Intravenous infusion of L-isomers of phenylalanine and tryptophan stimulate gastric acid secretion at physiologic plasma concentrations in normal subjects and after parietal cell vagotomy.

To determine whether intravenous infusion of individual amino acids stimulated gastric acid secretion in man, graded doses of phenylalanine, tryptophan, glycine, alanine, histidine, and NaCl control were infused on separate days in nine healthy subjects. Intravenous infusion of phenylalanine and tryptophan significantly stimulated gastric acid secretion to 50 and 52%, respectively, of the acid secretory response to intragastric peptone. Intravenous alanine and histidine were without effect, whereas glycine produced a slight response. Serum gastrin concentrations did not significantly change during intravenous amino acid infusion, except in response to 0.1 M phenylalanine. However, the increase in serum gastrin occurred 2 h after acid secretion had significantly increased in response to the 0.025 M phenylalanine infusion. Plasma amino acid concentrations were measured during intravenous amino acid infusion and in response to a steak meal in five of the subjects. At a time when acid secretion was significantly increased during intravenous infusion of phenylalanine and tryptophan, plasma amino acids were similar to, or less than, that observed after the steak meal, suggesting that circulating levels of these three amino acids have a physiologic effect on gastric secretion in man. Intravenous infusion of a combination of graded doses of phenylalanine plus a continuous infusion of 0.01 M tryptophan shifted the dose-response curve to the left and resulted in a significantly greater response than to either amino acid alone. In five subjects with parietal cell vagotomy, intravenous phenylalanine and tryptophan stimulated acid secretion, whereas histidine was without effect, similar to normal subjects. These studies indicate that intravenous infusion of small amounts of phenylalanine (0.025 M, 3.1 mmol/h) and tryptophan (0.01 M, 1.25 mmol/h) stimulated gastric acid secretion at plasma concentrations similar to those observed after a steak meal, suggesting a physiologic role for circulating levels of these amino acids on gastric acid secretion. Because acid secretion increased at a time when serum gastrin was unchanged and since there was no correlation between changes in serum gastrin and acid secretion, the responses to phenylalanine and tryptophan are probably mediated by a nongastrin-related mechanism(s). Since both phenylalanine and tryptophan stimulated secretion in vagotomized subjects, the response is vagally independent. These observations suggest that circulating levels of these two amino acids have either a direct or indirect effect on or near the human parietal cell.

Comparison of the effects of immediate-release omeprazole oral suspension, delayed-release lansoprazole capsules and delayed-release esomeprazole capsules on nocturnal gastric acidity after bedtime dosing in patients with night-time GERD symptoms.

BACKGROUND: Gastro-oesophageal reflux disease (GERD) patients on proton pump inhibitors before breakfast or dinner have acid recovery at night. Bedtime immediate-release omeprazole (IR-OME) demonstrated better control of nocturnal pH than pantoprazole before dinner. AIM: To compare repeated once daily bedtime dosing of IR-OME, lansoprazole and esomeprazole on nocturnal gastric acidity. METHODS: Open-label, randomized, crossover study enrolling 54 patients with nocturnal GERD symptoms comparing IR-OME, lansoprazole and esomeprazole at steady state for nocturnal acid breakthrough (NAB), percentage of time with gastric pH > 4 and median gastric pH. RESULTS: Onset of nocturnal acid control with IR-OME was rapid. During the first half of the night, percentage of time with gastric pH > 4 and median gastric pH were significantly higher after IR-OME compared to esomeprazole or lansoprazole (P < 0.001, both comparisons). Over the 8-h night-time period, acid control with IR-OME was significantly better than lansoprazole (P < 0.001), and comparable to esomeprazole. IR-OME reduced NAB compared with esomeprazole and lansoprazole (61% vs. 92% and 92%; P < 0.001, both comparisons). CONCLUSIONS: Bedtime IR-OME provided more rapid control of night-time gastric pH and decreased NAB compared with esomeprazole and lansoprazole. Nocturnal acid control with IR-OME was superior to lansoprazole and comparable to esomeprazole. Bedtime dosing with IR-OME may be effective for patients with night-time heartburn.

