Stimulation of gastric acid secretion in the rhesus monkey

Similar maximal rates of gastric acid secretion are achieved with histamine and gastrin stimulation in human, dog, or cat, but gastrin produces higher rates than histamine in the rat. Gastric acid secretion was measured in seven nonsedated, alert, chaired rhesus monkeys (Macaca mulatta). Dose-response studies were performed using intravenous histamine or tetragastrin. These studies showed histamine to be a much more efficacious and more potent stimulant of gastric acid secretion than tetragastrin in the monkey. Both histamine and tetragastrin had similar potency and efficacy in the dog, while tetragastrin, pentagastrin, and hog heptadecapeptide were similarly less active than histamine in the monkey. Background carbachol (4 g/kg/hr) did not affect the histamine or tetragastrin dose-response curves. Histamine stimulation with background tetragastrin (64 g/kg/hr) did not produce a dose-response curve statistically different from histamine alone. Tetragastrin stimulation with background histamine (60 g/kg/hr) increased the tetragastrin dose-response curve, with a probable additive effect. We conclude that the rhesus monkey differs from cat, dog, and man in that gastrin and its analogs are not able to stimulate maximal acid secretion to the level achieved by histamine.     

A specific gastrin receptor in human gastric mucosa

Biological active 125I-synthetic human gastrin (125I- SHG ) appeared to bind specifically on human gastric mucosal membrane preparations. Gastrin binding was reversible, saturable and of high affinity (Kd = 3.44 +/- 3.44 X 10(-10)M) with the binding site (3.66 +/- 0.34 fmol/mg protein) at 37 degrees C for 30 min (pH 7.4). Specific gastrin binding was present in the fundic mucosa and absent from the antral, duodenal, jejunal, and colonic mucosa. Gastrin analogues (tetragastrin, pentagastrin, caerulein, and synthetic human gastrin) inhibited 125I- SHG specific binding. However, the specific gastrin binding was not inhibited by glucagon, insulin, acetylcholine, atropine, histamine, or cimetidine. It was suggested that gastrin and histamine H2 receptor or gastrin and muscarinic cholinergic receptor did not share the same locus.     

Acid secretion and mucosal blood flow in the distal and proximal parts of the canine parietal cell mass in response to cholinergic stimulation

Dogs provided with one denervated gastric pouch in the distal part of the corpus fundus and another of equal size in the proximal part were studied during stimulation with bethanechol chloride. Dose-response curves were determined for acid output and for mucosal blood flow, which was measured with the neutral red technique. ED50 for acid output was almost identical for the two pouches, giving a value of 1.13 (median) for the ratio of ED50 proximal pouch to ED50 distal pouch, which is between the ratios of 3.54 and 0.65 noted for pentagastrin and histamine, respectively in earlier investigations. The ED50 for blood flow was significantly lower than that for the simultaneous acid output, with a value of 0.28 for the ratio of ED50 blood flow to ED50 acid output, which gives an intermediate position between the ratios for pentagastrin (0.13 and 0.21 for the distal and proximal pouch, respectively) and histamine (0.61 and 0.73) obtained in earlier investigations. It could be hypothesized that the above differences in ratio between these three agonists reflect a difference at the receptor level of the parietal cells and the arterioles.     

The role of the antrum and the vagus nerve in the metabolism of histamine in the human gastric mucosa.

The effects of antrectomy and proximal gastric vagotomy on the metabolism of histamine in the human gastric mucosa were studied in the basal state and during pentagastrin stimulation in patients with duodenal or gastric ulcer disease. Mucosal biopsy specimens were taken from the antral and oxyntic gland areas, whereafter histamine content, histidine decarboxylase activity, and histamine methyltransferase activity were simultaneously assayed. Vagotomy was followed by a decrease in the acid secretory capacity and an increase in basal serum gastrin levels. Histamine content of the oxyntic mucosa increased after vagotomy, but the ability of pentagastrin to form new amounts of the amine was impaired. Antrectomy caused a decrease in acid secretion and a fall in gastrin concentrations. Basal histamine content and rate of amine formation in the remaining oxyntic mucosa were unaffected by antrectomy. Antrectomy impaired the ability of pentagastrin to release histamine. Histamine methyltransferase was not affected by pentagastrin, vagotomy, or antrectomy. In conclusion, both antral gastrin and the vagus nerve seem to exert a regulatory influence on the metabolism of histamine in the human oxyntic mucosa. The withdrawal of these factors either causes impaired ability of pentagastrin to release histamine from its storage site or counteracts the ability of pentagastrin to accelerate histamine synthesis.     

