, its levels may reflect gastric D-cell activities.This study was supported by the Gastroenterology Section Research Fund 530569.     

Gastric acid and pancreatic polypeptide responses to modified sham feeding. Effects of truncal and parietal cell vagotomy.

The effects of truncal vagotomy and parietal cell vagotomy on gastric acid secretion and plasma gastrin and pancreatic polypeptide release were studied in 28 duodenal ulcer patients under basal conditions and after modified sham feeding and infusion of pentagastrin (2 micrograms/kg/h). Before vagotomy gastric acid output in response to modified sham feeding was significantly higher than basal acid secretion in all subjects tested and reached about 45% of the pentagastrin maximum. No difference in the increase in acid response, or in the pancreatic polypeptide response to modified sham feeding was found between patients with high and low basal secretion. Plasma gastrin concentration was unaltered by modified sham feeding before and after truncal vagotomy or parietal cell vagotomy, although after vagotomy it tended to reach higher values than before this procedure. After truncal vagotomy, basal pancreatic polypeptide concentration was decreased and modified sham feeding-induced pancreatic polypeptide increment was completely eliminated. Four weeks after parietal cell vagotomy, the modified sham feeding-induced increment in plasma pancreatic polypeptide was significantly decreased and observed only in seven of 12 patients. Four to five years after parietal cell vagotomy all subjects responded to modified sham feeding with pancreatic polypeptide increment similar to that before vagotomy and in three of 12 patients acid response to modified sham feeding was seen. This study indicates that truncal vagotomy eliminates gastric acid and plasma pancreatic polypeptide responses to vagal excitation while parietal cell vagotomy abolishes gastric acid response and reduces temporarily the pancreatic polypeptide response to modified sham feeding (possibly because of transient impairment of the vagal innervation of the pancreas). (2) A high ratio of basal to maximal acid output in non-operated duodenal ulcer patients is not associated with a low acid response to modified sham feeding, nor with a high pancreatic polypeptide concentration, and (3) Restitution of the pancreatic polypeptide response to modified sham feeding five years after parietal cell vagotomy does not indication ineffective denervation of the parietal cells.     

Hydrochloric acid, pepsin and mucus secretion in the stomach of healthy probands following a single insulin administration with simultaneous pentagastrin infusion

A single dose 0.2 U/kg b.w. of insulin was administrated after an hour of infusion of pentagastrin 2 micrograms/kg b.w. for 6 healthy volunteers aged about 27 (22-30); the investigation was carried out for 1.5 h. The control group consisted of 6 health volunteers aged about 27 (21-36) which were administrated infusion of pentagastrin. While applicating stimuli the gastric juice was aspirated for analysis. In 15-minutes fraction of gastric juice the volume, concentration and output of hydrochloric acid, pepsin, protein and carbohydrates components of gastric mucus: hexoses, hexosamine, fucose and sialic acid were measured. It was stated that insulin decreases gastric secretion stimulated by pentagastrin in two first 15-minutes fractions after administration of insulin dependently on decrease of gastric juice volume. Insulin-hypoglycemia is a stimulus decreasing gastric mucus secretion, stimulated by pentagastrin. On this ground the conclusion can be arrived, that pentagastrin evokes the mechanism decreasing gastric mucus secretion, probably adrenergic. Insulin does not change hydrochloric acid secretion, but it appears to be en extremely strong stimulus for pepsin secretion which proves hypothesis, that secretion of this enzyme is regulated mainly by vagus.     

Acid secretory response in the late follow-up of proximal gastric vagotomy for duodenal ulcer without Helicobacter pylori eradication