Damage and protection of the human gastric mucosa. A multiparameter assessment.

Studies in animals and humans have indicated that endogenous prostaglandins as well as synthetic prostaglandin analogues can prevent gastric mucosal damage induced by various agents. Methods were developed to assess induced damage and the effects of potentially protective agents (synthetic prostaglandin analogues and the histamine [H2]-receptor antagonist cimetidine) on the human gastric mucosa by measuring ion fluxes and transmucosal potential difference, as well as by observations with gastrointestinal endoscopy. Commonly ingested agents, such as aspirin, 1,300 mg, and 20 percent ethanol increased hydrogen ion and sodium ion fluxes, decreased potential difference, and caused gross mucosal damage, as observed by endoscopy. Conversely, acetaminophen, 2,600 mg, and 10 percent ethanol did not have any significant effects. Hyperosmolar solutions (1,800 and 3,600 mOsm/kg) also produced acute damage. Sodium taurocholate (10 mmol/liter) when instilled into the stomach, either at pH 1.1 or 7.0, produced both functional and structural damage. When given as a single dose, neither 15(R)15-methyl PGE2 nor the synthetic PGE1 analogue, misoprostol, prevented mucosal damage induced by aspirin and taurocholate (pH 1.1), respectively. Cimetidine, 400 mg orally, however, did reduce aspirin-induced mucosal damage, and this effect was independent of gastric acid inhibition.

Enprostil, a synthetic prostaglandin E2 analogue, inhibits meal-stimulated gastric acid secretion and gastrin release in patients with duodenal ulcer.

The effect of enprostil, a synthetic dehydro-prostaglandin E2, on meal-stimulated gastric acid secretion and gastrin release was studied in six patients with inactive duodenal ulcer disease. Each subject underwent seven tests in random order on separate days: placebo intragastrically and intraduodenally; enprostil 35 and 70 micrograms both intragastrically and intraduodenally; and ranitidine 150 mg intragastrically. After measuring basal gastric acid secretion and gastrin release, a liquid meal (500 ml, pH 5.5, 40 g protein, 30 g fat, 30 g carbohydrate, 550 Kcal, 768 mOsm) was given. Gastric acid secretion and gastrin release were measured over the next four hours. A second identical meal was instilled and both parameters were measured for an additional four hours. Thirty-five and 70 micrograms of enprostil administered intragastrically reduced total eight-hour gastric acid secretion by 58 percent and 82 percent, respectively (p less than 0.05). The 35 and 70 microgram doses administered intraduodenally decreased gastric acid secretion by 67 percent and 91 percent, respectively (p less than 0.05 compared with placebo). Ranitidine suppressed gastric acid secretion by 95 percent, which was similar to the suppression achieved with the 70 microgram dose of enprostil. The total meal-stimulated integrated gastrin response was significantly suppressed by both intragastric doses of enprostil and by the 70 microgram dose given intraduodenally (p less than 0.05). Compared with placebo, the 35 microgram intragastric and intraduodenal doses decreased the integrated gastrin response by 73 percent and 72 percent, respectively. The 70 microgram intragastric and intraduodenal doses of enprostil reduced the integrated gastrin response by 90 percent and 125 percent, respectively. Ranitidine did not alter the integrated gastrin response. It is concluded that enprostil significantly inhibited both meal-stimulated gastric acid secretion and gastrin release. The response to enprostil occurred in a dose-dependent manner and was similar regardless of the route of administration.

Unconventional application of standard light and electron immunocytochemical analysis to aldehyde-fixed, araldite-embedded tissues.