Estrogens and progesterone increase fetal and maternal guanylate cyclase activity

Since both estrogens and cyclic guanosine 3',5'-monophosphate stimulate protein synthesis, the objective of the present investigation was to determine if estrogens and their precursors might have part of their mechanism of action through stimulation of guanylate cyclase (E.C.4.6.1.2), the enzyme that catalyzes the conversion of guanosine triphosphate to cyclic guanosine 3',5'-monophosphate. The precursors of estrogen synthesis originate from cholesterol. Cholesterol itself had no effect on guanylate cyclase activity. The precursors of estrogen synthesis generated from cholesterol, namely, progesterone, 17 alpha-OH-progesterone, androstenedione, pregnenolone, 17 alpha-OH-pregnenolone, and dehydroepinandrosterone, however, caused a 2- to 3-fold enhancement of fetal and maternal guinea pig hepatic and uterine guaynlate cyclase activity at a concentration of 1 microM. In comparative studies, similar effects were seen on immature female Sprague-Dawley rat hepatic and uterine guanylate cyclase activity. Estrone, estradiol-17 beta, estriol, and the synthetic estrogen, diethylstilbestrol, enhanced guanylate cyclase activity in the same tissues 2- to 3- fold at the 1 microM concentration. Dose-response relationships revealed that these estrogens and their precursors had their maximal effect at 0.001 microM. Estradiol-17 alpha also enhanced uterine guanylate cyclase activity, but a 1000-fold greater concentration compared to the other estrogens was necessary to show any significant effect. The data in this investigation suggest that guanylate cyclase may play a role in the mechanism of action of estrogens and their precursors.     

Effect of enkephalin and naloxone on gastric acid and serum gastrin and pancreatic polypeptide concentrations in humans.

The effects of a synthetic enkephalin analogue with prolonged opioid activity, D-ala-2-enkephalin (ala-enk) and naloxone given alone or in combination, on vagally, pentagastrin- and histamine-induced gastric secretion and plasma hormonal responses to vagal stimulation have been studied in healthy subjects. D-ala-2-enkephalin reduced basal gastric acid and pepsin secretion, and caused a dose-dependent inhibition of gastric secretory responses to modified sham-feeding and pentagastrin but not to histamine. It increased serum gastrin concentration and suppressed plasma pancreatic polypeptide response to modified sham-feeding. Naloxone alone at lower dose levels did not affect gastric secretion and plasma hormonal concentrations but at higher doses it reduced both basal and modified sham-feeding-induced secretion. When combined with ala-enk it reversed in part gastric secretory and plasma hormonal changes induced by this peptide during modified sham-feeding and pentagastrin stimulation. These results indicate that (1) stable enkaphalin analogue inhibits basal and vagally or pentagastrin-induced gastric secretion, and affects plasma hormonal response to vagal stimulation, at least in part, via activation of opioid receptors and (2) endogenous opioid substances may be involved in the stimulation of gastric secretion in man.     

Testosterone and its precursors and metabolites enhance guanylate cyclase activity.

