(7) a Clinical Study on Regulation of Motility of Digestive Tract by Gastrointestinal Hormones

(7) A Clinical Study on Regulation of Motility of Digestive Tract by Gastrointestinal Hormones

Makoto Isbikawa The Second Department of Internal Medicine, Yamagata University School of Medicine

Akira Ishimori

The Third Department of Internal Medicine, Tohoku University School of Medicine

Introduction Gastrointestinal (G-I) hormones are known to play a physiological role in regulation of motility along digestive tract. It was also shownthat this hormonal regulation is disturbed in various diseases. In the present investigation, lower esophageal sphincter (LES) pressure, intragastric pressure and intrasigmoidal pressure are chosen to study the interaction of gastrin and secretin in physiological and pathological states.

Methods LES pressure : Three water-filled polyvinyl catheters of 1.5 mminternal diameter with side openings of 1.5 mmdiameter at the tips, were used to transmit intraluminal pressures to external transducers. Aspiration of gastric content and gastric infusion were done through a catheter. Studies were performed in patients with regurgitation esophagitis or hiatal hernia in addition to healthy subjects under fluoroscopic control. Intragastric pressure : Arubber balloon attached to two catheters was positioned in the pyloric antrum under fluoroscopic control and inflated with 50ml of the air. Studies were performed in patients with open gastric or duodenal ulcer beside healthy controls. Results were expressed by motility index. Intrasigmoidal pressure : A rubber balloon was positioned about 25 cm above the anus under romanoscopic control and inflated with 60ml of the air. Patients with habitual constipation or diarrhea were studied and compared with healthy controls. Results were expressed by motility index. In all experiments gastrin-like AOC-tetrapeptide and secretin preparation* were administered intravenously in about 2 minutes. * Supplied by Eisai Co. Ltd., Tokyo, Japan. 22 ISHIKAWA AND ISHIiMORI Jap. J. Med. 1975

Results LES pressure: It was confirmed in healthy controls that gastrin-like AOC- tetrapeptide elevated LESpressure, while secretin lowered it. Dose response between LES pressure and AOC-tetrapeptide observed in healthy controls, was found reversed in a case of regurgitation esophagitis as in Fig. 1. However, a relatively well preserved sensitivity to metoclopramide was found in regurgitation esophagitis, that was interpreted as suggesting selective nature of disturbed LESmechanismto gastrin in this disease. On the contrary, secretin was found to lower LES pressure against not only AOC-tetrapeptide, but also metoclopramide. Intragastric pressure : It was confirmed in healthy controls that AOC-tetrapeptide elevated intragastic pressure, while secretin lowered it. Motorresponse of the stomach to AOC-tetrapeptide does not differ significantly in peptic ulcer from healthy controls, and further no significant difference exists between gastric and duodenal ulcer. As to secretin, however, some cases of gastric ulcer was found to respond to it only slightly and temporarily, while a good response was observed in duodenal ulcer without exception as shown in Fig. 2. Intrasigmoidal pressure: It was found that both gastrin and secretin elevated intrasigmoidal pressure in healthy controls. Motor response of sigmoid to AOC- tetrapeptide tended to decrease in the order of healthy controls, habitual constipation and habitual diarrhea, although the difference was not significant. Fig. 3 demon- strates that secretin caused a temporary elevation of intrasigmoidal pressure in patients of abnormal bowel habit like in healthy controls and this response was observed more markedly in patients with habitual diarrhea.

Control regurgitation esophagitis cmH2 O - 0.37/kg cmH2 O 15|-AOC-tetrapeptide I.V. -à" 0.37/kg à"-à"0.57/kg AOC-tetrapeptide I.V. à"-à" 0.57/kg

JU 10h 10

(n=3) a 5h CO CO w (n=3) "'20 1520 / (min) v (min) time \ -51- (n=3) Fig. 1. Influence of AOC-tetrapeptide upon the lower esophageal sphincter (LES) pressure. 10 \15, Vol. 14, No. 1 GASTROINTESTINAL HORMONES 23

P e p tic u lc er Healthy control

secretin lU/kg I.V. sec retin l U / k g I.V . g a stric u lc e r 151- Si 15 T3 T 3

10 ? 10

*~J ｧ _ " "^ 0 ¥ ¥¥ d u o d e n al u lce r 0 0 ! I X- ^- _. i>- *- _-- i-ｫ ~.