A simple procedure for the immunocytochemical analysis of glutaraldehyde/formaldehyde-fixed, Araldite- or Epon-embedded tissues by either light or electron microscopy is presented. Retention of immunoreactive antigen in deplasticized sections was achieved by use of a low concentration of glutaraldehyde in the fixative in combination with a seldom-used plastic solvent. This protocol produced good ultrastructural preservation in tissues and large, high-quality, 2-micrometers thick, plastic-free sections. These semithin sections provided a level of structural and antigenic preservation, image resolution, and labeling intensity that surpassed all other conventional sectioning methods used for immunocytochemistry. The capacity to use a single tissue sample in studies designed for light and electron immunocytochemistry, in conjunction with existing autoradiographic and cytochemical techniques, makes this a very desirable method for routine tissue preparation in research and clinical applications.

Review article: gastroduodenal bicarbonate secretion.

The gastroduodenal epithelium is covered by an adherent mucus layer into which bicarbonate is secreted by surface epithelial cells. This mucus-bicarbonate barrier is an important first line of defence against damage by gastric acid and pepsin, and has been demonstrated in all species including human. Similar to gastric acid secretion, regulation of gastric and duodenal bicarbonate secretion can be divided into three phases: cephalic, gastric and duodenal. In humans, sham-feeding increases bicarbonate secretion in both the stomach and duodenum which is mediated by cholinergic vagal fibres in the stomach, but seems to be noncholinergic in the duodenum. Gastric distention and luminal acidification increases gastric bicarbonate production. Whereas there are no data relating to the gastric phase of human duodenal bicarbonate secretion, in animals, food and acid in the stomach independently stimulate duodenal bicarbonate output. To date, the duodenal phase of human gastric bicarbonate secretion has not been studied, but data from animals reveal that duodenal acidification augments bicarbonate secretion in the stomach. In all species tested, direct acidification of the duodenum is a potent stimulant of local bicarbonate production. In humans, the pH threshold for bicarbonate secretion is pH 3.0. Mediation of gastroduodenal bicarbonate secretion is provided by a variety of agonists and antagonists, tested mainly in animals, but some have been evaluated in humans. Prostaglandins of the E class and VIP are major factors that control bicarbonate secretion. Bicarbonate secretion, and the mucus-bicarbonate layer in general, is adversely effected by ulcerogenic factors such as aspirin, NSAIDs, bile salts, and cigarette smoking. Furthermore, duodenal ulcer patients have an impairment in bicarbonate production within the duodenal bulb, at rest and in response to stimulation. These findings indicate that the mucus-bicarbonate barrier is an important first line of defence in the pathogenesis of peptic ulcer disease.

Cimetidine decreases aspirin-induced gastric mucosal damage in humans.

Aspirin induces gastric mucosal damage in animals and humans. The purpose of this study was to examine whether cimetidine protects the human gastric mucosa from acute aspirin-induced damage. Eight healthy subjects were studied on 4 separate days. Cimetidine, 400 mg, or placebo was given orally 1 hour before initial endoscopy. The stomach was isolated and atropine given to suppress basal acid secretion. Each study consisted of four 15 min periods during which an acidic test solution was instilled into the stomach. During the second period only, either aspirin (1300 mg, 36 mmol) or control for aspirin (36 mmol HCl) was added to the test solution. Ion fluxes and gastric mucosal potential difference were measured, and endoscopy performed following each test. After placebo, aspirin significantly altered hydrogen ion flux and potential difference versus basal and control. Cimetidine decreased the damaging effect of aspirin. Endoscopic scores increased after aspirin plus placebo, whereas they remained unchanged after aspirin plus cimetidine. Therefore, cimetidine decreased aspirin-induced gastric mucosal damage in humans. As gastric acidity was identical during all studies, the effect of cimetidine was independent of gastric acid secretion.

Anti-secretory effects and pharmacokinetics of low dose ranitidine.

