Basal Acid Research Articles

Effects of Pirenzepine and Atropine on Basal Lower Esophageal Pressure and Gastric Acid Secretion in Man: A Placebo-Controlled Randomized Study

Pirenzepine is a tricyclic antimuscarine drug with antisecretory effect on gastric secretion and inhibitory effect on esophageal peristalsis (EP). The effect of pirenzepine in graded doses on basal and pentagastrin-stimulated lower esophageal sphincter pressure (LESP) was studied in 8 volunteers. The effect was compared with the effect of atropine and placebo using a double dummy technique. Intravenously administered pirenzepine and atropine inhibited basal LESP and EP regardless of the employed doses. No difference between atropine and pirenzepine could be demonstrated. The pentagastrin-stimulated LESP was inhibited in patients treated with pirenzepine perorally (50 mg b.i.d.). Basic acid output was significantly reduced by pirenzepine or atropine in contrast to peak acid output. We conclude that muscarinic receptors of type M play a role in the LES function in man.

Helicobacter pylori and gastric acid output in peptic ulcer disease

Helicobacter pylori is associated with peptic ulcer, and a causal relationship has been postulated. We investigated the association between Helicobacter pylori and gastric acid output. Two hundred forty-one patients were studied: 173 with duodenal ulcer, 51 with gastric ulcer (41 corpus, 10 prepyloric), and 17 with combined gastric and duodenal ulcer. In 194 patients (80%), Helicobacter pylori could be demonstrated histologically from gastric antral biopsies. The presence or absence of Helicobacter pylori was not influenced by age, sex, or use of tobacco or analgesics. Patients with duodenal ulcer or combined gastric and duodenal ulcer had similar gastric acid outputs irrespective of the presence or absence of Helicobacter pylori. However, gastric ulcer patients with Helicobacter had higher basal and maximal acid outputs when compared to patients without Helicobacter (mean basal output: 4.1 mmol/hr vs 2.4, P less than 0.05; mean maximal output 19.5 mmol/hr vs. 14.4, P less than 0.05). Although Helicobacter pylori is associated with both gastric ulcer and duodenal ulcer, its significance may be different in the two diseases.

Basal and pentagastrin-stimulated gastric secretion in young horses

Equine gastric secretion was studied using a gastric cannula model after fasting (basal) and pentagastrin infusion. Gastric secretory rate, pH, osmolality, and electrolyte concentrations and outputs were determined over a 5-h period. Dose-response tests estimated that the maximally effective intravenous dose of pentagastrin was between 3 and 6 micrograms.kg-1.h-1. Basal secretory rate was 278 +/- 29 (SE) ml/15 min, and the pH was 2.00 +/- 0.31. Pentagastrin infusion at 6 micrograms.kg-1.h-1 increased secretory rate to 533 +/- 60 ml/15 min and decreased pH to 1.41 +/- 0.11. Basal gastric acid concentration and output were 38 +/- 5 meq/l and 211 +/- 36 mu eg.kg-1.h-1, respectively. Pentagastrin increased acid concentration to 60 +/- 5 meq/l and acid output to 474 +/- 61 mu eq.kg-1.h-1. Gastric fluid osmolality remained hypotonic during both basal and pentagastrin conditions. Sodium concentration remained high in comparison with hydrogen ion concentration, and sodium output increased during pentagastrin infusion. Equine gastric secretion did not attain maximal acid concentrations nor the marked drop in pH, which has been reported for other monogastric species. These data suggest that in the horse a large nonparietal component exists that modifies parietal secretions and is increased by pentagastrin stimulation.

Relationship between maternal milk PGE2 and gastric acid secretion in newborn rats

We previously demonstrated that in rats gastric acid secretion declines after birth and drops steeply on day 12 of life. In the present study, we investigated the part played in this decline by prostaglandin E2 (PGE2) from maternal milk. PGE2 content was first measured in the milk of untreated dams 0, 1, 5, 10, 12, 15, and 18 days after parturition. PGE2 levels were high during the first 5 days (123.5-200.5 pg/ml), declined significantly between days 10 and 15 (56.6-85.4 pg/ml; P less than 0.05), and dropped to 18.4 pg/ml on day 18. We also found that depleting milk of PGE2 prevented drop of acid secretion in 12-day-old suckling rats. Injecting lactating dams with indomethacin significantly reduced milk PGE2 content by 65% vs. milk of untreated dams. Surprisingly, administration of sesame oil, the indomethacin vehicle to the dams, increased milk PGE2 content by 182%. In the pups of the indomethacin-treated dams, acid secretion did not drop. On the contrary, in vivo basal and histamine-induced acid output rose markedly by 40 and 50%, respectively, and in vitro the net movements of 36Cl and 22Na measured in the isolated stomach indicated that active Cl- secretion had resumed. Mucosal PGE2 did not appear to be significantly involved in early development of acid secretion because administration of indomethacin to pups from untreated dams did not significantly modify the secretion measured on day 12. Data indicate that maternal milk depletion of PGE2 prevents the drop of gastric acid secretion previously observed in 12-day-old pups and suggest that in infant rats maternal PGE2 plays a physiological part in regulating acid secretion.

