Original Papers Digestion 13: 1-7 (1975)

Effect o f Pentagastrin and Gastric Alkalinization on Lower Esophageal Sphincter Pressure in Diffuse Esophageal Spasm V.F. Eckardt and K.H. Holtermüller Department of Medicine (I), University of Mainz, Mainz

Key Words. Achalasia • Esophageal spasm • Gastrin • Gastrointestinal motility • Lower esophageal sphincter • Manometry Abstract. The purpose of this study was to evaluate the effect of intravenous pentagas­ trin and gastric alkalinization on the lower esophageal sphincter (LES) pressure in seven patients with diffuse esophageal spasm as compared to nine normal controls. Intravenous injections of 0.2 and 0.4 Mg pentagastrin/kg body weight increased LES pressure signifi­ cantly more in patients than in control subjects (p < 0.05, p < 0.01). Following gastric alkalinization both groups showed increases in LES pressure, but these were significantly greater for patients with diffuse esophageal spasm (p < 0.05) than for controls. The results of our study indicate that the LES in patients with diffuse esophageal spasm is supersensi­ tive to pentagastrin and gastric alkalinization.

Received: April 29, 1975; accepted: June 13, 1975.

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Controversial evidence exists regarding a possible relation between diffuse esophageal spasm and achalasia. In both disorders dysphagia is the predominant symptom. However, manometric characteristics that distinguish the patient with achalasia are: absence of peristalsis, elevated lower esophageal sphincter (LES) pressure and incomplete LES relaxation during swallowing (7). In contrast, manometric studies in patients with diffuse esophageal spasm reveal powerful, repetitive esophageal contractions (13, 14, 23, 24) and an LES which relaxes normally upon swallowing (10). Both disorders have in common that the eso­ phageal body reacts in a supersensitive fashion to subcutaneous injections of cholinergic agents (16, 19, 20) which has been ascribed to denervation of the esophagus. In patients with achalasia physiological and pathological studies demonstrate disappearance and destruction of Auerbach’s plexus in the esopha­ gus (11, 21), and electron microscopic studies in diffuse esophageal spasm reveal degeneration in the vagal esophageal nerves (3). Finally, the proposal that diffuse

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esophageal spasm and achalasia are related disorders is supported by the clinical observation of transition from diffuse esophageal spasm to achalasia (18). It has been shown recently that the LES in patients with achalasia is super­ sensitive to exogenous gastrin (8) and cholinergic stimulation (6). This finding suggests that in achalasia not only the esophageal body, but also the LES is characterized by denervation. No such information exists regarding the sphincter in diffuse esophageal spasm. The purpose of our study was to investigate the effect of pentagastrin and gastric alkalinization, which previously was thought to increase endogenous gastrin (5, 22) on LES pressure in patients with diffuse esophageal spasm.

Studies were performed in seven patients with diffuse esophageal spasm having a mean age of 58.3 ± 6.0 (mean ± SE) years and in nine controls with a mean age of 52.6 ± 4.4 years. All patients fulfilled at least three of the following five criteria: (1) a history of dysphagia and substemal chest pain which occurred spontaneously and during meals; (2) radiographic demonstration of irregular localized contractions alternating with areas of dilatation during a barium swallow; (3) simultaneous repetitive esophageal contractions as demonstrated by manometry, as well as (4) presence of tertiary contractions, and (5) peri­ staltic activity exceeding a pressure of 50 mm Hg. In all patients the LES relaxed normally upon swallowing. Organic esophageal lesions were excluded in patients by X-ray and endos­ copy. In our control persons esophageal disease was excluded by history and barium swallow. Intraluminal manometry was performed with three constantly perfused polyvinyl catheters having an inner diameter of 1.4 mm. Each catheter had a side hole of 1.2 mm and was perfused with a constant flow of 0.5 ml/min. The recording catheters were arranged to measure intraluminal pressures at three points 5 cm apart. A fourth catheter with multiple perforations over a 5-cm segment was used for gastric perfusion. The most proximal orifice of the tube used for gastric perfusion was 10 cm distal to the most distal pressure recording side hole. All tubes were combined in a 4-ml assembly. Pressures were transmitted to Statham transducers whose output was traced directly on a Hellige multichannel recorder. Respiration and swallowing were simultaneously recorded by means of pneumographs placed around the subject’s chest and neck. Studies were performed on two different days after a 12-hour fasting period with the patient resting quietly in a supine position. The tube assembly was positioned first with all orifices in the stomach, and end-expiratory intragastric pressure was used as a zero refer­ ence. Then the catheters were slowly withdrawn until the lower orifice recorded LES pressure, while the two remaining side holes monitored motor activity in the body of the esophagus. The effect of exogenous gastrin on LES pressure was studied in all patients and con­ trols. Pentagastrin was given intravenously as multiple 30-sec injections of doses from 0.02-0.4 Mg/kg body weight. After each injection the sphincter pressure was recorded for at least 20 min or until the pressure returned to its previous resting level. The constructed dose response curve reflects the mean values of maximal LES pressure appearing within 20 min of a single injection.