The purpose of this study was to examine the anti-secretory effect of low doses of orally administered ranitidine on meal-stimulated gastric acid secretion and assess its pharmacokinetics. The effect of 20, 40, 60 and 80 mg of ranitidine p.o. and placebo were tested on 5 separate days (Latin square, double-blind) in 15 healthy males (mean age 35 years). Gastric acid secretion was measured prior to and for 8 h following two sequential mixed liquid meals administered at 4-h intervals. Venous blood samples were obtained at frequent intervals before and following each dose for determination of plasma ranitidine concentration by high pressure liquid chromatography. Each dose of ranitidine significantly (P < 0.01) decreased the peak and cumulative 4-h acid secretory responses to the first meal (range 58-93%), and the 60 and 80 mg doses significantly inhibited the response to the second meal by 31 and 43%, respectively. Total 8-h meal-stimulated acid outputs were decreased significantly in a dose-related manner (range 38-73%). Peak plasma ranitidine occurred approximately 1 h after dosing. Ranitidine tmax, t1/2 and clearances were independent of dose; however, AUC and Cmax were dose-related. Inhibition of acid secretion was related to plasma ranitidine concentration; the mean IC50 was 27 (+/- 6.4) ng/ml. We conclude that modest doses (equivalent to 7-27% of the daily therapeutic dose) of ranitidine effectively suppress meal-stimulated gastric acid secretion in a dose-related manner. If these doses are of clinical efficacy, it may be possible for substantial cost savings to occur.

Gastric acid suppression is greater during intravenous ranitidine infusion versus bolus injections of famotidine.

It has been proposed that famotidine may be effective in maintaining intragastric pH > or = 4 for up to 12 h with a single i.v. 20 mg bolus injection and thereby prevent acute stress-related mucosal haemorrhage. The present study was designed to compare a ranitidine continuous i.v. infusion (6.25 mg/h) vs. famotidine bolus injection (20 mg every 12 h) on 24-h intragastric pH and gastric acid secretion. Twenty-eight healthy volunteers (15 males, 13 females; 20-56 years) participated in two 24-h treatment periods; each test was in random order separated by 7-10 days. After an overnight fast, subjects were intubated and gastric pH and acid secretion measured hourly. Whereas ranitidine maintained gastric pH above 4 for the entire 24-h period, mean pH steadily decreased to a nadir of 2.9 and 3.7, respectively, 12 h after each famotidine injection (P < 0.01 vs. ranitidine). Furthermore, gastric acid secretion increased to 4.4 +/- 1.2 mmol/h 12 h after famotidine injection compared to 1.1 +/- 0.3 mmol/h with ranitidine (P < 0.01). We conclude that ranitidine delivered as a continuous i.v. infusion (6.25 mg/h) is superior to bolus famotidine injections (20 mg) at 12-h intervals in suppressing gastric acid secretion and maintaining an intragastric pH > or = 4. More frequent famotidine dosing, or delivery by continuous i.v. infusion, may be required to provide prolonged acid suppression.

Ultrastructure of myofibroblasts and decidualized cells in leiomyomatosis peritonealis disseminata.

A case of leiomyomatosis peritonealis disseminata studied by light and transmission electron microscopy is reported. The lesion, from a pregnant woman, was found to contain predominantly myofibroblasts and decidualized cells in a rich collagen stroma, while relatively few leiomyocytes and fibroblasts were observed. The development and fate of this entity are discussed in view of the present findings and those previously reported.

Effect of basal gastric acid secretion on the pharmacodynamics of ranitidine.

