Actions of Motilin on Gastrointestinal Motility and Plasma Immu.Noreactive Motilin Concentration in Interdigestive and Postprandial States WILLIAM Y

Endocrinol. Japon. 1980, S. R. No. 1, 173-177

Actions of Motilin on Gastrointestinal Motility and Plasma Immu.noreactive Motilin Concentration in Interdigestive and Postprandial States WILLIAM Y. CHEY AND K. Y. LEE The Isaac Gordon Center for Digestive Diseases and Nutrition Department of Medicine, The Genesee Hospital and University of Rochester, School of Medicine an Dentistry, Rochester, New York 14607

Synopsis

Among biological actions of motilin on gastrointestinal motility, its action to induce phase III, activity front, of interdigestive myoelectric complex (IMC) appears to be of physiological significance. Synthetic motilin in a dose as little as 0.06ƒÊg/kg-h was shown to induce phase III in dog. A cyclic increase in fasting plasma immunoreactive motilin concentration (PIMC) occurred in phase III in dog and in a later

part of phase II in man, suggesting strongly that there is an intimate relationship between cyclic increase in fasting PIMC and IMC. The observation also suggested that gastric acid secretion increases in phase II and phase III of IMC. The cyclic increase in the acid secretion may be related to a coincidental cyclic increase in PIMC. Ingestion of a meat meal results in a significant decrease in PIMC and abolishes the cyclic increase in PIMC, while IMC changes to digestive pattern after a meal. The significant decrease in PIMC is not attributed to the 3 known gut hormones including gastrin, octapeptide of CCK and secretin.

When motilin, a 22amino acid polype- contraction of the canine stomach (Brown ptide, was originally discovered and isolated et al., 1971; Jennewein et al., 1975 ; Lee from the hog duodenal mucosa by Brown et al., 1974), lower esophageal sphincter et al. in 1971, this hormone candidate was (Jennewein et al., 1975 ; Gutierrez et al., considered as an exciting agent that stimu- 1977, Meissner et al., 1976), and small lates the contraction of gastric fundus in intestine (Jennewein et al., 1975 ; Lee et al., dog. As synthetic porcine motilin or its 1974). Motilin was also shown to increase analogues had become available, its bio- the number of spike potentials of myoele- logical actions on the gastrointestinal tract ctric activity in the canine antrum and small were investigated by various groups of intestine (Castresana et al., 1978 ; Wingate workers. Among the known biological et al., 1976). Among known gut hormones actions of motilin or its analogue, its effect that stimulate motility such as motilin, on the motility of gastrointestinal tract has cholecystokinin and pentagastrin, motilin, been investigated extensively in recent appeared to be the most potent one in terms years. of producing spike potentials in the canine antrum and duodenum (Fig 1) (Casteresana Action of motilin on gastrointestinal et al., 1978). In these studies, the dosage motility. of motilin employed now turns out to be a Motilin, given intravenously, stimulates pharmacological one. Another significant Presented at Symposium on VIP, Motilin, and Glu- observation has been that motilin (Itoh et cagon, Otsuka Hieisanso, Japan, July 21-22, 1979. al., 1976; Lee et al., 1978) or 13-norleucine- Endocrinol. Japon. 174 CHEY AND LEE December 1980

Fig. 1. Trends for mean percent incidence of spike potentials following i.v. injection of synthetic porcine motilin and CCK-OP (from Castresana et al., Digestion 17, 300, 1978).

Fig. 3. Mean PIMC in each phase of IMC in 6 dogs (from Lee et al., Am. J. Dig. Dis. 23, 789, 1978).

(Lee et al., 1978) produced the plasma levels of immunoreactive motlin comparable to that observed in phase III of interdigestive myoelectric activity. Thus, this action of motilin on interdigestive myoelectric activity is probably a physiological one.

Plasma immunoreactive motilin concentrations, myoelectric activity and gastric Fig. 2. Plasma immunoreactive motilin concentra- secretion of acid in interdigestive state. tions (PIMC) and % spike potentials on slow waves of the duodenum in a dog during intra- Using the immunoassay method (Bloom venous infusion of saline and synthetic porcine et al., 1976; Itoh et al., 1978 ; Tai and motilin in a dose of 0.06ƒÊg/kg-h. Hatched bars Chey, 1978), the plasma level of motilin has represent phase III of interdigestive myoelectric been measured and the relationship between complex (IMC) during control period. A cyclic increase in PIMC (dotted line) coincided with phase the plasma levels of motilin and the proxi- III (hatched bar). Solid bars represent phase III mal duodenal motility has been investigated. during the experiment with i.v. infusion of motilin. In the Fall of 1976, while we were investi- Phase III (the right solid bar) was induced as PIMC increased to reach plateau level (solid line) gating a possible relationship between