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Methods

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LES pressures were also recorded prior to and during gastric alkalinization with 5 ml 0.1 N NaHCO,/min over a 20-min perfusion period. Immediately prior and at the end of the perfusion period, blood was drawn for serum gastrin determination. As previously described (17), serum gastrin radioimmunoassay was determined with the use of a rabbit antibody against human gastrin I. In contrast to our previously published method, charcoal was used to separate the 'bound’ and ’free’ fraction of the hormone measured. Under these conditions the interassay coefficient of variation is 10 %. All unknown samples were analyzed in triplicate in two assays. For statistical evaluation of our data we used the Student t test for paired and inde­ pendent samples.

Results

Fig. I. Dose response curve of single intravenous injections of pentagastrin on LES pressure in patients and controls (gray area). Vertical brackets indicate ± SEM.

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In our patients the resting LES pressure (16.6 ± 3.3 mm Hg) did not differ significantly from resting sphincter pressures in control subjects (20.0 ± 3.3 mm Hg). Following a dry swallow complete sphincter relaxation was re­ corded in all persons of both groups. In figure 1 dose response curves of the LES to intravenous pentagastrin injections are shown. In patients each dose of pentagastrin caused a greater

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SPHINCTER PRESSURE mm Hg

-5 0



O - Resting

increase in LES pressure than in our control subjects. This difference was statisti­ cally significant for a dose of 0.4/ug/kg body weight ( p < 0.01). Two of our patients had low resting pressures (5 and 10 mm Hg) and showed only slight increases in LES pressure following pentagastrin injections. The response pattern of these two patients accounted for the large standard error as indicated on figure 1. This indicates that in patients with diffuse esophageal spasm lower doses of pentagastrin are required to produce the same effect on the LES when compared to normal controls. In figure 2 the effect of gastric alkalinization on LES pressure is shown. During gastric alkalinization sphincter pressure increased in controls from 16.8 ± 2.8 to 23.9 ± 3.9 mm Hg and in patients from 17.4 ±3.1 to 36.3 ± 6.5 mm Hg. This increase was statistically significant for both groups ( p < 0.01). However, the increase in LES pressure during gastric alkalinization was more pronounced in patients than in controls (p < 0.05). To evaluate the effect of gastric alkalin­ ization, serum gastrin was measured in six patients and-in seven of our control subjects prior and at the end of gastric perfusion. Mean serum gastrin levels increased in patients from 32.5 ± 2.4 to 37.5 ± 2.2 pg/ml and in controls from 26.3 ± 3.0 to 33.8 ± 3.6 pg/ml. However, the changes in serum gastrin were not statistically significant. In four of our patients sphincter relaxation during alka­ linization became incomplete and never fell below 10 mm Hg.

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Fig. 2. LES pressure before and during gastric alkalinization in patients and control subjects. Vertical brackets indicate t SEM.

