Effect of alcohol and alcoholic beverages on nonstimulated pancreatic secretion in humans.

The effects of alcoholic beverages on pancreatic secretion, blood trypsin levels, the release of gastrin and cholecystokinin were studied and compared with those of an alcohol and a glucose solution. Studies were done on six healthy male volunteers. The trypsin level was measured in the duodenal aspirate, while blood trypsin and gastrin levels were measured by radioimmunoassay and the cholecystokinin level was measured by bioassay. Studies were done on 5 different days, and on each day, the effects of either a glucose solution; an alcohol solution; or wine, beer, and gin solutions infused into the stomach were compared. The glucose solution stimulated trypsin secretion (a threefold increase above the basal measure) and the release of cholecystokinin without changes in the blood trypsin level. Blood alcohol levels, after the alcohol solution and all alcoholic beverages, were similar, and subjects showed mild symptoms of intoxication. Pancreatic enzyme secretion and trypsin blood levels were not significantly affected by either alcohol or the alcoholic beverages. Wine and beer caused significant release of gastrin and cholecystokinin. Under the conditions of this study, which reproduce those of excessive alcohol drinking, alcohol and alcoholic beverages did not stimulate pancreatic enzyme secretion, although wine and beer increased the release of gastrin and cholecystokinin. We conclude that alcohol and alcoholic beverages do not affect nonstimulated pancreatic enzyme secretion.

Dopamine receptors in human gastrointestinal mucosa.

Dopamine is a putative enteric neurotransmitter that has been implicated in exocrine secretory and motility functions of the gastrointestinal tract of several mammalian species including man. This study was designed to determine the presence of dopamine binding sites in human gastric and duodenal mucosa and to describe certain biochemical characteristics of these enteric receptor sites. The binding assay was performed in triplicate with tissue homogenates obtained from healthy volunteers of both sexes using 3H-dopamine as a ligand. The extent of nonspecific binding was determined in the presence of a 100-fold excess of unlabeled dopamine. Scatchard analysis performed with increasing concentrations of 3H-dopamine (20-500 nM) revealed a single class of saturable dopamine binding sites in gastric and duodenal mucosa. Binding parameters obtained from the regression lines of the Scatchard plots of gastric mucosa of males were Bmax = 73.4 +/- 4.0 pmoles/mg protein; KD = 154 +/- 20 nM and Bmax = 95 +/- 13.6 pmoles/mg protein and KD = 826 +/- 200 nM in females. In duodenal mucosa of males these parameters were Bmax = 63.9 +/- 15.9 pmoles/protein; KD = 235 +/- 53 nM and Bmax = 83.2 +/- 19.4 pmoles/mg protein; KD = 568 +/- 104 nM in females. The results of this report demonstrate the presence of specific dopamine receptors in human gastric and duodenal mucosa. These biochemical data suggest that molecular abnormalities of these receptor sites may be operative in the pathogenesis of important gastrointestinal disorders.(ABSTRACT TRUNCATED AT 250 WORDS)

Dysphagia. A practical approach to diagnosis.

Our diagnostic approach to a patient with dysphagia begins with detailed history taking and physical examination. On the basis of findings, a radiographic and/or endoscopic study of the esophagus is done. We usually have barium-swallow radiography done initially, and if the radiographs are equivocal, upper gastrointestinal endoscopy is performed. Manometric studies are reserved for patients with suspected motility disorders.

Dopamine antagonists in the upper gastrointestinal tract.

Certain dopamine antagonists have gained increasing clinical use because of their effect on the motility of the upper gastrointestinal tract. Dopamine, while acting through specific dopaminergic receptors, inhibits lower oesophageal sphincter pressure (LOSP) and gastroduodenal motility. When given with dopamine, the specific dopamine antagonists metoclopramide and domperidone counteract these effects. When given alone, these agents elicit an increased LOSP and stimulate gastroduodenal motility and gastric emptying. They have consequently proved to be of value in certain cases of gastroparesis, and in relieving nausea and vomiting. They also appear to be useful in the management of reflux oesophagitis.