(from Lee et al., Am. J. Dig. Dis. 23, 789, 1978). plasma gastrin levels and phasic activities of interdigestive myoelectric complex, the motilin level revealed a cyclic increase and motilin (Wingate et al., 1976), induces phase the peak concentration was observed in III activity, activity front, in interdigestive phase III of the proximal duodenal my- state in dog. Indeed, a synthetic porcine oelectric activity in dog (Lee et al., 1978) motilin in a dose of 0.06 or 0.125ƒÊg/kg- (Fig 3). A similar observation was made hr was able to induce phase III activity in by Itoh et al (Itoh et al., 1978). The dog (Fig 2). The dosage of motilin employed cyclic increase occurred regardless of the S. R. No. 1 PLASMA MOTILIN AND MOTILITY 175

Fig. 4. Cyclicincreases in PIMC and IMC in a dog. In this and following figures, the hatched section represents % spike potentials on slow waves and solid bars represent phase III of IMC. Cyclic increasesin PIMC occurred whether main gastric cannula was open or closed.

presence or absence of acid in the stom- Fig. 5. Fasting gastric secretion of acid in a dog ach (Fig 4) (Lee et al., 1978). Since our in relation to phasic activity of IMC. Gastric original reports (Chey et al., 1878 ; Lee et secretion increased during phase II and III of IMC. al., 1978), we have confirmed the identical observation in 15 additional dogs. Recently, it has been shown that a similar cyclic increase occurs in man also (Vantrappen et al., 1979 ; You and Chey, 1979). However, in the latter species, the motilin level peaked toward the end of phase II rather than phase III as occurred in dog. The mechanism of the cyclic increase in the motilin level in interdigestive state is not known Fig. 6. Effect of i.v. atropine on PIMC and IMC at present time. in a dog (from Chey et al, Gut Hormones,edited In addition to the changes in the motilin by S. R. Bloom, Churchill Livingston, p.355, level in interdigestive state, we have ob- 1978). served a cyclic increase in gastric acid secretion which occurs in phase II and fluenced by the cholinergic nerve in inter- and phase III of interdigestive myoelectric digestive state. The mechanism of the complex (Fig 5). The rise in acid secretion cholinergic influence on the cyclic increase paralleled with the increase in the motilin in the motilin concentration will require level (Fig 3,4,5). further investigation. In view of our observations in dogs (Fig 6) (Chey et al., 1978) as well as in Effects of a meat meal and gut hormones man (You and Chey, 1979) that atropine on plasma motilin concentrations and abolishes the cyclic increase of plasma myoelectric activity of the duodenum. motilin level, the release of endogenous When the dogs were fed with a meat motilin appears to be significiantly in- meal, the interdigestive myoelectric activity Endocrinol. Japon. 176 CHEY AND LEE December 1980