Dissociative analysis of ventromedial hypothalamic obesity syndrome

Electrolytic lesions of the ventromedial hypothalamus (VMH) produce an obesity syndrome characterized by hyperphagia, adiposity, and heightened parasympathetic tone. Experiments were conducted to evaluate the possibility that these symptoms arise from damage to distinct and separated loci within the hypothalamus. Rats received either VMH lesions, perifornical hypothalamic (PFH) knife cuts, ventromedial hypothalamic nucleus (VMN) lesions, or sham surgery (Sham). When maintained ad libitum, VMH and PFH rats were hyperphagic, overweight, and became obese. VMN rats were not hyperphagic, nor did they gain excessive weight, but they did develop an obesity reflected as a significantly elevated level of carcass fat. Under restricted feeding conditions, both VMH and VMN rats became obese; PFH rats did not. Also, only VMH lesions and PFH knife cuts increased basal gastric acid secretion. These data demonstrate dissociations between hyperphagia and obesity, as well as between stomach secretion and obesity, in the VMH syndrome. The implications of these findings for a dissociative model of the VMH obesity syndrome are discussed.

Effect of exercise and obesity on skeletal muscle amino acid uptake

The genetically obese Zucker rat has a reduced capacity to deposit dietary protein in skeletal muscle. To determine whether amino acid uptake by muscle of obese Zucker rats is impaired, soleus strip (SOL) and epitrochlearis (EPI) muscles from 10-wk-old lean and obese Zucker rats were studied in vitro by use of [14C]alpha-aminoisobutyric acid (AIB). Muscles from fasted rats were incubated under basal conditions at rest or after a 1-h treadmill run at 8% grade. To equate total work completed, lean and obese rats ran at 27 and 20 m/min, respectively. Muscles were pinned at resting length, preincubated for 30 min at 37 degrees C in Krebs-Ringer bicarbonate buffer containing 5 mM glucose under 95% O2-5% CO2, and then incubated up to 3 h in Krebs-Ringer bicarbonate with 0.5 mM AIB, [14C]AIB, and [3H]inulin as a marker of extracellular fluid. Basal AIB uptake in EPI and SOL from obese rats was significantly reduced by 40 and 30% (P less than 0.01), respectively, compared with lean rats. For both lean and obese rats, exercise increased (P less than 0.05) basal AIB uptake in EPI and SOL, but the relative increases were greater in the obese rats (EPI 54% and SOL 71% vs. EPI 32% and SOL 37%). These results demonstrate that genetically obese Zucker rats have reduced basal skeletal muscle amino acid uptake and suggest that physical inactivity may partially contribute to this defect.

Inhibition of the alpha-amidation of gastrin: effects on gastric acid secretion

Formation of biologically active amidated gastrin from glycine-extended progastrin processing intermediates (G-Gly) is achieved via the action of peptidyl-glycyl alpha-amidating monooxygenase. Since this enzyme requires copper for optimal activity, we examined the effects of a known copper chelator, diethyldithiocarbamate (DDC), on gastrin posttranslational processing and gastric acid secretion in vivo. DDC (400 mg.kg-1.day-1 ip X 3 days) administered to male Sprague-Dawley rats decreased antral amidated gastrin content, but increased antral G-Gly content. The ratio of amidated gastrin to G-Gly, which reflects in situ amidating activity, was decreased in DDC-treated rats. In contrast, tissue amidating potential, assayed directly under optimal copper concentrations in vitro, was increased in the antrum and unchanged in the pituitary. DDC markedly increased both basal and gastrin-stimulated gastric acid outputs despite the presence of normal serum amidated gastrin levels. These results suggest that copper chelation with DDC inhibits amidating activity in situ but selectively increases antral amidating enzyme synthesis. The marked increase in acid secretion despite normal circulating amidated gastrin concentrations, combined with the enhanced secretory response to exogenously administered gastrin, suggests the possibility that gastrin receptors are upregulated by the events precipitated via DDC administration.