Effect of intestinal hormones and peptides on intragastric pressure in dogs.

Intragastric pressure was measured in dogs with gastric fistulas by using a flaccid balloon containing 500 ml of water. Intravenous infusion of cholecystokinin (20% pure), the carboxyl-terminal octapeptide of cholecystokinin, secretin, and vasoactive intestinal peptide produced dose-related decreases in intragastric pressure with maximal decreases of 40% or more. Glucagon and gastric inhibitory peptide produced smaller decreases in intragastric pressure. Motilin caused a dose-related increase in intragastric pressure that lasted only about 7 min despite continuing infusion of the peptide. The half-dose of cholecystokinin or of octapeptide of cholecystokinin for pancreatic protein secretion and the half-dose of secretin for pancreatic bicarbonate secretion each produced significant inhibition of intragastric pressure, suggesting that these hormones play a physiological reole in regulating gastric pressure.

Dopamine as a possible neurotransmitter in gastric relaxation.

In dogs with gastric fistulas, intragastric pressure was measured with a flaccid ballon containing 500 ml of water. Graded doses of dopamine caused graded decreases in intragastric pressure. The effect was blocked by pimozide or by metoclopramide but was not significantly affected by phenoxybenzamine, propranolol, guanethidine, or FLA-63 (a beta-hydroxylase inhibitor). Pretreatment with metoclopramide or with pimozide shifted the volume-pressure diagram of the stomach to the left; that is, at any given volume the pressure was greater after than before these drugs. In dogs with vagally innervated gastric pouches and gastric fistulas, feeding for 1 min (while allowing the food to leave the stomach through the gastric fistula) caused a prompt decrease in pressure in the pouch that lasted for about 5 min. Pretreatment with metoclopramide decreased the magnitude and duration of this receptive relaxation. It is concluded that these findings are consistent with (but do not establish) the hypothesis that dopamine is the neurotransmitter for receptive relaxation of the stomach, because dopamine mimics receptive relaxation, and dopamine antagonists partially block reflexly induced receptive relaxation.

Duodenal volume and osmoreceptors in the stimulation of human pancreatic secretion.

It is generally accepted that the intestinal phase of pancreatic secretion is initiated by the stimulation of chemoreceptors sensitive to fat and protein degradation products and hydrogen ions. The effect of the volume and osmolality of food emptied by the stomach into the duodenum has received less attention. We investigated the effects of these factors on the stimulation of pancreatic secretion by studying 8 healthy male volunteers (ages 23-69 yr), in random order on 3 separate days. On day 1, an amino acid mixture (L-phenylalanine, L-tryptophan) was infused intraduodenally at increasing rates, 0.2, 0.8, and 3.2 ml X min-1. On day 2, normal saline was infused into the intestine at the same increasing rates. On day 3, mannitol solutions of increasing osmolality 370, 520, and 700 mosmol X kg-1 were infused into the duodenum at 0.2 ml X min-1. Duodenal contents were continuously aspirated via a double-lumen tube and PEG 4000 was used as a recovery marker. All studies were repeated 90 min later during i.v. infusion of atropine (20 micrograms X kg-1 X h-1). Increasing volumes of amino acids significantly increase amylase and bicarbonate output (p less than 0.05) in a stepwise fashion. Increasing volumes of saline also caused a similar stepwise increase in amylase and bicarbonate output. Furthermore, increasing osmolality caused an increase in enzyme output up to 520 mosmol X kg-1 and no increase was seen thereafter. The responses seen with volume and osmolality were approximately 40% of that obtained with the amino acids. All responses were significantly reduced (p less than 0.05) during atropine infusion. We conclude that the human duodenum contains receptors for volume and osmolality that stimulate both pancreatic enzyme and bicarbonate secretion. Both mechanisms are atropine sensitive, suggesting they are mainly neurally mediated.