action that induces phase III, activity front, of interdigestive myoelectric activity in dog appears to be of a physiological significance. Synthetic porcine motilin in a dose that occurs in phase III of interdigestive myoelectric complex was able to produce phase Fig. 7. Effect of a meat meal on PIMC and IMC III in dog (Lee et al., 1978). in a dog. Open circlesrepresent PIMC. The cyclic increase in the fasting plasma motilin concentration occurs both in dog and man. The motilin concentration rea- changes to digestive pattern that shows a ches the peak in phase III in dog and in uniform spike activity. Paralleled with the the later part of phase II in man (Vantrap- change in myoelectric activity, the plasma pen et al., 1979; You and Chey, 1979). In motilin concentration showed a steady and both species, atropine given intravenously significant decrease, thereby, the cyclic in- can abolish both cyclic increase in the crease was no longer present (Fig 7). The motilin levels and interdigestive myoelectric identical observation was made in 3 dogs activity. Based on these observations, 4(Lee et al ., 1980). In order to determine motilin again does appear to play a signi- a possible effect of three well known gut ficant role on the development of inter- hormones on the cyclic increase in the digestive myoelectric activity. The me- plasma motilin level and interdigestive chanism of action of motilin in this respect myoelectric activity, synthetic human gas- has not been clarified. An additional inter- trin I (G-17), GIH secretin and octapeptide esting observation has been that a cyclic in- Apfcholecystokinin (CCK-OP) were admini- crease in acid secretion occurs in dog also. stered individually and a combination of the Gastric acid secretion occurs as phase II three. While both gastrin and CCK-OP begins and gradually increase to reach the converted interdigestive pattern of myoele- peak in phase M. Whether or not this ctric activity to its digestive pattern, the increase in the acid secretion is induced by cyclic increase in the plasma motilin con- a steady rise in motilin concentration re- centration did not change. Secretin affected mained to be investigated. neither the cyclic increase of motilin nor It is of interest to note that after in- interdigestive myoelectric activity. The gestion of a meal, cyclic increase in the combination of 3 hormones also failed to fasting motilin level was abolished and abolish the cyclic increase of motilin. interdigestive myoelectric activity was con- Thus, none of these hormones that increase verted to digestive pattern of myoelectric in the plasma after ingestion of a meal is activity so that phase III, activity front, was Tesponsible for the decrease in the plasma abolished. The postprandial change in the motilin levels during the postprandial period, plasma motilin levels, however, were not Bamely the abolishment of cyclic increase attributed to the three gut hormones that in the interdigestive motilin level. increase after a meal. Two of the three, gastrin and CCK-OP, could convert interdigestive myoelectric activity to digestive Comment pattern. Thus, dissociation between cyclic increase in the fasting plasma motilin and Although motilin or its biologically phase III, activity front, of interdigestive active analogues were shown to stimulate myoelectric activity can occur. This dis- motility of the gastrointestinal tract, its sociation cannot be explained adequately at S. R. No. 1 PLASMA MOTILIN AND MOTILITY 177 this time. The observation suggests, howe- Brown, M. C., V. Mutt and J. R. Dryburgh (1971). Can. J. Physiol. Pharmacol. 49, 399. ver, that the cyclic increase is not likely to Castresana, M., K. Y. Lee, W. Y. Chey and H. occur as a result of phase III or phase III- Yajima (1978). Digestion 17, 300. like myoelectric activity. Chey, W. Y., K. Y. Lee and H. H. Tai. In Gut Hor- Because of the cyclic increase in the mones (edited by S. R. Bloom), Churchill Living- ston, Edinburgh, London and New York, p.355 fasting plasma motilin concentrations, it is (1978). expected to have significant variations in the Gutierrez, J. G., K. D. Thanik, W. Y. Chey and plasma motilin levels depending on the H. Yajima (1977). Am. J. Dig. Dis. 22, 402. time of blood sampling in the same dog or Itoh, Z., R. Honda, K. Hiwatashi, S. Takeuchi, I. Aizawa, R. Takayanagi and E. F. Couch (1976). subject. Thus, one requires caution in Scand. J. Gastroent. 11 (Suppl. 39), 93. interpreting the experimental data dealing Itoh, Z., S. Takeuchi, I. Aizawa, K. Mori, T. Tami- with plasma motilin concentrations unless nato, Y. Seino, H. Imura and N. Yanaihara (1978). the experiment is designed to avoid this Am. J. Dig. Dis. 23, 929. Jennewein, H. M., H. Hummelt, R. Siewert and F. variation. Waldeck (1975). Digestion 13, 246. Little is known about the release of Lee, K. Y., W. Y. Chey H. H. Tai and H. Yajima endogenous motilin at this time. In dog, (1978). Am. J. Dig. Dis. 23, 789. motilin is not released in a significant Lee, K. Y., J. Hendricks and W. Y. Chey (1974). Gastroenterology 66, 246. amount by a meat-containing meal or Lee, K. Y., M. S. Kim and W. Y. Chey (1980). hydrochloric acid in a physiological amount. Am. J. Physiol 238, G280. Nor did we observe any effect of fat on the Meissner, A. J., K. L. Bowes, R. Zwich and E. E. release of motilin, while a fat meal ap- Daniel (1976). Gut 17, 925. Mitznegg P., S. R. Bloom, N. Christofides, H. Bester- pears to increase plasma concentration of man, W. Domschke, S. Domschke, E. Wunsch motilin in man (Mitznegg et al., 1976). and L. Demling (1976). Scand. J. Gastroent. 11 Undoubtedly, research will continue to (Suppl. 39), 53. Tai, H. H. and W. Y. Chey (1978). Anal. Biochem. uncover factors that stimulate endogenous 87, 350. motilin release for years to come. Vantrappen, G., J. Janssens, T. L. Peeters, S. R. Bloom, N. D. Christofides and J. Hellemans (1979). Dig. Dis. and Sci. 24, 497. Wingate, D. L., H. Ruppin, W. E. R. Green, H. H. References Thompson, W. Domscke, E. Wunsch, L. Demling and H. D. Ritchie (1976). Scand. J. Gastroent. 11 (Suppl. 39), 111. Bloom, S. R., P. Mitzneggand M. G. Bryant (1976). You, C. H. and W. Y. Chey (1979). Clin. Res. 27, Scand. J. Gastroent.11 (Suppl. 39), 47. (In press).