Omeprazole: A Novel Antisecretory Agent for the Treatment of Acid-Peptic Disorders

Omeprazole represents the first agent of a unique class of acid inhibitory drugs, the proton pump inhibitors. Omeprazole inhibits basal gastric acid secretion, as well as gastrin-, histamine-, or pentagastrin-stimulated secretion, which results in decreased gastric acidity, decreased gastric acid output, and decreased gastric volume. Omeprazole is acid labile, necessitating its oral administration in an enteric-coated formulation. Bioavailability appears to be dose-dependent, with more drug being absorbed with increasing dosage as well as after repeated dosing. This is probably secondary to decreased gastric acidity and, therefore, less degradation of the administered drug. Despite its relatively short half-life (1-2 h), omeprazole's pharmacologic action is prolonged. Clinical trials have shown omeprazole to be at least as effective as histamine2-receptor antagonists in the treatment of gastric ulcers, duodenal ulcers, gastroesophageal reflux, and Zollinger-Ellison syndrome. Adverse reactions have been minimal. Omeprazole has been approved by the Food and Drug Administration for short-term therapy of severe erosive esophagitis, poorly responsive symptomatic gastroesophageal reflux disease, and long-term management of Zollinger-Ellison syndrome.

Inhibitory Effect of Galanin on Basal and Pentagastrin-Stimulated Gastric Acid Secretion in Rats

The dose-dependent effects of galanin on basal and pentagastrin-stimulated gastric acid secretion in pentobarbital-anesthetized rats were examined. Intravenous infusion of galanin at doses of 0.31, 0.62, 1.25, 1.87, 3.11, and 6.22 nmol/kg-1/h-1 into pentagastrin-stimulated rats produced a diminution in gastric acid secretion which was maximal (54.7%) at the level of the 1.87 nmol/kg-1/h-1 dose. Furthermore, the effect was biphasic, since both lower and higher doses of peptide were less effective. At the optimum concentration of 1.87 nmol/kg-1/h-1 galanin also inhibited basal gastric acid secretion. We conclude that endogenous galanin might be involved in the physiologic regulation of gastric acid secretion.

Effects of metkephamid (LY127623), a selective delta opioid receptor agonist, on gastric function

Metkephamid, a delta opioid receptor agonist, blocked cold-restraint stress ulcers, reduced absolute ethanol-induced gastric ulcers and, at the lowest and highest doses examined, reduced basal gastric acid secretion in conscious rats, all to a significant degree. The dose effects on stress ulcer formation parallel those seen against maximal electroshock seizures and suggest that both central as well as peripheral delta opioid receptors mediate gastrointestinal responses to stress.

Effects of human epidermal growth factor on natural and delayed healing of acetic acid-induced gastric ulcers in rats.

We examined the effect of human epidermal growth factor (hEGF) on the healing rate of gastric ulcers induced in rats. These ulcers were produced by a submucosal injection of 0.03 ml of 20% acetic acid into the stomach. Healing of the ulcers was delayed when a daily s.c. injection of indomethacin (1 mg/kg) was given for 4 wks. hEGF (100 and 300 micrograms/kg), given s.c. for 2 and 4 wks, significantly accelerated both natural and delayed healing of the ulcers. hEGF significantly inhibited both basal (pylorus ligation) and histamine-stimulated acid secretion (acute fistula). Thus, hEGF accelerates the healing of acetic acid-induced gastric ulcers, presumably because of its potent antisecretory activity.

Relationship between inhibition of acid secretion and healing of peptic ulcers.

Although current concepts of ulcer pathophysiology postulate an imbalance between the principal aggressive factors of acid and pepsin and an impairment of mucosal defence, effective acid reduction by a variety of antisecretory drugs is associated with a significant acceleration of duodenal and gastric ulcer healing in controlled clinical trials. The healing of duodenal ulcer is related to the degree and duration of acid reduction with currently available H2-receptor antagonists. The highly significant correlation between the reduction of nocturnal acidity and ulcer healing reflects the ability of these drugs to inhibit basal and nocturnal acid secretion to a greater extent than stimulated daytime secretion. The extent to which the addition of daytime acid inhibition to that of nocturnal acid inhibition is responsible for further accelerating ulcer healing has not yet been determined, although a model has been proposed recently to explore this effect. Omeprazole has a marked effect on the duration and the degree of inhibition of intragastric acidity which is dose-dependent. In clinical trials of duodenal ulcer treatment, this efficacy and duration of effect is associated with an increased rate of healing and a leftward shift of the healing time curve.