Both testosterone and cyclic GMP stimulate DNA synthesis. Because cyclic GMP and testosterone seem to have similar actions, the objective of this investigation was to determine if testosterone and its precursors might have part of their mechanism of action through stimulation of guanylate cyclase [GTP pyrophosphate-lyase (cyclizing), EC 4.6.1.2], the enzyme that catalyzes the formation of cyclic GMP from GTP. The precursors--namely, progesterone, pregnenolone, 17 alpha-progesterone, 17 alpha-hydroxypregnenolone, androstenedione, and dehydroepiandrosterone--caused a 2- to 3 1/2-fold enhancement of guanylate cyclase activity in rat liver, kidney, skeletal muscle, and ventral prostate at a concentration of 1 microM. These precursors are generated from cholesterol, which had no effect itself on guanylate cyclase activity. Testosterone, 19-nortestosterone, 17-methyltestosterone, and 5 alpha-dihydrotestosterone enhanced guanylate cyclase activity 2- to 5-fold in the same tissues at 1 microM. Etiocholanolone, androsterone, and epiandrosterone, metabolites of testosterone metabolism, enhanced guanylate cyclase activity 1 1/2- to 2-fold at this same concentration. Dose-response relationships revealed that testosterone and its precursors and metabolites had their maximal effect at 1 microM but still had some effect at 0.001 microM. The data in this investigation suggest that the guanylate cyclase-cyclic GMP system plays a role in the mechanism of action of testosterone and its precursors.     

Selective inhibition of pentagastrin- and cholecystokinin-stimulated exocrine secretion by proglumide

The effectiveness and selectivity of proglumide, a putative cholecystokinin/gastrin receptor antagonist in vitro, were examined on gastric acid and pancreatic secretion in vivo. Gastric secretion was measured in conscious dogs in the basal state and during infusion of pentagastrin, histamine, or bethanechol, alone or in combination with proglumide (300 mg/kg . h). Pancreatic secretion was measured in anesthetized rats in response to cholecystokinin-octapeptide or secretin, alone or in combination with proglumide (100 mg/kg). Proglumide inhibited pentagastrin-stimulated secretion but had no effect on basal, histamine-stimulated, or bethanechol-stimulated gastric acid secretion. Inhibition of pentagastrin-stimulated secretion was of the competitive type. An apparent inhibitory constant was calculated to be 300 mg/kg . h; this dose is capable of eliciting plasma concentrations of approximately 1 mM. This estimate corresponds closely to that derived from measurements in isolated canine parietal cells. Proglumide also inhibited cholecystokinin-stimulated but not secretin-stimulated pancreatic secretion. The lack of effect of proglumide on basal, histamine-stimulated, or bethanechol-stimulated gastric acid secretion implies that background gastrin has no direct or synergistic influence on stimulation by other secretagogues. The selective effect of gastrin receptor antagonists contrasts with the effectiveness of muscarinic and histamine H2-receptor antagonists against secretion induced by all types of stimulants. Accordingly, the antisecretory potential of gastrin receptor antagonists is confined to digestive secretion when the effect of gastrin is optimal. Their potential as antitrophic agents in duodenal ulcer disease, however, has not been explored yet.     

Factors related to gastric hypersecretion during pregnancy and lactation in rats

We attempted to elucidate the factor involved in gastric hypersecretion of rats during pregnancy and lactation. Acid secretion in pylorus-ligated and vagally denervated fistula rats stimulated with histamine, tetragastrin, and methacholine increased from midterm pregnancy and persisted during lactation. Pepsin secretion remained unaltered during pregnancy but increased during lactation. Vagal denervation itself abolished this hypersecretion. In late pregnancy, a delayed appearance of maximal acid response to histamine was apparent, as compared to nonpregnant rats, and was abolished by aminoguanidine treatment. There was a delay in the maximal response to tetragastrin but not to methacholine. Serum histamine concentrations were 3–4 times higher in late pregnancy, as compared to nonpregnant, lactating and nonlactating rats. Gastric DNA and protein concentrations were significantly increased in lactating rats with concomitant elevation of food intake and serum gastrin levels. Those changes disappeared in nonlactating rats, and gastric secretion was much the same in the nonpregnant rats. These results indicate that acid hypersecretion during pregnancy was exclusively associated with vagal innervation plus high serum histamine levels, while acid and pepsin hypersecretion in lactating rats were associated with vagal innervation plus hyperplastic gastric mucosa and high serum gastrin levels.     

