Motilin and Clinical Application

Peptides, Vol. 18, No. 4, pp. 593–608, 1997 Copyright q 1997 Elsevier Science Inc. Printed in the USA. All rights reserved 0196-9781/97 $17.00 / .00

PII S0196-9781(96)00333-6

REVIEW

Motilin and Clinical Application ZEN ITOH Gastrointestinal Research Laboratory, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi 371, Japan Received 20 September 1996; Accepted 11 December 1996 ITOH, Z. Motilin and clinical application. PEPTIDES 18(4) 593–608, 1997.—Motilin is a regulatory polypeptide of 22 amino acid residues and originates in motilin cells scattered in the duodenal epithelium of most mammals and chickens. Motilin is released into the general circulation at about 100-min intervals during the interdigestive state and is the most important factor in controlling the interdigestive migrating contractions. Recent studies have revealed that motilin stimulates endogenous release of the endocrine pancreas. Clinical application of motilin as a prokinetic has become possible since erythromycin and its derivatives were proved to be nonpeptide motilin agonists. q 1997 Elsevier Science Inc. Acidification of the stomach Autoradiography Brain motilin Cholinergic neuron Duodenal alkalinization Gastric emptying Insulin Duodenal ulcer Endocrine cells of the gut Erythromycin 5-HT 3 receptor Interdigestive migrating contractions Motilides Pancreatic polypeptide Receptor binding Serotonin neuron Vagus nerve

DISCOVERY OF MOTILIN

from a side fraction produced during the purification of secretin by Mutt and Jorpes, and named it motilin (18,20). In 1973, Brown et al. announced the complete amino acid sequence of motilin, a 22-amino acid residue polypeptide with a molecular weight of 2700, as shown in Fig. 2 (17). The amino acid sequence shown in this Fig. 2 is the corrected sequence that was announced in 1974 (194). Following the preliminary report on the structure of porcine motilin, Wu¨nsch et al. of the Max– Planck Institute synthesized [Nlu13-Glu14 ]motilin, and demonstrated in vitro motor-stimulating activity identical to that of natural motilin (231). The chemical structure of motilin has now been elucidated in other species including the dog (173), rabbit (6), cat (45), and chicken (42), as shown in Fig. 2.

IT was already known in the early 1960s that duodenal acidification inhibits gastric acid secretory and motor activity in the dog and man, but John C. Brown of Canada studied the effect of duodenal alkalinization on gastric function. Brown et al. (19) constructed a Heidenhain pouch in the body of the dog stomach, and completely denervated it extrinsically by anastomosing the splenic artery and vein with the renal artery and vein after the left kidney was removed. Motility of the pouch was recorded by connecting a cannula attached to the pouch to a low pressure Statham transducer, and a continuous pH recording in the duodenum was made by inserting a pH electrode into the duodenum through the Mann–Ballman fistula. Then they found that the introduction of 30 ml of Tris buffer, pH 9.0, and fresh pig pancreatic juice, pH 7.2, was almost immediately followed by increased activity in the pouch, as shown in Fig. 1. Two mechanisms of action were postulated for the alkaline buffer effect on the duodenum: inhibition of the release of an inhibitory substance from the duodenal mucosa or release of a humoral stimulating agent. Brown subsequently examined duodenal extracts for their gastric motor-stimulating properties. These were secretin prepared by Boots Pure Drug Company, and Cecekin (cholecystokinin) by Vitrum and pancreozymin by Boots, and found that the pancreozymin of Boots has a powerful fundic pouch motor-stimulating activity (16,21). The fact that motor activity in the extrinsically denervated pouch is stimulated by the duodenal alkalinization and IV administration of Boots pancreozymin prompted Brown and his group to separate the humoral stimulating agent from the duodenal mucosa, and they collaborated with V. Mutt of Karolinska Institute, and successfully separated a distinct polypeptide

Existence of Motilin Soon after motilin became available, Pearse et al. (159), by utilizing the antiserum to motilin in their immunohistochemical study, demonstrated in 1974 that the enterochromaffin cells of the mammalian small intestine contain the 22-amino acid peptide motilin, which was known to be responsible for the production of 5-hydroxytryptamine. But conflicting results were reported thereafter concerning the immunolocalization of motilin in endocrine cells of the upper small intestine—both argentaffin (EC) and nonargentaffin cells (37,61,78,79,176,177,199). Kishimoto et al. (109) of Hammersmith Hospital showed in 1981 that the motilin cells in canine and human duodenal mucosa correspond to a sub-class of argyrophil nonargentaffin cells by using both C- and N-terminal reacting antibodies. It is now agreed that the motilin cell is characterized by relatively small (180 nm in man, 200 nm in the dog), solid granules with a homogeneous core and 593

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FIG. 2. Amino acid sequence of motilin in various species of mammals and chicken. Human motilin is identical with porcine motilin.

recent autoradiographic demonstration of motilin receptors in the rabbit cerebellium by the Peeters’ group (43), the physiological role has not been elucidated. FIG. 1. Effect of duodenal alkalinization on intrapouch pressure in the completely extrinsically denervated fundic pouch in conscious dogs. The recordings show three sets of changes in duodenal pH and intrapouch pressure. ‘‘B’’ indicates intraduodenal instillation of 30 ml alkaline buffer solution, and ‘‘P’’ denotes intraduodenal administration of 30 ml pancreatic juice. In response to duodenal alkalinization by these procedures, intrapouch pressure was increased (19).