Effect of pentagastrin and caerulein on intragastric pressure in the dog.

When gastric acid was not neutralized, doses of pentagastrin as small as 1 mug kg-1 hr-1 decreased intragastric pressure in dogs. When gastric acid was neutralized the smallest effective dose of pentagastrin was 8 mug kg-1 hr-1 which is 16 times the D50 for acid secretion. Thus the decrease in intragastric pressure by small doses of pentagastrin is mediated at least in part by acid secretion. Even with gastric neutralization, a dose of caerulein as small as 63 ng kg-1 hr-1, which is the D50 for pancreatic protein secretion, decreased intragastric pressure. These findings support the view that inhibition of gastric pressure occurs with physiological doses of the cholecystokinin-like peptide caerulein but only with pharmacological doses of pentagastrin.

Changes in the relative frequency of gastric adenocarcinoma in southern California.

The incidence of gastric cancer is decreasing in most counties of the developed world, but at the Los Angeles County-University of Southern California Medical Center, we diagnosed 99.8 cases of gastric adenocarcinoma per 10(5) discharges in the period 1982 to 1986 as opposed to 62.2 per 10(5) discharges in 1972 to 1976 (P less than .0001). This change involved primarily Hispanics younger than 30 years of age with 30 cases per 10(5) vs 4.2 cases per 10(5) (P less than .0001) and whites older than 30 years: 87 cases per 10(5) vs 54 cases per 10(5) (P less than .05) during 1982 to 1986 and 1972 to 1976, respectively. There was no change in the relative frequency rates of gastric adenocarcinoma among African Americans and Asians. Although these changes do not seem important enough to make the detection of gastric cancer a high-priority public health problem, they should alert physicians working in areas with high Hispanic populations of the relative possibility of the occurrence of gastric malignancy even in young patients. Also, we have found that gastric cancer is still prevalent in whites of low socioeconomic class.

Antropyloroduodenal activity during gastric emptying of liquid meals in humans.

The present study examines the possible roles of the pylorus and the proximal duodenum in the gastric emptying of two liquid meals in six healthy volunteers. Gastric emptying of a saline meal (150 mM) and an acid meal (120 mM hydrochloric acid) were measured by the double-sampling dye dilution technique while antroduodenal motility was monitored with a continuously perfused catheter system. Pyloric region pressures were measured with a Dent sleeve. The acid meal (t1/2 = 13.5 +/- 1.8 min) emptied significantly (P less than 0.01) slower than the saline meal (t1/2 = 3.5 +/- 0.7 min). This slowing in the emptying of the acid meal was associated with significant (P less than 0.05) increments in tonic pyloric activity and phasic contractions of the proximal duodenum. Thus the gastric emptying of liquid meals is a complex process involving all components of the gastroduodenal region.

Pyloric-sphincter studies in peptic-ulcer patients: pylorus in peptic ulcer.

Pyloric pressure was assayed by a manometric procedure in the basal state and after intraduodenal infusion of HCl. 13 control subjects, 11 patients with benign gastric ulcer, 8 with duodenal ulcer, and 2 with coexistent gastric and duodenal ulcers were studied. Mean resting pyloric pressure in gastric-ulcer patients (5.17 +/- 0.71) mm Hg) was significantly lower than controls (9.40 +/- 0.85 mm Hg) and did not increase after HCl perfusion into the duodenum. Mean basal pyloric pressure in duodenal-ulcer patients (11.30 +/- 1.57 mm Hg) did not differ significantly from controls and increased after intraduodenal perfusion of HCl to 15.72 +/- 2.40 mm Hg. The two patients with coexistent ulcers had manometric patterns similar to gastric-ulcer patients. Decreased pyloric-sphincter pressure in gastric-ulcer patients may be the mechanism responsible for the increased duodeno-gastric reflux observed in these patients.

Effect of single and repeated doses of metoclopramide on the mechanisms of gastroesophageal reflux.