BACKGROUND/AIMS: The profile of acid secretory responses was studied in 20 patients who had had proximal gastric vagotomy (PGV) surgery performed 11-22 years previously in order to treat duodenal ulcers (DU). The presence of Helicobacter pylori was detected in all of the patients. METHODOLOGY: The recurrence of DU was diagnosed in 10 patients and the other 10 remained without recurrence during the follow-up period. The control groups included 10 DU patients with refractory responses to H2 receptor antagonists and 10 "normal" subjects. Both control groups had untreated Helicobacter pylori infection. Measures of 1) basal acid output, 2) acid output for 30 min under continuous i.v. infusion of 0.2 ug/kg/h of pentagastrin acid, and 3) the response for 30 and 60 min after starting a sham feeding, modified by the "chew and spit" technique under simultaneous i.v. infusion of 0.2 ug/kg/h of pentagastrin were performed. Serum gastrin was measured during fasting and at sham feeding. The densities of the gastrin cells of antrum and duodenum were estimated by morphometric counting. RESULTS: Both basal output and acid response to sham feeding plus pentagastrin infusion were higher in the DU controls and DU recurrence patients. The response to pentagastrin infusion did not show any discriminant value. Fasting serum gastrin values increased after PGV, either with or without DU recurrence. Gastrin cell hyperplasia was not demonstrated in any of these groups. CONCLUSIONS: The secretory profile of patients with both late DU recurrence after PGV and Helicobacter pylori infection lies between DU patients refractory to the H2 receptor antagonist approach and those free of DU recurrence after PGV--both of them with current Helicobacter pylori infection. The characteristic pattern of late DU recurrence after PGV and untreated Helicobacter infection is that of increased basal acid output and higher acid secretion responsiveness to sham feeding plus pentagastrin in the presence of higher serum levels of gastrin.     

Release and action of epidermal growth factor on gastric secretion in humans

Epidermal growth factor (EGF) has recently been localized in salivary, pancreatic, and Brunner's glands in humans, but little is known about its release and its action on gastric secretion. This study, performed on healthy subjects, was designed to determine the release of immunoreactive EGF in plasma and in salivary and gastric secretions under basal conditions and after modified sham feeding (MSF), ordinary feeding, and infusion of pentagastrin without and with addition of exogenous recombinant human EGF (hEGF). Under basal conditions the EGF concentrations in plasma and salivary and gastric secretions were 52 +/- 8 pg/ml, 2.5 +/- 0.3 ng/ml, and 0.12 +/- 0.03 ng/ml, respectively. MSF and ordinary feeding increased significantly EGF plasma level and salivary output but not gastric EGF output, and atropinization failed to effect these plasma and salivary EGF responses to MSF. Intravenous infusion of pentagastrin increased both plasma and salivary but not gastric EGF, and addition of exogenous hEGF in graded doses (0.25-1.0 micrograms/kg) resulted in a dose-dependent increase in the plasma level of EGF and in significant inhibition of gastric acid and pepsin outputs. The increment in plasma EGF, which resulted in significant inhibition of gastric secretion, was several times greater than that observed after MSF or feeding. EGF infused in a constant dose (0.12 or 1.0 micrograms/kg-h) resulted in an increment in plasma EGF similar to that observed after MSF alone.     

Inhibitory effect of cimetidine on gastric acid secretion vagally activated by physiological means in duodenal ulcer patients.

Vagal activation of gastric acid secretion by modified sham feeding in six patients with duodenal ulcer produced a peak acid response amounting to 52% of the peak acid output after pentagastrin stimulation (PAOpg). Cholinergic reflex stimulation of gastric acid secretion by fundic distension in another six patients with duodenal ulcer produced a peak acid response of 45% of PAOpg. Intravenous infusion of cimetidine in a dose of 100 mg/h markedly inhibited the acid sham feeding response by 90-100% and almost abolished the acid response to fundic distension. The results suggest that gastric acid secretion evoked by physiological vagal activation in man is profoundly inhibited by H2-receptor blocking agents.     

Effects of fundic vagotomy and cholinergic replacement on pentagastrin dose responsive gastric acid and pepsin secretion in man.

The effects of fundic vagotomy on acid and pepsin secretion in 12 patients (10 males, two females; nine duodenal ulcer, three gastric ulcer) were studied using a pentagastrin dose response before and after Vagotomy. In the intact stage H, Cl, and pepsin output all had the same ED50, 120-127 pmol/kg/h. Vagotomy reduced basal output of acid by 78%, Cl- by 50%, and pepsin by 62%. Postvagotomy basal outputs were not related to preoperative levels, while maximum acid output was reduced by an average of 35%, proportionally to the preoperative output (r = 0.94). Vagotomy uncompetitively (ED50 increase, Vmax decrease) inhibited the pentagastrin dose response of acid, chloride, and pepsin output. Postoperatively, a six-fold greater dose of pentagastrin (450 vs 76 pmol/kg/h) was required to stimulate acid to 50% of its preoperative maximum output. For pepsin secretion the increase was 12-fold (185 vs 15 pmol/kg/h). In five of the nine duodenal ulcer patients pentagastrin dose responses were repeated with a background infusion of urecholine, 20 micrograms/kg/h. Urecholine increased basal and peak acid, pepsin, and chloride outputs, and the ratio of basal: maximal almost to prevagotomy levels; it also restored the sensitivity to pentagastrin. Serum gastrin was not significantly changed by urecholine or by vagotomy. We conclude that the level of basal acid and pepsin secretion in ulcer patients, which is largely eliminated by vagotomy, is dependent on the vagus and not on serum gastrin. The effects of vagotomy are functional, are due to cholinergic withdrawal, and usually can be restored by cholinergic replacement.     