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These data indicate: (1) LES resting pressure in diffuse esophageal spasm does not differ significantly from LES pressure in normal controls; (2) in diffuse esophageal spasm the LES is supersensitive to pentagastrin: and (3) gastric alkalinization produces greater increases in LES pressure in patients with diffuse esophageal spasm than in control subjects. Di Marino and Cohen (10) have recently shown that in contrast to achalasia most patients with diffuse esophageal spasm have a normal LES pressure and relaxation. Our data are in agreement with this finding. However, by comparing the response of LES pressure to intravenous pentagastrin injections in patients and controls, we have shown that patients with diffuse esophageal spasm are more sensitive to pentagastrin. Low doses of pentagastrin produced marked changes in sphincter pressure. A similar response to gastrin has been reported for the LES in achalasia (8) and has been ascribed to denervation supersensitivity. Furthermore, in achalasia and diffuse esophageal spasm the esophageal body responds in a supersensitive fashion to cholinergic agents (19, 20) which can also be explained as a denervation phenomenon (2). This hypothesis is supported by electron-microscopic studies which demonstrated degenerative changes of affer­ ent vagal esophageal nerves in diffuse esophageal spasm (3). Thus, there is evi­ dence that both disorders, achalasia and diffuse esophageal spasm, are charac­ terized by denervation affecting the esophageal body and the LES. It has previously been shown that LES pressure increases during gastric alkalinization (4, 5). This effect was initially explained on the basis of endoge­ nous gastrin release, but recent studies have failed to show an increase of measurable gastrin during gastric alkalinization (15). Since then other factors have been postulated as being responsible for the effect of gastric alkalinization on LES pressure. Recently, secretin inhibition (12) and motilin release (9) have been added as new hypotheses to explain the effect of gastric alkalinization on the LES. However, the evidence that either one of these hypotheses is correct is missing. Furthermore, increases in LES pressure could still be due to endogenous gastrin release, if only one fraction of serum gastrin increases without altering total radioimmunoassayable gastrin. Brady and McGuigan (1) have recently shown that heptadecapeptide gastrin is not measurable under fasting conditions but increases significantly in response to feeding, whereas such a response was not demonstrable for big gastrin. The effect of gastric alkalinization on different fractions of gastrin awaits further studies. In our patients and controls sphincter pressure also increased during gastric alkalinization. This increase, however, was significantly greater in patients with diffuse esophageal spasm than in control subjects. We also could not demon­ strate a significant increase of serum gastrin during gastrig alkalinization, but did not measure different fractions of gastrin. Whatever the meachanism is, by which

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Discussion

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gastric alkalinization acts on LES pressure, our studies demonstrate a different response of patients with diffuse esophageal spasm and controls to these mea­ sures. Among many possible explanation, one could postulate that patients with diffuse esophageal spasm react with increased sensitivity to endogenous release of gastrin or motilin or inhibition of secretin. References

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1 Brady, P.G. and McGuigan, J.E.: Molecular species of gastrin in serum of normal individuals and duodenal ulcer patients. Gastroenterology 68: 952 (1975). 2 Cannon, W.B.: A law of denervation. Am. J. med. Sci. 198: 736 -750 (1939). 3 Cassella, R.R.; Ellis, F.J., jr., and Brown, A.L.: Diffuse spasm of the lower part of the esophagus. J. Am. med. Ass. 191: 107-110(1965). 4 Castell, D.O. and Harris, L.D.: Hormonal control of gastroesophageal sphincter strength. New Engl. J. Med. 282: 886-889 (1970). 5 Castell, D.O. and Levine, S.M.: Lower esophageal sphincter response to gastric alkalin­ ization. Ann. intern. Med. 74: 223-227 (1971). 6 Cohen, B.R. and Guelrud, M.: Cardiospasm in achalasia: demonstration of supersensi­ tivity of the lower esophageal sphincter. Gastroenterology 60: 769 (1971). 7 Cohen, S. and l.ipshutz, K'.: Lower esophageal sphincter dysfunction in achalasia. Gastroenterology 61: 814-820 (1971). 8 Cohen, S.; Lipshutz, It'., and Hughes, It'.: Role of gastrin supersensitivity in the patho­ genesis of lower esophageal sphincter hypertension in achalasia. J. clin. Invest. 50: 1241-1247 (1971). 9 Debas, H.T.: The LES merry go round. Gastroenterology 68: 615-616 (1975). 10 Di Marino, A.J. and Cohen S.: Characteristics of lower esophageal sphincter function in symptomatic diffuse esophageal spasm. Gastroenterology

Effect of pentagastrin and gastric alkalinization on lower esophageal sphincter pressure in diffuse esophageal spasm.

The purpose of this study was to evaluate the effect of intravenous pentagastrin and gastric alkalinization on the lower esophageal sphincter (LES) pr...
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