Decreased lower esophageal sphincter pressure, transient relaxations of the lower esophageal sphincter, and acute increases in intra-abdominal pressure are among the most common pathogenic factors in gastroesophageal reflux. This study examines the effect of metoclopramide on these factors in patients with gastroesophageal reflux disease. Six patients with clinical and endoscopic evidence of esophagitis underwent esophageal manometry and intraesophageal pH monitoring over a 5-h period (1 h basal, and 4 h postprandially). The study was done on three different days: on day 1, after placebo, on day 2, after 10 mg po metoclopramide (order randomized), and on day 3, after metoclopramide 10 mg po quid for 7 days. Metoclopramide given for 1 wk significantly increased the basal lower esophageal sphincter pressure as compared to placebo and a single dose (p < 0.05). It also significantly decreased reflux episodes during the 3rd and 4th hour postprandially when given both as a single dose or after 1 wk of treatment. There was no significant difference in the other parameters measured. Repeated metoclopramide doses decrease reflux episodes in patients with reflux esophagitis by increasing basal lower esophageal sphincter pressure and possibly by accelerating gastric emptying.

Sham feeding disrupts the interdigestive motility complex in man.

We have examined the effect of sham feeding on the interdigestive motility complex (IDMC) and the release of pancreatic polypeptide (PP) in a group of normal volunteers. The duration of the intervals in phase III of the IDMC was significantly delayed (p less than 0.01) after sham feeding, whereas there was an increase in plasma PP levels in all subjects. These results support the presence of an inhibitory vagal mechanism for the distal stomach and intestinal motility.

The effect of variations in intragastric pressure and gastric emptying of a saline meal in humans.

We have investigated the effect of variations in intragastric (IG) pressure on gastric emptying (GE) of a saline meal in six healthy subjects and six vagotomized patients. IG pressure was measured by an IG flaccid bag and GE by a marker. Studies were done during infusion of 0, 3, and 9 micrograms x kg-1 x min-1 dopamine without and after an injection of domperidone, a dopamine antagonist. Graded doses of dopamine decreased IG pressure and delayed GE emptying in both healthy and vagotomized subjects. A significant correlation was found between variations of IG pressure and GE. Both dopamine effects were antagonized by domperidone. These studies indicated that dopamine or its agonist and domperidone may be indicated in vagotomized patients with accelerated or delayed GE of liquids, respectively.

Effect of intravenous lipid on human pancreatic secretion.

Parenteral alimentation, including intravenous fat, is sometimes used in the treatment of patients with pancreatitis, although the effect of intravenous fat on human pancreatic secretion has not been systematically studied. Intravenous fat, however, has been shown to stimulate pancreatic protein secretion in the dog. The purpose of these studies was to clarify the effect of intravenous fat on human pancreatic secretion. Pancreatic secretion was assessed by measurement of enzymes and bicarbonate in duodenal aspirate collected via a double-lumen tube from 6 healthy volunteers. Four studies were randomly conducted on different days. On day 1, graded concentrations of Intralipid (5%, 10%, and 20%) were given intravenously for 1 h each, while secretin (8.2 pmol . kg-1 . h-1) was given as a background. On day 2, the same doses of Intralipid were infused intravenously without secretin. On day 3, the same doses of Intralipid were perfused into the intestine, and, finally, on day 4, 20% Intralipid was given by intestinal infusion for 2 h while 10% Intralipid was infused intravenously during the second hour. Significant stimulation of enzyme secretion was observed only during the infusion of fat into the intestine, not after intravenous infusion at any concentration. Pancreatic enzyme secretion, stimulated by intraintestinal fat, was not significantly modified by simultaneous intravenous lipid infusion. We conclude that since intravenous fat does not stimulate pancreatic secretion, its use in conditions where pancreatic stimulation is undesirable appears safe.

Cholinergic stimulation of human pancreatic secretion.