Gastric luminal somatostatin secretion of normals and patients with pernicious anemia and with Zollinger-Ellison syndrome

We studied the release of gastric luminal somatostatin-like immunoreactivity (SLI) in response to a pentagastrin infusion (0.9 g/kg/hr, intravenous) in five normal volunteers, five patients with pernicious anemia, and two patients with Zollinger-Ellison syndrome. In addition, we studied the gastric luminal SLI secretion in response to a gastric luminal acid perfusion in two patients with pernicious anemia. Our results have shown that: (1)pentagastrin caused a parallel increase in luminal hydrogen ions and SLI release in normal volunteers; (2) Zollinger-Ellison patients had elevated basal acid and SLI levels that did not increase further with pentagastrin; (3) pentagastrin did not increase gastric acid or luminal SLI secretion in pernicious anemia patients; and (4) in pernicious anemia patients, a gastric luminal acid perfusion caused a significant increase in gastric luminal SLI over baseline values. In conclusion, gastric luminal hydrochloric acid appears to be a factor which stimulates the secretion of luminal SLI in human beings.This study was supported by the Gastroenterology Section Research Fund.This study was presented at the annual meeting of the American Gastroenterological Association in Chicago, Illinois, in May 1987.     

Inhibition of Pentagastrin-induced Gastric Acid Secretion in Man by Glucagon Given Intravenously

The effect of 2 mg of glucagon given intravenously on the pentagastrininduced gastric acid secretion was studied in 8 patients with peptic ulcer disease. On the maximal acid output produced by pentagastrin glucagon induced a moderate but significant depression of the secretion. When a submaximal pentagastrin infusion of 0.0025 μg/kg/min was given, glucagon induced approximately a 50 % decrease of the gastric acid output. Glucagon inhibits the basal as well as the pentagastrin-stimulated gastric acid secretion, but not the secretion in response to a maximal dose of histamine.     

The influence of smoking and intravenous nicotine on gastric mucus

Smoking predisposes to peptic ulcer. Bound N-acetylneuraminic acid (NANA) is an essential constituent of mucus. In order to examine whether smoking changes gastric mucus secretion, the concentration of N-acetylneuraminic acid was measured in the gastric juice of 10 non-smokers and 10 smokers. Gastric juice was aspirated during intravenous infusion of 0.67 microgram/kg/hr pentagastrin given alone or together with 5 micrograms/kg/hr nicotine. Instead of intravenous nicotine, the 10 smokers smoked 5 cigarettes over a period of 2 hours. In the fasting gastric juice and during infusion of pentagastrin the gastric concentration and output of bound N-acetylneuraminic acid were similar in smokers and in non-smokers. Acute nicotine administered intravenously or by smoking left gastric output of bound N-acetylneuraminic acid unaffected. It is concluded that neither chronic nor acute consumption of nicotine affects gastric turnover or adherence of mucus to the mucosa.     

Effect of gastric inhibitory polypeptide on pentagastrin-stimulated acid secretion in man

Eight male subjects were given pentagastrin by intravenous infusion in doses of 25, 74, 222, 667, and 2000 ng/kg/hr, each dose for 30 min. On another day the same subjects were given the same doses of pentagastrin while gastric inhibitory polypeptide (GIP) was being infused intravenously in a dose of 2 g/kg/hr. At the 222 ng/kg/hr dose of pentagastrin, acid output was significantly lower with GIP; at all other doses of pentagastrin, acid output did not differ significantly in tests with and without GIP. Pepsin output in the tests with and without GIP did not differ significantly at any dose of pentagastrin. Plasma concentration of GIP, measured by radioimmunoassay, showed a mean±SE plateau level of 7.4±1.4 ng/ml during GIP infusion and 0.4±0.1 ng/ml peak level after a standard meal. We conclude that the increase in blood concentration of GIP produced by feeding is probably inadequate to cause significant inhibition of gastric acid or pepsin secretion in man.     