Plant growth-promoting hormones activate mammalian guanylate cyclase activity

In vivo injections of plant growth-promoting hormones increase the growth of animals as well as plants. Plant growth-promoting hormones and positive plant growth regulators are known to increase RNA and protein synthesis. Since cyclic GMP also increases RNA and protein synthesis, the object of the present investigation was to determine whether physiological levels of plant growth-promoting hormones and positive plant growth regulators have part of their mechanism(s) of action through stimulation of the guanylate cyclase (EC 4.6.1.2)-cyclic GMP system. Representatives of the three classes of growth-promoting hormones were investigated. Thus, auxins (indole-3-acetic acid, indole-3-butyric acid, beta-naphthoxyacetic acid, and 2,4,5-trichlorophenoxy acetic acid), gibberellins (gibberellic acid), and cytokinins [N6-benzyl adenine, kinetin (6-furfuryl aminopurine), and beta-(2-furyl) acrylic acid] all increased rat lung, small intestine, liver, and renal cortex guanylate cyclase activity 2- to 4-fold at the 1 microM concentration. Dose response curves revealed that maximal stimulation of guanylate cyclase by these plant growth regulators was at 1 microM; there was no augmented cyclase activity at 1 nM. The guanylate cyclase cationic cofactor manganese was not essential for augmentation of guanylate cyclase by these plant growth-promoting regulators. The antioxidant butylated hydroxytoluene did not block the enhancement of guanylate cyclase by these plant growth-promoting factors. These data suggest that guanylate cyclase may play a role in the mechanism of action of plant growth-promoting hormones and even of positive plant regulators at the cellular level.     

Histamine metabolism in human gastric mucosa. Effect of pentagastrin stimulation

The metabolism of histamine in the human gastric mucosa was studied in the basal state and during pentagastrin stimulation. Studies were made in healthy volunteers and in patients with peptic ulcer disease. Mucosal biopsies were taken from antral and oxyntic gland areas whereupon histamine content, histidine decarboxylase activity, and histamine methyltransferase activity were simultaneously assayed. Histamine content of the oxyntic gland mucosa was decreased as a consequence of pentagastrin administration in all groups studied, and this decrease was numerically largest in patients with duodenal ulcer disease. Pentagastrin induced a significant increase in histidine decarboxylase activity of the oxyntic gland mucosa with the most profound increase seen in patients with duodenal ulcer. The highest rates of histamine formation were present in the oxyntic mucosa of patients with Zollinger-Ellison syndrome. The activity of histamine methyltransferase was the same in all groups studied and was not changed by pentagastrin. In conclusion, pentagastrin administration in humans is followed by a significant mobilization of histamine only from the oxyntic gland mucosa, an effect that is more pronounced in patients with duodenal ulcer disease.     

Antisecretory actions of aminophylline in the rat and dog.

The effect of aminophylline on gastric acid secretion has been studied in the rat and dog. Aminophylline was shown to possess antisecretory activity when given either by oral or parenteral administration in an acute gastric fistula rat preparation. In the chronic gastric fistula dog aminophylline at 50 mg/kg intragastrically induced a small but significant stimulation of basal acid secretion. This dose of aminophylline also significantly inhibited acid secretion induced by gastrin tetrapeptide, and 2-deoxy-D-glucose but did not block acid secretion induced by histamine.     

Inhibitory effect of somatostatin on gastric acid secretion and serum gastrin in dogs with and without duodenogastric reflux.

The hypersecretion of gastric acid in response to pentagastrin, caused by duodenal reflux, was tested in dogs. An infusion of 0.25 micrograms/kg/h was found to restore the raised responses seen in the reflux dogs to control levels. Somatostatin was a strong inhibitor of pentagastrin-stimulated acid secretion and of gastrin release, but it was a weak inhibitor of histamine. These studies suggest that somatostatin may have played a part in acid homeostasis.     

