Donald O. Castell

Effects of oral calcium blocker, diltiazem, on esophageal contractions

Animal studies have shown that calcium blocking drugs decrease lower esophageal sphincter pressure and inhibit peristaltic amplitude and duration. In a single-dose acute study, we compared the effects of a new oral calcium blocker, diltiazem (90, 120, 150 mg) with placebo in five volunteers and 10 patients with chest pain/dysphagia and high amplitude peristaltic contractions in the distal esophagus-nutcracker esophagus. In volunteers, diltiazem had no effect on esophageal contractions when compared to baseline values or placebo. In contrast, most doses of diltiazem significantly (<0.05) decreased amplitude and duration of peristaltic contractions in patients with nutcracker esophagus. Despite adequate blood levels, interstudy analysis was not statistically significant because placebo also decreased these parameters. During an eight-week open-labeled study, diltiazem 90 mg QID significantly (P<0.01) improved symptoms of chest pain and dysphagia. Side effects were minimal. Although oral diltiazem has minimal effect on baseline esophageal contractions our chronic study suggests it may modify transient increases in neuromuscular tone associated with esophageal chest pain. These observations warrant further placebo-controlled studies.

Beneficial effect of indomethacin on acid-induced esophagitis in cats

Acid-induced esophageal injury in the cat, produced by infusion of 0.1 N HCl (1 ml/min for 30 min) on 4 consecutive days, has been shown previously to adversely affect lower esophageal sphincter (LES) pressure. We studied the role of prostaglandins in acid-induced esophagitis and the associated LES hypotension by simultaneous treatment of some animals with indomethacin (150 μg/kg intravenous), a specific inhibitor of prostaglandin synthesis, either during production of esophagitis or during recovery. LES pressures and esophageal histology were compared to control groups which received acid alone. Indomethacin treatment resulted in more rapid healing of the esophageal inflammation and prevented or promptly corrected the esophagitis-associated LES hypotension. These studies provide further evidence that prostaglandins play an important role in the pathogenesis of acid-induced esophagitis and LES hypotension and raise the possibility that indomethacin, a prostaglandin synthetase inhibitor, may be of benefit in prevention or therapy of esophagitis.

Computer-aided analysis of human esophageal peristalsis: I. Technical description and comparison with manual analysis

Manual and computer analysis of esophageal peristaltic activity induced by swallows of 5ml water were compared in 6 healthy subjects under basal conditions and following i.v. injection of 4 pharmacological agents: edrophonium (E, 0.08mg/kg), atropine (A, 0.6mg), pentagastrin (PG, 0.6mcg/kg), and glucagon (GL, lmcg). Esophageal manometry was performed using a low compliance perfusion system and recorded on paper for standard manual analysis. The signal was concurrently taped on an analog recorder for subsequent digitization and analysis on a PDP-11 computer using a locally developed program. With both methods we determined the wave amplitude, duration, average upward slope (dP/dT), and velocity of wave progression. In addition, the computer allowed calculation of area under each wave and maximum upward slope (Max dP/dT). We found no significant difference between results of the parameters measured using both methods. Wave amplitude was significantly increased by E and significantly decreased by A. Average upward slope was decreased and velocity was significantly increased only by A. Computer-calculated wave area and Max dP/dT were significantly changed by both E and A. PG and GL had no effect on any of the measured parameters of the peristaltic wave. Esophageal peristalsis can be analyzed using a computer-aided method, providing a rapid and objective measurement of classical parameters and access to more in-depth analysis.