Pharmacology of pepsinogen secretion: influence of pentagastrin on pepsinogen secretion in man

To investigate the effect of pentagastrin on serum and urinary pepsinogens and gastric pepsin, eight healthy male volunteers were studied twice during continuous intragastric perfusion with either NaCl 0.9% or 0.1 M HCl in random order. To the perfusate 3 mg/ml phenol red was added as inert recovery marker. Gastric content was aspirated in 15-minute samples, 4 basally and subsequently 6 during continuous i.v. infusion of pentagastrin 1.5 micrograms/kg/h. Furthermore, serum and urine samples were collected immediately before and after each test. Gastric pepsin output increased after pentagastrin. There were no differences in basal or stimulated pepsin output during saline or HCl perfusion despite marked differences in intra-gastric acidity and acid delivery to the duodenum. In addition, no significant changes in serum pepsinogen levels or urinary pepsinogen excretion were observed after pentagastrin infusion. It is concluded that pentagastrin stimulates gastric pepsin secretion directly, but does not stimulate the release of pepsinogens into the systemic circulation.     

The effect of pirenzepine on basal, pentagastrin- and insulin-stimulated gastric acid secretion in patients with peptic ulcer disease.

The effect of pirenzepine on basal and stimulated acid secretion was tested in five patients with peptic ulcer disease and gastric hypersecretion. Two types of stimulation were compared, namely pentagastrin by intravenous infusion (1 microgram/kg/h) and hypoglycaemia induced by insulin given subcutaneously (0.125 IU/kg). Basal acid output/30 min was reduced by 44% and 69%, respectively. Pentagastrin-stimulated acid output was reduced by 30%/120 min, and insulin-stimulated acid output by 47%. The reduction was similar during the first and second hour of stimulation in both series. These results strengthen our previous impression that pirenzepine may interfere with cholinergic receptors at the parietal cell level. As the inhibition of gastric acid secretion by pirenzepine is similar to that produced by oral doses of cimetidine, pirenzepine may be useful in the treatment of peptic ulcer disease.     

Gastric mucosal blood flow response to stimulation and inhibition of gastric acid secretion

The effect of stimulation (with graded doses of intravenous pentagastrin) and inhibition (with an H2-blocker or a proton pump inhibitor) of acid secretion on corpus mucosal blood flow was investigated. Hydrogen gas clearance was used to measure blood flow in the basal portion of the mucosa of anesthetized rats. A dose-related increase in acid output increments above resting level was observed with the doses of pentagastrin from 0 (saline infusion) to 40 micrograms/kg.h. With the doses of pentagastrin from 0 to 80 micrograms/kg.h there was a dose-related increase in mucosal blood flow increments above resting levels. A linear correlation (r = 0.7) was observed between increments in acid output and increments in mucosal blood flow with increasing doses of pentagastrin from 0 to that producing maximal acid secretion (40 micrograms/kg.h). Inhibition of pentagastrin-stimulated acid secretion by cimetidine or omeprazole returned stimulated gastric mucosal blood flow to baseline levels.     

Endogenous nitric oxide as a mediator of gastric mucosal vasodilatation during acid secretion.

The role of the endothelium-derived vasodilator, nitric oxide, as a mediator of the increase in gastric mucosal blood flow and as a modulator of the acid secretory response induced by pentagastrin was investigated in the anesthetised rat. Intravenous administration of the selective inhibitor of endogenous nitric oxide synthesis, NG-monomethyl-L-arginine (12.5 and 50 mg/kg), which dose-dependently increased systemic arterial blood pressure, did not affect resting acid output. However, NG-monomethyl-L-arginine significantly reduced resting gastric mucosal blood flow at the higher dose, as determined by hydrogen gas clearance. Infusion of pentagastrin (80 micrograms kg-1.h-1) stimulated gastric acid secretion and elevated gastric mucosal blood flow. Pretreatment with NG-monomethyl-L-arginine (12.5 mg/kg IV) did not affect this stimulation of acid output but substantially attenuated (by 65% +/- 10%; P less than 0.01) the associated increase in gastric mucosal blood flow. Pretreatment with NG-monomethyl-L-arginine (50 mg/kg IV) induced a minor inhibition of pentagastrin-stimulated acid secretion but abolished the increase in gastric mucosal blood flow. When administered during pentagastrin infusion, NG-monomethyl-L-arginine (50 mg/kg IV) did not affect the acid secretory response but induced a 76% +/- 8% inhibition (P less than 0.05) of the elevated gastric mucosal blood flow. The effects of NG-monomethyl-L-arginine on blood pressure, acid secretion, and gastric mucosal blood flow were abolished by pretreatment with the precursor for nitric oxide synthesis, L-arginine (300 mg/kg IV). These findings in the rat suggest that endogenous nitric oxide, synthesized from L-arginine, does not directly modulate the acid secretory response induced by pentagastrin but makes a substantial contribution to the mucosal vasodilatation associated with the stimulation of gastric acid secretion.     