Direct effect of glibenclamide on guanylate cyclase activity in the rat in vitro

Summary Glibenclamide enhanced the activity in the rat of guanylate cyclase in a number of extra-pancreatic tissues. Thus, glibenclamide enhanced guanylate cyclase activity in vitro two- to threefold in liver, kidney, heart, spleen and colon at a concentration of 1 mol/l. Dose-response curves of glibenclamide on hepatic guanylate cyclase revealed that more than half-maximal stimulation was observed at a concentration as low as 10 nmol/l (p< 0.001) and no stimulation of guanylate cyclase was seen when the concentration was decreased to 1 nmol/l. Maximal enhancement was seen at 100 nmol/l of glibenclamide. Varying the concentration of the guanylate cyclase co-factor manganese had no effect on the glibenclamide enhancement of guanylate cyclase. In addition to the increased insulin receptors found recently in monocytes and fibroblasts, the present findings may help explain the extra-pancreatic effects of glibenclamide and possibly of other sulphonylurea drugs.     

An experimental study on histamine H2-receptor antagonist on calcium, gastrin and histamine induced gastric acid secretion in rat

The suppressive effect of histamine H2-receptor antagonist, cimetidine, on gastric secretion was investigated in Ghosh-Schild rat. The study above was done in basal state under infusing normal saline (1 ml/h) and stimulated state by histamine-di-chloride (3.5 mg/kg-h), tetragastrin (50 mcg/kg-h) or calcium chloride (4 mg/kg-h). Dose related increase of cimetidine (1.7, 3.5, 7.0 and 14.0 mg/kg-h) were observed and correlated with the degree of inhibition of acid secretion. Cimetidine had a potent inhibitory activity on either basal and stimulated acid output by the agents above. Basal acid secretion was completely abolished by 3.5 mg/kg-h of cimetidine to the level of anacidity. The degree of inhibition by the same dose of cimetidine was different among the agents used as stimulant on acid secretion and it followed in the order of calcium, gastrin and histamine subsequently. This study indicated that histamine H2-receptor participated the gastric secretion induced by either gastrin or calcium other than histamine itself. This fact indicated the important role of endogenous histamine in gastric secretion induced by calcium and gastrin.     

Effect of bilateral nephrectomy on serum gastrin concentration, gastric histamine content, histidine decarboxylase activity, and acid secretion in the rat.

Nephrectomy caused a marked increase in the concentration of circulating gastrin immunoreactivity but did not increase basal acid secretion. In normal rats, both histamine and pentagastrin stimulated gastric acid output, but after nephrectomy only histamine was effective. Histidine decarboxylase in the oxyntic mucosa was greatly activated following nephrectomy. Thus, in the nephrectomized rat gastrin (and pentagastrin) no longer evoked acid secretion, whereas it retained its ability to activate gastric histidine decarboxylase. The results suggest that the kidney is important for metabolism and excretion not only of gastrin but of humoral antagonists of gastrin-induced acid secretion as well.     

Mucosal expression and luminal release of epidermal and transforming growth factors in patients with duodenal ulcer before and after eradication of Helicobacter pylori.

BACKGROUND: Epidermal growth factor (EGF) and transforming growth factor-alpha (TGF alpha) are potent gastric acid inhibitors and stimuli of mucosal growth and protection but their involvement in Helicobacter pylori associated duodenal ulcer has been little examined. AIM: To assess gastric acid secretion, plasma gastrin concentrations, mucosal content of EGF and TGF alpha, and mucosal expression of these peptides and their receptor (EGFr) as well as salivary and gastric luminal release of EGF under basal conditions and after pentagastrin stimulation in 10 healthy subjects and in 25 H pylori positive patients with duodenal ulcer before and after two weeks of triple anti-H pylori therapy and four weeks after the termination of this therapy. RESULTS: Pentagastrin stimulation caused a significant increase in salivary and gastric release of EGF both in healthy controls and patients with duodenal ulcers but in the patients, the eradication of H pylori resulted in several fold higher gastric luminal (but not salivary) EGF release than before the anti-H pylori therapy. Mucosal contents of immunoreactive EGF and TGF alpha and mucosal expression of EGF, TGF alpha, and EGFr in H pylori positive patients with duodenal ulcer were significantly higher than those in healthy H pylori negative controls and this increase persisted after eradication of H pylori. Basal plasma gastrin was significantly reduced after two weeks of triple therapy and four weeks after the H pylori eradication all ulcers were completely healed. CONCLUSIONS: (1) H pylori infection in patients with duodenal ulcer was accompanied by enhanced plasma gastrin and increased mucosal content and expression of TGF alpha, EGF, and EGFr; (2) H pylori eradication resulted in ulcer healing, reduction in plasma gastrin, and enhancement of gastric (but not salivary) luminal release of EGF, particularly after pentagastrin stimulation; and (3) enhanced mucosal content and expression of TGF alpha, EGF, and EGFr and increased luminal release of EGF may contribute to ulcer healing after eradication of H pylori.     