Twelve patients with inactive ulcer disease were administered placebo and ranitidine via bolus and continuous intravenous infusions, at doses ranging from 50 every 8 h, to 12.5 mg/h for 24 h. Gastric acid was collected for 20 min each h for 24 h, and ranitidine serum concentrations were measured approximately every 2 h, during each of the six study periods. Cosinor analysis of gastric acid secretion during placebo treatment revealed a significant circadian rhythm in all subjects. Mesor acid output ranged from 1.7 to 11.6 mmol/h (mean 5.6 +/- 2.8 mmol/h) and the amplitude ranged from 0.7 to 6.5 mmol/h (mean 2.8 +/- 1.6 mmol/h). Peak acid output (acrophase) occurred at 10 p.m. +/- 3 h. A pharmacodynamic model, relating ranitidine serum concentration to hourly acid secretion, was derived, which incorporated the circadian change in basal acid output. Data for this fractional response model included basal acid secretion--as determined by time of day, measured acid secretion, and associated serum ranitidine concentration. The 50% inhibitory concentration (IC50) for ranitidine ranged from 10-75 ng/ml, with a mean of 44 ng/ml. The variation in IC50 and in basal acid secretion combined to produce a wide variation in the pharmacodynamic response to ranitidine. The model-predicted serum concentrations, required to maintain acid secretion at 0.1 mmol/h, ranged from 250 to 1550 ng/ml, at the time of peak evening acid secretion. Despite a constant degree of acid inhibition by ranitidine during the day, higher serum concentrations are required during times of peak acid output to maintain adequate suppression of hydrogen ion secretion.

Duodenal mucosal bicarbonate secretion in humans: a brief review.

The human proximal duodenum serves as the crucible for the neutralization of gastric acid. Methods have been developed and validated that permit isolation of 4-cm segments of either the proximal or distal duodenum. These isolated segments were free of contamination from gastric, pancreatic, and biliary secretions. At rest the healthy human proximal duodenum produced approximately 175 mumol cm-h: or, assuming that the duodenal bulb is approximately 4 cm in length, 700 mumol h. The distal duodenum (the third part) produced significantly less bicarbonate, approximately 25 mumol/cm-h. HCl produced a prompt and sustained increase in bicarbonate output from both duodenal segments. Bicarbonate output was less in the distal duodenum, indicating a proximal-to-distal gradient. Synthetic prostaglandin E1 caused a dose-related increase in output. Substitution of the NaCl perfusate with Na2SO4 produced a brief decrease, suggesting a chloride bicarbonate exchange mechanism. Vasoactive intestinal polypeptide significantly increased proximal duodenal bicarbonate output. Bicarbonate production by the duodenal mucosa is probably an important defensive factor in maintaining mucosal integrity.

Human duodenal mucosal bicarbonate secretion--physiological and clinical aspects.

Over the past few years, we have addressed some of the components that regulate human duodenal bicarbonate secretion (DBS) using a technique for the isolation of a 4-cm duodenal segment from gastric, pancreaticobiliary and distal intestinal secretions. Our observations are summarized as follows. Resting DBS is, to a large extent, maintained by vagal innervation; atropine decreases basal bicarbonate secretion by approximately 80%. Luminal acidification with HCI (H+) is a major physiological stimulus of DBS, resulting in a prompt and significant increase of 3- to 4-fold. H(+)-stimulated DBS is likely to be mediated, at least in part, by prostaglandins of the E class, and by VIP. Each of the latter stimulates DBS independently in a dose-related manner. Since atropine is without effect on the response induced by luminal H+ and sham feeding, in both cases DBS is probably stimulated via a non-cholinergic pathway(s). Moreover, since basal, H(+)- and PGE2-stimulated proximal DBS are unaltered when the plasma-to-lumen bicarbonate concentration gradient is abolished, it may be concluded that DBS in humans involves active transport processes. It is significant that compared to normal subjects, patients with duodenal ulcers show markedly diminished basal and H(+)-stimulated proximal DBS. Furthermore, there is surprisingly little overlap between duodenal ulcer (DU) patients and normal subjects. These findings suggest that an intrinsic cellular or subcellular defect in proximal duodenal mucosal bicarbonate secretion is present in patients with duodenal ulcer disease.

Effect of sodium taurocholate on the human gastric mucosa at acid and neutral pH's.