Comparison of intraduodenal and intravenous administration of amino acids on gastric secretion in healthy subjects and patients with duodenal ulcer.

The ability of an amino acid mixture given intraduodenally or intravenously to stimulate gastric secretion is compared in healthy subjects and in duodenal ulcer patients. Graded amounts of amino acids by both routes produced a similar increase in acid output in healthy subjects, reaching about 30% of the maximal response to pentagastrin. Serum gastrin concentrations remained virtually unchanged but serum alpha amino acid nitrogen levels were about twice as high with intravenous as with intraduodenal administration. Intravenously administered amino acids produced a significantly higher acid output in patients with duodenal ulcer than in healthy subjects, but did not produce a significant increase in gastric acid or pepsin secretion when combined with a pentagastrin infusion as compared with pentagastrin alone. Cimetidine (2 mg/kg/h) added to intravenous amino acid infusions caused almost complete suppression of acid secretion. This study indicates that amino acids are capable of stimulating gastric secretion after intraduodenal and after intravenous administration. The response to the latter is significantly higher in patients with duodenal ulcer than in healthy subjects, does not appear to involve gastrin release, is not affected by pentagastrin, and is strongly suppressed by histamine H2-blocker.     

Ranitidine inhibits gastric acid and pepsin secretion following sham feeding

The effect of an oral therapeutic dose of 150 mg of ranitidine on the acid and pepsin response to sham feeding and pentagastrin was examined in healthy volunteers, using a double-blind random-isation method. Gastric juice was collected up to 255 minutes after ingestion of the drug. In placebo-treated subjects, basal acid secretion rate and the secretion rate following sham feeding and injection of 6 micrograms/kg of pentagastrin were 5.3 meq/h +/- 2.0 SEM, 12.3 +/- 3.2, and 24.4 +/- 5.4, respectively. The corresponding values in ranitidine-treated subjects were 0.1 +/- 0.1, 0.5 +/- 0.2, and 3.4 +/- 1.2, respectively. The reduction of acid secretion in all three instances is statistically significant (p less than 0.025, p less than 0.05, and p less than 0.05, respectively). Basal, sham feeding-stimulated, and pentagastrin-stimulated pepsin secretion rates in the placebo-treated group were 38.4 mg/h +/- 7.0 SEM, 68.6 +/- 13.2, and 39.2 +/- 8.0, respectively. In the ranitidine-treated group, the values were 5.0 +/- 3.4, 13.2 +/- 5.6, and 19.6 +/- 5.0, respectively. The reduction of pepsin secretion during basal state and following sham feeding is statistically significant (p less than 0.005 and p less than 0.01). Thus, oral ranitidine inhibits the acid and pepsin response to sham feeding in man. Its inhibitory effect on the acid response to pentagastrin lasts for at least 4 hours.     

Gastric antisecretory effects of esaprazole in rats.

The effects of esaprazole on gastric secretion (volume, pepsin and acid output) were investigated on animal models, both in vivo and in vitro. In conscious rats whose vagal activity was stimulated by pylorus ligation, esaprazole decreased volume, acid output and pepsin secretion. In anaesthetized stomach-perfused rats, esaprazole inhibited gastric acid secretion evoked by both vagus nerve stimulation or bethanechol infusion. By contrast, on isolated guinea-pig gastric fundus, esaprazole failed to counteract the acid output stimulated by histamine, bethanechol or pentagastrin. In addition to this, phasic contractions evoked by acetylcholine on isolated guinea-pig ileum were antagonized by esaprazole only at high concentrations. The present results suggest that the inhibitory actions of esaprazole on secretory parameters involve the cholinergic parasympathetic pathway, probably through both direct and indirect mechanisms.