Effects of vasoactive intestinal polypeptide (VIP) on lower esophageal sphincter in awake baboons: Comparison with glucagon and secretin

The effects of vasoactive intestinal polypeptide (VIP), glucagon, and secretin on lower esophageal sphincter pressure were investigated in awake baboons. The three hormones were compared with respect to effect on (1) resting lower esophageal sphincter pressure and (2) maximal stimulatory response to pentagastrin. VIP was shown to reduce resting and pentagastrin-stimulated lower esophageal sphincter pressure with significantly greater potency than either secretin or glucagon. For reduction of resting lower esophageal sphincter pressure, the potency ratio of VIP to secretin was 16:1 and of VIP to glucagon was 32:1 (P<0.05). For inhibition of pentagastrin-stimulated sphincter pressure, the potency ratio of VIP to secretin was 32:1 and of VIP to glucagon ws 64:1 (P<0.02). This demonstration of significantly increased potency of VIP over known inhibitory hormones strengthens the suggestion that VIP may have a physiologic role in the control of lower esophageal sphincter function.

Abnormal gastric emptying response to pentagastrin in duodenal ulcer disease

The effect of pentagastrin on gastric emptying in duodenal ulcer disease (DU) is unknown. The evaluation of this effect is complicated by the simultaneous action of the hormone on gastric secretion. We compared gastric emptying and net gastric output in 17 patients with active DU to that of 11 healthy controls. A dye-dilution technique was used to determine net acid output, net fluid output, fractional emptying rate, and acid emptying rate during a basal period and after pentagastrin (6 μg/kg/hr, intravenously). Net basal acid output observed in controls (54±10 μEq/min; mean±se) was used as the primary criterion for separating DU patients into 12 normosecretor (30±10 μEq/min) and 5 hypersecretor patient groups (163±40 μEq/min). The pentagastrin-stimulated net acid output was significantly greater in hypersecretor patients than in controls (P<0.01) but was normal in normosecretor patients. Basal fractional emptying and acid emptying rates were significantly greater in hypersecretors than in controls (P<0.05) but were normal in normosecretors. In contrast, both normo- and hypersecretor patients had significantly greater fractional emptying (P<0.01) and acid emptying rates than controls (P<0.05) during pentagastrin infusion. Thus, a greater load of acid transiently enters the duodenum in duodenal ulcer disease following pentagastrin stimulation, even in the absence of gastric hyperscretion.

Evaluation of the Angelchik Antireflux Prosthesis Using a Model for Esophageal Reflux in Rhesus Monkeys

Minimal data are available about the Angelchik antireflux prosthesis although it has been inserted in more than 14,000 patients. The present animal study was designed to evaluate the effectiveness and mechanism of action of this prosthesis. A reproducible model of esophageal reflux in primates was created using a double myotomy. Lower esophageal sphincter (LES) pressure and reflux score were improved significantly in animals by insertion of an Angelchik antireflux prosthesis, a modified antireflux prosthesis, or a Nissen fundoplication. Manometrically determined LES length was increased after insertion of an Angelchik antireflux prosthesis but not by a Nissen fundoplication or sham operation. Complications after insertion of the modified prosthesis included intraluminal erosion, fibrous stricture, and slippage of the device over the stomach.

Clinical applications of esophageal manometry.

In recent times, there has been considerable controversy over the accuracy, reproducibility, and importance of pressures measured in the esophagus and its sphincters. This has led to confusion about the potential clinical utility of esophageal manometry in the diagnosis of abnormalities of esophageal function. There are at least two important aspects that should be considered when formulating an opinion concerning the clinical utility of manometry. The first aspect relates to the frequent use of esophageal manometry in the research laboratory, both clinical and basic. Recently, there has been widespread use of manometric techniques to study pharmacophysiology of the esophagus in health and disease. Studies performed in a variety of species, including man, primates, cats, dogs, and opossum, have provided much new information on esophageal functiorL One should keep in mind, therefore, that a major use of esophageal manometry is in the research environment for the purpose of understanding both normal function and disease. It is important not to confuse this aspect of esophageal manometry with the question of its clinical utility. A second important aspect in the current development of esophageal manometric testing relates to the vastly improved technology presently available. With the development of direct intraluminal transducers and low-compliance infusion systems, it is now possible to perform more precise and quantitative measurements of abnormal esophageal pressures. These developments clearly promise the prospect of greater clinical utility for esophageal manometry, it is important to recognize that much of the older literature provides values for esophageal pressure measurements recorded with highly compliant infusion systems, making measurements of contractile amplitude of the peristaltic sweep grossly inaccurate. One should also recognize the importance, therefore, of studying patients only in