Influence of Chronic Rioprostil Treatment on Gastric Endocrine Function

The influence of 4 weeks of treatment with the prostaglandin E1 analogue, rioprostil, 300 micrograms b.i.d., or placebo, on gastric endocrine function is tested in healthy male volunteers. Basal serum gastrin levels and postprandial gastrin output are unchanged after treatment with rioprostil. Similarly, plasma pancreatic polypeptide levels are unaffected. Antral gastrin tissue concentrations as well as antral somatostatin concentration and volume densities of antral G-cells and D-cells are unchanged. Neither basal nor pentagastrin-stimulated gastric acid secretion after rioprostil therapy differ from pretreatment values. Rioprostil, given in a dose of 100 micrograms b.i.d. to rats for 1 week significantly increases antral mucosal height but has no influence on the mucosal concentrations and cell densities of the gastric peptides, gastrin and somatostatin. It is concluded that rioprostil in the dose used does not affect the endocrine stomach after 4-weeks' administration at a dose of 300 micrograms b.i.d.

Effects of NC-1300-B, a new benzimidazole derivative, on hog gastric H+, K+-ATPase, gastric acid secretion and HCl.ethanol-induced gastric lesions in rats.

This study was designed to determine the effect of a newly synthesized benzimidazole derivative NC-1300-B on H+, K+-ATPase (proton pump) in the hog gastric mucosa and on the basal gastric acid secretion and necrotizing agent-induced gastric lesions in rats. NC-1300-B inhibited the proton pump in a concentration-dependent manner and concentrations which inhibited the enzyme activity by 50% were 4.4 x 10(-6) M at pH 6.0 and 3.1 x 10(-5) M at pH 7.4. NC-1300-B administered orally or intraperitoneally 0.5 hr before ligating the pylorus inhibited the gastric acid secretion in a dose-dependent manner. The ED50 values (doses which inhibit acid output or lesion formation by 50%) for acid secretion were 11.5 and 11.0 mg/kg with oral and intraperitoneal administration, respectively. The antisecretory effect in a dose of 100 mg/kg persisted for up to 72 hr. NC-1300-B administered orally or intraperitoneally 0.5 hr before HCl.ethanol administration protected against damage of the gastric mucosa in a dose-dependent manner. The ED50 values for lesion formation were 13.3 and 23.0 mg/kg with oral and intraperitoneal administration, respectively. This protection with an oral dose of 100 mg/kg persisted for up to 72 hr. While pretreatment with 5 mg/kg of indomethacin given subcutaneously did not appreciably reverse the NC-1300-B protection, the pretreatment with 10 mg/kg of N-ethylmaleimide given subcutaneously potently reversed the NC-1300-B protection. NC-1300-B administered intragastrically at 30 mg/kg significantly inhibited the amplitude of gastric contraction for 50 min after intragastric administration. These effects of NC-1300-B on gastric secretion and lesion formation are much the same as those of the established proton pump inhibitor omeprazole, except for the short duration of the action of omeprazole (less than 24 hr).

Tolbutamide inhibits gastrin release in man.

Tolbutamide significantly decreased fasting plasma gastrin after 5 min of intravenous infusion in patients with atrophic gastritis, duodenal ulcer, or insulin-dependent diabetes mellitus (IDDM) as well as in healthy volunteers. Increased plasma insulin and decreased blood glucose were observed in patients with atrophic gastritis, duodenal ulcer and healthy volunteers, but not in patients with IDDM. Suppression of plasma gastrin in healthy volunteers was also observed following oral administration of tolbutamide. Despite the observed decrease in plasma gastrin, neither basal nor tetragastrin-stimulated acid output was changed for 30 min following tolbutamide infusion in healthy volunteers. Thus, our data suggest that tolbutamide inhibits gastrin release in man via mechanisms independent of changes in plasma insulin, blood glucose or acid secretion.

Pathogenesis of digitoxin-induced duodenal ulcers in pregnant rats. Roles of gastric acid and duodenal alkaline secretion.