This study was conducted to determine whether taurocholate alters human gastric function and structure at a neutral pH, when ionized, and to contrast this with its effect at an acid intraluminal pH, when pronated. Five fasted healthy subjects were studied on 4 days in random order. Net ion fluxes, mucosal damage (as quantitated endoscopically), and potential difference were measured. The control solution instilled into the stomach in the first, third, and fourth 15-min periods contained 200 ml of 100 mM HCl, 54 mM mannitol, and [14C]polyethylene glycol. Taurocholate (10 mM) was added to the control solution (pH 1.1) or citrate buffer (pH 7.0) during the second 15-min period. The effect of citrate buffer alone or control solution alone was also tested. Because hydrogen and sodium fluxes could not be quantitated at pH 7 in the presence of citrate buffer, the net ion fluxes during the 15 min immediately after exposure to the test agent were measured. At both pH 1.1 and 7.0 taurocholate produced similar and significant increases in net hydrogen ion flux (-1.7 +/- 0.4 and -1.8 +/- 0.3 mmol/15 min, respectively), net sodium ion flux (1.8 +/- 0.4 and 1.7 +/- 0.2 mmol/15 min, respectively), decreases in potential difference, and mucosal erosions. The net hydrogen ion fluxes were significantly greater than occurred after citrate buffer alone or the HCl control. The net sodium fluxes after taurocholate in citrate were significantly greater than the pH 1.1 acid control, but not citrate buffer alone. These findings indicate that pronated (pH 1.1) or ionized (pH 7.0) taurocholate significantly damaged the in vivo human gastric mucosa. Taurocholate at pH 7 could in part be responsible for the gastric mucosal injury that occurs in patients with bile reflux gastritis.

Intestinal phase of gastric acid secretion in humans with and without portacaval shunt.

To examine the effect of proximal small intestinal stimulants of gastric acid secretion in cirrhotic patients with portacaval shunt, unshunted cirrhotics, and normal subjects, a mixture of L-amino acids was administered intraduodenally, into the proximal jejunum, or intravenously to 8 cirrhotic patients with portacaval shunt and to 8 unshunted subjects (4 cirrhotic and 4 healthy volunteers). In addition, the effect of intrajejunally administered hyperosmolar mannitol (850 mosmol/kg) and intrajejunal balloon distention (40 mmHg) was determined. In the shunted and unshunted groups gastric acid secretion significantly increased equally in response to intravenous and intraduodenal amino acid infusion, whereas amino acids administered intrajejunally did not significantly alter acid secretion. Perfusion of the jejunum with hyperosmolar mannitol resulted in significant stimulation of acid secretion in the shunted subjects, whereas in the unshunted subjects it caused significant inhibition. In addition, jejunal balloon distention significantly stimulated secretion in the shunted subjects, but not in the unshunted group. Serum gastrin did not change significantly during any of the experiments and plasma amino acids were not different after jejunal compared with duodenal perfusion. These studies indicate the following: Enteral and parenteral amino acids increase gastric acid secretion similarly in subjects with and without portacaval shunt. The intestinal phase of gastric acid secretion is initiated by intraduodenal, but not intrajejunal, amino acids. As plasma amino acid concentrations were similar regardless of the route used, this suggests that the intestinal phase of acid secretion cannot be fully explained by the postabsorptive stimulation by amino acids. Intrajejunal distention with a balloon or infusion of hyperosmolar mannitol into the proximal jejunum stimulates acid secretion only in subjects with portacaval shunt.

A new method for quantitation of ion fluxes across in vivo human gastric mucosa: effect of aspirin, acetaminophen, ethanol, and hyperosmolar solutions.