0 5 10 20 0 5 10 20 30' 40 50 60 30 40 50

(min) time (min) time Fig. 2. Influence of secretin upon the intragastric pressure.

Healthy control Patients

20] secretin lU/kg I.V. 20h secretin lU/kg I.V. i X

*§ 15(- -a lb

à"3loi Diarrhea "o

0! 20 30 10 10 20 30 40 50 60 40 50 60 (min) time (min) Fig. 3. Influence of secretin upon the intrasigmoidal pressure.

Discussion LES mechanism plays an important role in prevention of reflux of acid gastric juice into esophagus, which otherwise maycause peptic digestion of mucousmembrane there under certain conditions. In the present investigation, it was confirmed that the administration of AOC-tetragastrin elevates LES pressure, while secretin lowers it, supporting the view that LESmechanism is regulated humorallyly2). However, the finding that the dose response of LES pressure to AOC-tetrapeptide observed in healthy controls is reversed in patients with regurgitation esphagitis, suggests strongly that the disturbance of LES mechanism may involve a failure in the hormonal control of it in certain diseases as reported already35. However, in our patients of regurgita- 24 Ishikawa and Ishimori Jap. J. Med. 1975 tion esophagitis plasma gastrin levels were found to fluctuate within the normal range. Therefore, the disturbance of LES mechanism in regurgitation esophagitis is thought to be caused at the level of the sensitivity of LES function, but not at the level of gastrin metabolism as in achalasia3). Furthermore, the failure in LES function was shown to be selective or specific in its nature at least in regurgitation esophagitis, because the sensitivity of LES function to other chemical stimuli such as metoclopramide may be well preserved as observed in the present study. This finding seems to support the view that the conservative treatment with medical preparations such as metoclopramide could be used for the treatment of regurgitation esophagitis4)5). The present study demonstrated that secretin inhibits the elevation of LES pressure caused by not only AOC-tetrapeptide, but also metoclopramide, suggesting that secretin is not a simple antagonist to gastrin as far as LESmechanismis con- cerned. In this connection, it is interesting to note the report that gastrin elevates LES pressure through acetylcholin release from postganglionic nerve fibers. It has been reported7) that gastric motility is promoted in duodenal ulcer as compared with gastric ulcer. However, no significant difference was observed between them in the sensitivity of gastric motor function to AOC-tetrapeptide, although some difference was seen in response to secretin. This should be elucidated further, since it has been reported elsewhere that the secretin-like activity in duodenal mucosa is higher in duodenal ulcer than in gastric ulcer. It is possible that the disturbance in secretin mechanismis involved in the different motility of the stomach between gastric ulcer and duodenal ulcer. It is interesting to note that gastrin and secretin cooperate in the samedirection, namely in promotion of sigmoidal motility, which is quite reasonable. However, the comparison of motor response of sigmoid to these hormonesbetween healthy controls and patients with abnormal bowel habit suggests that the patho-physiological basis of the trouble could be sought also in other ways.

Summary Gastrin and secretin were found to antagonize in regulation of LESfunction and gastric motility, but to cooperate in regulation of sigmoidal motility. The hormonal regulation of these motor functions was found to be disturbed in regurgitation esophagitis, peptic ulcer and habitual constipation or diarrhea respective- ly. The disturbance in the sensitivity of these motor functions to G-I hormones is stressed to play an important pathophysiological role in these diseases.

References 1) Giles, G.R. et al.: Gut 10: 730 (1967). 2) Cohen, S. & Lipshutz, W.: J. Clin. Invest. 50: 449 (1971). Vol. 14, No. 1 GASTROINTESTINAL HORMONES 25

Cohen, S. et al.: J. Clin. Invest. 50: 1241 (1971). Stanciu, C. & Bennett, J.R.: Gut 14: 275 (1973). Dilawari, J.B. & Misiewicz, J.J.: Gut 14: 380 (1973). Lipshutz, W. et al.: Gastroenterology 61 : 454 (1971). Dragstedt, L.R.: Rev. Internat. Hepat. 16: 615 (1966). Ishimori, A. & Takebe, T.: Jap. J. Gastroenterology 71 : 371 (1974) (Jap.)