BRL 24924, a 5-hydroxytryptamine type 3 antagonist, and gastric secretion of acid and pepsin in vivo

BRL 24924, a specific 5-hydroxytryptamine type 3 (5-HT3) receptor antagonist, was evaluated for effects on gastric secretion of acid and pepsin and possible influences on the effects of serotonin on gastric secretion. Experiments were carried out in conscious dogs with a gastric fistula during a background stimulation of gastric secretion by continuous infusions of pentagastrin, bethanechol or histamine. During infusion of pentagastrin or histamine, BRL 24924, by itself, influenced gastric secretion with stimulation during a low potent background stimulation and inhibition during a potent background stimulation. A serotonin-counteracting effect of BRL 24924 on gastric secretion was found only during infusion of pentagastrin. The secretory stimulation attained by BRL 24924 could be blocked by atropin suggesting a cholinergic mechanism--5-HT4 receptors? The inhibitory effects on gastric secretion and the serotonin-counteracting effects of BRL 24924 are supposed to be via 5-HT3 receptors.     

Effects of pentagastrin, G17, and G34 on the electrical and mechanical activities of canine antral smooth muscle

Intracellular microelectrode technique and standard organ bath technique were used to investigate the effects of pentagastrin, G17, and G34 on the electrical and mechanical activities of canine antral circular muscle. All three molecular forms increased the amplitude and duration of the plateau of the gastric action potential and the frequency of spontaneous action potentials. They also increased the amplitude and frequency of spontaneous contractions. G17 was equal to or less potent than pentagastrin in all of its actions on this tissue. G34 had an equal or greater activity than G17. The electrical studies indicate that G17 is active in this tissue in a physiological range of concentrations. The ED50 for the effect of G17 to increase the amplitude of the plateau potential is less than that for the effect of G17 on gastric secretion, indicating that this is a physiological action of gastrin. Atropine studies indicate that only part of the in vitro inotropic action of gastrin is caused by the release of acetylcholine from nerve terminals, but that the chronotropic action is attributable to a direct effect on the smooth muscle membrane.     

Plasma Gastrin and Gastric Secretory Response to Duodenal Perfusion with Liver Extract in Healthy Human Subjects

The stomachs of 8 healthy volunteers were intubated with a Levine tube under radiological control. In addition, a thin polyethylene tube was placed in the proximal duodenum. After a 1-hour period with no perfusion, the duodenum was perfused for two hours with 15% liver extract (LE) (pH 4.5-5.5; 1027 mosm/kg water) at a rate of 100 ml/hour either alone or in combination with intravenous infusion of different doses of exogenous pentagastrin. All subjects were also tested with the tubes in place for 3 hours, but with no perfusion or pentagastrin. Reflux to the stomach was monitored by addition of radio-activeB₁₂ to the perfusates. Plasma gastrin, gastric acid, and pepsin were measured in 15-minute periods. During perfusion of the proximal duodenum, where reflux of the perfusates was less than 4%, only a slight and inconstant change in plasma gastrin was seen. Gastric acid and pepsin outputs were increased to approx. 18% and 25% of the maximal pentagastrin stimulation respectively. Whereas 15% LE was shown to release gastrin by antral perfusion however, such release was not found by duodenal perfusion, except where reflux to the antrum was seen. The results suggest that intestinal stimulation of gastric secretion exists, but has not been found to be gastrin dependent in the present investigation.