The effect of graded doses of bethanechol on pancreatic secretion and plasma levels of pancreatic polypeptide and somatostatin was investigated in six healthy volunteers. In other studies the effect of a bethanechol background on the secretin-CCK stimulation of pancreatic secretion was also studied. Bethanechol caused a moderate stimulation of amylase secretion with a weak stimulation of bicarbonate secretion. These effects were not associated with significant changes in the plasma level of pancreatic polypeptide and somatostatin. Bethanechol enhanced the response to secretin and CCK. These results confirm a cholinergic pathway in the stimulation of pancreatic secretion in man.

Effect of bolus osmolality on human esophageal function.

The effect of bolus osmolality on human esophageal function is undefined. We sought to define the response of the human esophagus to boluses with a wide range of osmolalities in 10 healthy male volunteers. Intraluminal pressure events were measured with an infused catheter system, and lower esophageal sphincter pressure was monitored continuously with a Dent sleeve. Each subject was given a series of 10 swallows of each of seven boluses, which consisted of water, mannitol solutions with osmolalities of 142, 296, 449, 704, and 1481 mOsm/kg, and orange juice (585 mOsm/kg), in a randomized fashion. Tracings were coded and analyzed blindly. Alterations in bolus osmolality did not elicit any significant changes in amplitude and duration of contraction, velocity of wave propagation, or the duration of relaxation of the lower esophageal sphincter. We conclude that bolus osmolality does not play a significant role in the control of human esophageal motility, and that this lack of effect is explained by consideration of esophageal muscle mechanics.

Impaired acid secretion and pancreatic polypeptide release in some patients with achalasia.

Achalasia is characterized by an intrinsic denervation of the esophagus. It is not known whether this process extends to other parts of the gastrointestinal tract. By means of the modified sham feeding test, we studied the innervation of the stomach and the pancreas in 13 patients with achalasia. We compared the results with those from a group of 15 healthy controls and a group of 10 vagotomized patients. We saw two patterns of response in the achalasia group: 6 patients secreted acid and released pancreatic polypeptide, as did the controls. The other 7 patients neither secreted acid nor released pancreatic polypeptide after modified sham feeding, as did the vagotomized patients. We conclude that some patients with achalasia have denervation of the stomach and pancreas, as assessed by the modified sham feeding test. These differences are unrelated to age, sex, and duration and severity of the disease or treatment. Interestingly, all patients who responded normally developed reflux esophagitis after dilatation. Besides being an interesting pathophysiologic observation, the response to modified sham feeding can help identify those patients at greater risk of developing reflux esophagitis after esophageal dilatation.

Comparative effect of gastrin on hydrogen ion secretion, antroduodenal motility and the interdigestive motility complex (IDMC) in man.

The physiological role of gastrin in H+ secretion is well established. We decided to study the effects of physiological doses of gastrin (as evidenced by H+ secretion and postprandial serum gastrin levels) on antroduodenal motility in order to delineate its role in antral motility regulation. Nine healthy male subjects, mean age 31 years, had two studies on different days. On day 1, gastroduodenal motility was monitored with a continuously perfused catheter system while gastric secretions were aspirated. After a basal period of 45 min, human synthetic gastrin (hG-17) was infused intravenously in consecutive doses of 6.25, 25, 100, and 400 pmol/kg/hr during 45 min each. On day 2, all subjects had a standard protein meal. Blood was withdrawn on both days for gastrin measurement by RIA. Increasing amounts of hG-17 caused a stepwise increase in serum gastrin and acid output. The D50 for H+ secretion was 25 pmol/kg/hr hG-17. The mean postprandial gastrin level was 31 +/- 5 pM, a level which was comparable to that seen during infusion of hG-17 6.25 pmol/kg/hr. At these serum gastrin levels, antral motility was either reduced or unchanged. Duodenal motility was unchanged. A reduction in the antroduodenal motility ratio was seen at these levels, but there was no interruption of the interdigestive motility complex. These results suggest that at physiological levels, gastrin by itself does not seem to have a major role in human antroduodenal motility regulation.