Prostaglandin E1 effects on resting and cholinergically stimulated lower esophageal sphincter pressure in cats

Intraluminal esophageal manometry with a sleeve catheter was used to compare the magnitude of decrease in lower esophageal sphincter (LES) pressure produced by an arterial or venous infusion of prostaglandin E1 in cats. Arterial PGE1 produced significantly lower LES pressures than venous PGE1 (p less than 0.05). Maximal decrease of 75% in basal LES pressure occurred with an associated 15% decrease in systolic blood pressure. The site of action of PGE1 in producing LES hypotension was studied by injection of either edrophonium, or bethanechol during the maximal PGE1 effect. Bethanechol, which acts directly on sphincteric smooth muscle, produced an increase in LES pressure during both saline and PGE1 infusion, while the increases in LES pressure seen with edrophonium during saline infusion were blocked during the PGE1 infusion. From these studies, we conclude that PGE1 produces LES hypotension in the cat by an inhibitory effect on the cholinergic pathway responsible for maintaining LES tone. These studies pharmacologically reproduce the LES pressure abnormality previously reported in the cat during acid-induced esophagitis and support the hypothesis that PGE1 may be involved in the pathogenesis of acute acid-induced lower esophageal sphincter abnormalities.

Gastric Retention in Peptic Ulcer Disease A Reappraisal

The saline load test is a popular method to demonstrate gastric retention. This technique, however, does not permit evaluation of volumes contributed by gastric secretion. We have studied 11 normal subjects and 7 patients with pyloric outlet obstruction using a dyedilution technique. We measured simultaneously rates of water secretion, fractional emptying rates, total intragastric volumes, and the fractions of gastric volume contributed by gastric secretion both during fasting and following a 250-ml water load. Total intragastric volume was significantly increased in patients with outlet obstruction compared to normal subjects both during fasting and following the water load (P<0.01). This increase resulted from significantly increased water secretion (P<0.01) combined with significantly decreased gastric emptying (P<0.01). Thus, gastric retention produced in patients with outlet obstruction by delayed emptying appears to be magnified by gastric hypersecretion of water. These data in no way invalidate the use of the saline load test in the diagnosis of gastric retention states, but help define the role of gastric secretion in the residual volumes measured following the load.

Do prostaglandins cause gastrointestinal mucosal injury

Summary and conclusionsWe have reviewed various examples of the injurious effects of prostaglandins on the gastrointestinal tract along with evidence that, in certain disease states, nonsteroidal antiinflammatory agents may have a prophylactic or therapeutic effect. The most important areas in which these drugs may be useful are in treatment or prevention of esophagitis, food intolerance symptoms, cholera, radiation-induced diarrhea, and ulcerative colitis.Although these two sets of facts appear to be contradictory, they may actually represent two distinct phenomena. The examples of deleterious effects of prostaglandins on gastrointestinal mucosa are all examples of inflammatory changes. Many changes occur in acute inflammation, including leukocytosis and chemotaxis of neutrophils to the area of inflammation. Release of many substances, including prostaglandins, histamine and bradykinin, occurs into the inflamed site. The prostaglandins involved in inflammation of the gastrointestinal mucosa may be quite different in source, type, and quantity from endogenous prostaglandins which play a role in cytoprotection. In addition, because other substances in addition to prostaglandins are involved in inflammation, and nonsteroidal antiinflammatory agents do not act exclusively by inhibition of prostaglandin synthesis, the therapeutic benefit of antiinflammatory agents in gastrointestinal mucosa may be due to several mechanisms.Therefore, in spite of the strong evidence indicting nonsteroidal antiinflammatory drugs as occasionally harmful to the gastric, duodenal, and intestinal mucosa, we should not lose sight of their important potential therapeutic role in other areas of the gastrointestinal tract.