A new, sensitive, and reproducible method for measuring hydrogen and sodium ion fluxes across the human gastric mucosa was developed and validated. By the use of a double-balloon tube that obstructed the pylorus, the stomach was converted into an in vivo Pavlov-type pouch. Duodenogastric reflux was prevented, and emptying of gastric contents into the duodenum was, on the average, 6%, thereby eliminating two important sources of error in quantitative gastric ion fluxes in humans. Transmucosal potential difference and endoscopic appearance of the gastric mucosa were also evaluated during each experiment. The mean percentage variation between duplicate tests for hydrogen ion was 3.2%, for sodium 17.5%, and the potential difference was 2.5%. Instillation of acetylsalicylic acid (36 mM, 1300 mg) in 200 ml of 100 mM hydrochloric acid for just 15 min resulted in a mean net hydrogen ion loss of 3.4 mmol/15 min, a net sodium ion gain of 1.9 mmol/15 min, a decrease in the potential difference of 23 mV, and marked gastric mucosal changes. Furthermore, exposure for 15 min to 20% ethanol (vol/vol, in 200 ml of 100 mM hydrochloric acid) and two separate hyperosmolar solutions (3600 mosmol/kg and 1800 mosmol/kg, both in 200 ml of 100 mM hydrochloric acid) also resulted in marked changes of net hydrogen ion loss (3.1, 4.8, 5.2 mmol/15 min, respectively), net sodium ion gain (2.4, 3.3, 2.4 mmol/15 min, respectively), decrease in potential difference (32, 30, 36 mV, respectively), and gross damage to the gastric mucosa. Each parameter was significantly different from the control test. Acetaminophen (86 mM, 2600 mg) or 10% ethanol (vol/vol) in 200 ml of 100 mM hydrochloric acid did not significantly alter ion fluxes or potential difference. Acetaminophen also did not significantly alter the endoscopic appearance of the gastric mucosa, whereas 10% ethanol had only a modest effect. In the control, aspirin, and acetaminophen experiments, maximal changes in the four parameters (i.e., hydrogen and sodium ion fluxes, potential difference, and endoscopic score) were significantly correlated with one another.

Modulation of bicarbonate secretion in rabbit duodenum: the role of calcium.

Surface epithelial bicarbonate secretion protects the proximal duodenum from acid peptic injury. Cyclic adenosine monophosphate and calcium serve as intracellular mediators of intestinal transport. Experiments were performed to examine whether calcium participates in duodenal bicarbonate transport. Stripped duodenal mucosa from rabbits was studied in Ussing chambers. HCO3- transport was stimulated by the calcium ionophore A23187, carbachol, vasoactive intestinal peptide, prostaglandin E2, dibutyryl-cyclic adenosine monophosphate, and electrical field stimulation. A23187 stimulated HCO3- secretion and Isc; tetrodotoxin failed to inhibit this effect. The calcium-channel blocker verapamil abolished HCO3- secretion stimulated by carbachol, vasoactive intestinal peptide, and electrical field stimulation, but failed to alter basal, prostaglandin E2- or dibutyryl-cyclic adenosine monophosphate-stimulated HCO3- secretion. Therefore, calcium is likely required during stimulation of duodenal epithelial HCO3- transport by carbachol, vasoactive intestinal peptide, and electrical field stimulation. Prostaglandin E2 and dibutyryl-cyclic adenosine monophosphate appear to activate duodenal HCO3- secretion by a calcium-independent pathway(s).

Cigarette smoking inhibits acid-stimulated duodenal mucosal bicarbonate secretion.

OBJECTIVE: To determine the effect of cigarette smoking on proximal duodenal mucosal bicarbonate secretion, an important defense mechanism against acid and peptic damage. DESIGN: Prospective study. SETTING: Clinical research laboratory in a university hospital. PATIENTS: Thirteen healthy adults (7 smokers and 6 nonsmokers) who had no history of peptic ulcer disease. INTERVENTIONS: Participants smoked (1 cigarette/15 min during a period of 1 hour, smokers only) or sham smoked (puffing on an unlit cigarette) during duodenal perfusion with either saline, hydrochloric acid, or prostaglandin E2 (PGE2). MEASUREMENTS: Collection of proximal duodenal secretions using a modified duodenal tube with occluding balloons and quantitation of duodenal mucosal bicarbonate secretion. RESULTS: During sham smoking both smokers and nonsmokers had comparable basal as well as H(+)-stimulated and PGE2-stimulated duodenal mucosal bicarbonate secretion. Compared with sham smoking, smoking did not significantly alter basal bicarbonate secretion (201 mumol/cm per hour [95% CI, 152 to 250 mumol/cm per hour] compared with 178 mumol/cm per hour [CI, 134 to 222 mumol/cm per hour], respectively). However, compared with sham smoking, smoking markedly reduced (P < 0.01) the increase in duodenal bicarbonate secretion in response to luminal acidification by approximately 80% (from 242 mumol/cm per hour [CI, 41 to 443 mumol/cm per hour] to 53 mumol/cm per hour [CI, -107 to 197 mumol/cm per hour]); a decrease was observed in each participant. In contrast, smoking had no significant effect on the response to luminal PGE2. CONCLUSIONS: Cigarette smoking markedly inhibited acid-stimulated human duodenal mucosal bicarbonate secretion. This adverse effect of smoking may, at least in part, explain the role of cigarette smoking in the pathogenesis and natural history of duodenal ulcer disease.