Late-stage pregnant rats (day 17) had higher rates of gastric acid secretion (45-55 mu eq/15 min) as compared to nonpregnant and middle-stage pregnant (day 10) rats (20-25 mu eq/15 min). In contrast, basal rates of duodenal alkaline secretion were significantly lower (2-3 mu eq/15 min) in pregnant rats (day 10 and 17) than those in nonpregnant rats (approximately 5 mu eq/15 min), although the duodenal mucosa responded to acid with a significant rise in HCO3- output in these three groups of rats. In pregnant rats (day 17), a single injection of digitoxin, a Na+ K+-ATPase inhibitor (10 mg/kg, subcutaneously), had no effect on basal acid and alkaline secretions, but significantly blocked the acid-induced HCO3- secretion for more than 18 hr from 6 hr after administration. This drug, when given once daily for four days (10 mg/kg, subcutaneously), produced well-defined ulcers in the proximal duodenum with few lesions in the stomach of female rats, and the severity and incidence were significantly higher in late-stage pregnant rats than in the other two groups of rats. Following repeated administration of digitoxin (10 mg/kg) to late-stage pregnant rats (days 17-20), acid secretion significantly declined after two days of treatment, while the acid-induced HCO3- secretion was significantly attenuated after one day of treatment and remained inhibited during the whole period. These results suggest that an impairment of the mechanisms related to acid-induced HCO3- secretion may be associated with the induction of duodenal ulcers caused by digitoxin in female rats, and the high incidence of these ulcers in late-stage pregnant rats may be due to acid hypersecretion.

Effect of proximal gastric vagotomy on serum pepsinogen I and II concentrations and acid secretion in duodenal ulcer patients.

Acid secretion and basal serum pepsinogen I and II concentrations were measured in 14 duodenal ulcer patients before and at intervals up to six years after proximal gastric vagotomy. Vagotomy led to significant and long-standing reductions in basal, vagally mediated (induced by sham feeding), and peak pentagastrin-stimulated acid secretion. Serum pepsinogen I concentrations also decreased significantly after vagotomy but to a significantly lesser extent than acid secretion. There was no correlation between serum pepsinogen I concentrations and peak acid secretion, either before or after vagotomy. Serum pepsinogen II concentrations decreased only slightly and transiently after vagotomy. Thus, proximal gastric vagotomy reduces acid hypersecretion and pepsinogen I hypersecretion, but not pepsinogen II hypersecretion, in duodenal ulcer patients.

Inhibitory effect of prolonged administration of tetragastrin on experimentally induced intestinal metaplasia in wistar ratss

The effect of tetragastrin on the induction of intestinal metaplasia by intragastric administration of 5% NaOH solution was investigated in Wistar rats. The prolonged administration of tetragastrin in depot form from 1 week after NaOH treatment resulted in a significant increase in basal gastric acid secretion and a significant reduction in the incidence and number of intestinal metaplasia in experiment week 35. A histologic examination showed goblet cell metaplasia and intestinal metaplasia without Paneth cells in rats treated only with olive oil. Only goblet cell metaplasia was found in rats treated with tetragastrin. These results show that the prolonged administration of tetragastrin to rats after NaOH treatment increases gastric acid secretion and suppresses the induction of intestinal metaplasia.

Stimulation of gastric acid secretion increases mucosal blood flow in immediate vicinity of parietal cells in baboons.

In acute experiments carried out in 27 baboons under general anesthesia, the regional gastric mucosal and muscle layer blood flow and gastric acid secretion were measured during 4 hr. Baboons were allocated to each of the following six groups: control, gastric acid stimulation with histamine 40 micrograms/kg/hr intravenous, inhibition of basal or stimulated acid secretion with either ranitidine 50 mg intravenous or omeprazole 1 microgram/kg/hr. There were no significant cardiovascular alterations during the experiments. Histamine stimulation produced a concomitant rise in acid secretion and increase in blood flow only to the mucosal layer of the parietal-cell-bearing area of the stomach. Neither the underlying muscle layer nor the non-parietal-cell-bearing fundic or antral mucosa took part in this response, suggesting that a mechanism controlling blood flow is present in close proximity to the parietal cells. It was also established that the increase in blood flow occurs in response to parietal cell activity and not as a result of the action of histamine on the vascular system. Suppression of both basal and stimulated acid secretion did not cause a fall of mucosal blood flow below basal levels in any part of the stomach, indicating that drugs that inhibit parietal cell activity can be used in conditions where gastric mucosal ischemia should be avoided.

Gastric Secretion in Cirrhosis and Non-Cirrhotic Portal Fibrosis

Studies on basal and pentagastrin-stimulated gastric secretion were carried out in 20 patients with cirrhosis, 20 with non-cirrhotic portal fibrosis (NCPF) and 20 control subjects. There was no significant difference in the basal volume and acid output between the three groups. However, maximal volume and acid output were significantly lower in patients with cirrhosis and NCPF compared with the control group. There was no correlation between the acid secretion and the degree of hepatocellular dysfunction in patients with cirrhosis. Moreover, the gastric hyposection was as marked in the patients with NCPF as in those with cirrhosis, although the former did not suffer from any hepatic decompensation. It is concluded that gastric hyposecretion is not due to a derangement of hepatocyte function but may be secondary to portal hypertension and collateral circulation.