Protective effect of acetaminophen against aspirin- and ethanol-induced damage to the human gastric mucosa.

Aspirin and ethanol damage the gastric mucosa in humans, whereas acetaminophen does not. Acetaminophen increases prostacyclin activity in animals and thus may increase endogenous prostaglandin synthesis. The effect of acetaminophen was examined in five healthy subjects after intragastric aspirin or ethanol. Hydrogen and sodium ion fluxes were measured in the pylorus-occluded stomach that prevents duodenogastric reflux and gastric fluid losses. Studies were in random order and on 8 separate days. Potential difference was measured throughout and mucosal erosions were endoscopically quantitated (endoscopist masked, no premedication). The isoosmolar test solution (200 ml, 100 mM HC1, 54 mM mannitol, [14C]polyethylene glycol) was instilled into the stomach and removed 15 min later for four 15-min periods. Either aspirin (1300 mg) or ethanol (20% vol/vol) was added to the test solution only during the second 15 min. Acetaminophen (2600 mg) was given orally 1 h before aspirin or ethanol administration. To determine if the effect of acetaminophen was related to prostaglandin synthesis, prostaglandin production was inhibited with indomethacin (50 mg orally 12 h and 1 h before acetaminophen). Aspirin and ethanol alone each produced significant changes in net hydrogen and sodium fluxes, potential difference, and endoscopic changes. Acetaminophen significantly inhibited hydrogen ion flux, change in potential difference, and endoscopic damage; however, it did not totally abolish these changes. The protective effect of acetaminophen was abolished by pretreatment with indomethacin, suggesting that the effect of acetaminophen is likely to be prostaglandin-mediated. Indomethacin alone was without effect. These results demonstrate that oral acetaminophen protects the human gastric mucosa against the damaging effects of aspirin and ethanol.

Cyclooxygenase inhibition with indomethacin increases human duodenal mucosal response to prostaglandin E1.

In humans, prostaglandins of the E1 class stimulate duodenal mucosal bicarbonate secretion, whereas the cyclooxygenase inhibitor, indomethacin, decreases both mucosal PGE2 and bicarbonate production. The purpose of this study was to determine whether a synthetic prostaglandin E1, enisoprost, diminished the inhibitory effects of indomethacin on mucosal bicarbonate secretion. In seven healthy subjects the proximal 4 cm of duodenum was isolated by occluding balloons. The isolated test segment was perfused with 154 mM NaCl (2 ml/min, 37 degrees C). Each subject participated in four separate tests in random order. Indomethacin, 50 mg, or placebo was given 13 and 1 hr before testing. After measuring basal bicarbonate secretion, either 100 micrograms of prostaglandin E1 or placebo (in 154 mM NaCl) was perfused into the test segment over 30 min. As anticipated, PGE1 significantly increased duodenal mucosal bicarbonate secretion, and indomethacin decreased resting bicarbonate secretion. Indomethacin pretreatment significantly enhanced (P less than 0.03) the mucosa's response to PGE1 compared to PGE1 alone. These results further support the observations that endogenous prostaglandins, in part, regulate human proximal duodenal bicarbonate secretion. Furthermore, suppression of endogenous prostaglandin generation results in an increased sensitivity of the duodenal mucosa to PGE1.