closely applied membrane, round in man, and round to irregularly shaped in the dog (222). Argentaffin EC cells, originally found to react with some anti-motilin sera (78,176), were reported to fail to react with either of the two antisera employed by Usellini et al. in 1984 (222), and the reactivity of motilin cell granules with Grimelius’ silver fits well with the argyrophilia found in motilin-immunoreactive cells during light microscopy studies by Kishimoto et al. (109). These findings strongly suggest that it is important to identify the characteristic of the antiserum before we draw a conclusion. Recently, Kobayashi (110,111) clearly demonstrated the difference between motilin and EC cells, as shown in Fig. 3. It is now concluded that motilin-immunoreactivity has been localized in a specific open type of endocrine cell scattered in the epithelium of the upper small intestine. Some studies (63,175) report the existence of motilin immunoreactivity in nerve tissues in the muscle layers, but these observations have not been confirmed. Recent studies have demonstrated the existence of motilin cells by immunocytochemistry and/or motilin immunoreactivity in the upper small intestine of the monkey (23,238) dog (175,238), cat (45), rat (184,226) and rabbit (6,188). The existence of motilin in the brain or in nerve tissues has been strongly debated. Most extensive studies were done by Beinfeld and her group, and it was reported by O’Donohue et al. in 1981 (151) that motilin immunoreactivity was found in the rat cerebellum in concentrations comparable with those found in the intestine. Chan–Pelay et al. (30) and Nilaver et al. (150) reported the presence of motilin immunofluorescence cells detectable in cerebellum Purkinje cells. Fratta et al. (65) reported that most Purkinje cells in the cerebellum exhibited motilin-positive immunofluorescence in cell bodies, dendrites and axons, whereas Korckat et al. (116) showed that motilin immunoreactivity was detectable in the cell nucleus, not in the synaptosomes in the rat brain. Poitras et al. (175) described a small amount of motilin-like immunoreactivity in dog brain eluted predominantly with the void volume on gel chromatography. According to recent studies in northern hybridization analysis with cDNA probes for motilin by Bond et al. (10) and Daikh et al. (41), there is no detectable mRNA in the brain of various species of animals, and therefore the existence of motilin in the mammalian brain is now very doubtful (149). Although there are reports indicating the action of motilin in the brain (54,68,153,165,166,182), and a

Action of Motilin in the Gastrointestinal Tract Because motilin was first synthesized in Germany (230,231), the initial studies on the biological activity of motilin were carried out very activity mainly by the Demling’s group in Erlangen, and it is not too much to say that most of the in vitro biological activity of motilin that we know of today was clarified by them; that is, the in vitro activity of motilin can be demonstrated only in the human and rabbit stomach and duodenum (52,202,203), and the action on smooth muscle is direct and calcium dependent (52,203). These findings have been confirmed by others (2,46,130,170,196). Nevertheless, as demonstrated by our studies and others thereafter in conscious dogs and human subjects, the recognition of motilin as an indispensable humoral agent to induce premature phase III contractions in the stomach during the interdigestive state is more important than the in vitro studies

FIG. 3. Difference between motilin cell and enterochromaffin (EC) cell in the human duodenum. (A) Immunofluorescence cytochemistry was performed on the Bouin-fixed and paraffin-embedded section. The motilin cell (large arrow) is strongly fluorescent, whereas EC cells (small arrows) are weakly fluorescent. (B) After fixation in glutaraldehyde, the sections were silver-impregnated by the Masson–Hamperl’s method. All the EC cells shows an argentaffin reaction, but the motilin cell is nonargentaffin (110).

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MOTILIN for gastrointestinal physiology, and the essential role of motilin could not be elucidated by in vitro studies alone. Changes in contractile activity before and after feeding are quite different, as seen in Fig. 4, and it is important to know that motilin is active in the period before feeding, namely, during the interdigestive state. Since 1973 in Japan, Yajima et al. and Yanaihara et al. have worked on the chemical synthesis of various kinds of gut hormones including motilin, vasoactive intestinal polypeptide, and gastric inhibitory polypeptide in addition to the three classical gut hormones, gastrin, secretin, and cholecystokinin. Yajima et al. (233) succeeded in synthesizing the whole molecule of porcine motilin, the chemical structure of which was revised in 1974, and we collaborated with his group in the bioassay of their synthesized materials. We then discovered that IV administration of synthetic porcine motilin in conscious dogs induces a series of strong contractions in the fasted canine stomach that are quite similar to the spontaneously occurring phase II and III contractions in the stomach (89,92). Figure 5 shows that the 20-min IV infusion of synthetic motilin at a dose of 0.3 mg/kg/h induces phase III-like contractions in the stomach, and the motilininduced contractions migrate along the small intestine in a caudad direction toward the terminal ileum. Similar findings were soon reported by Wingate et al. ( 228,229 ) . We soon found that contractile activity in the lower esophageal sphincter ( 90 ) , the sphincter of Oddi ( 83 ) , and the gallbladder ( 97 ) is closely associated with phase II and III activity in the stomach, and these associated activities are reproducible by an IV administration of exogenous motilin in doses of 0.1 – 0.3 mg / kg / h ( 82,87,91,97,211,212 ) . In addition to these findings on motor activity of the gastrointestinal tract, secretion of digestive enzymes in the stomach ( 113,114,146 ) and pancreas (98,107,114,115,124,225) was found to be associated with phase III activity in the stomach and under the control of the plasma motilin concentration in the dog and man. Most of these findings have all been obtained in dog experiments in vivo, but it must be mentioned that, strangely, motilin does not stimulate any contraction in in vitro preparations of dog stomach and small intestine (170,196,203). Nevertheless, because motilin stimulates contraction in the isolated dog stomach, which is completely denervated extrinsically and perfused through the celiac artery (138), motilin receptors must be present somewhere in the stomach, but the existence of motilin receptors has never been demonstrated by means of a binding study and autoradiography, and smooth muscle strips of dog stomach do not react to motilin in vitro as mentioned above. The existence of motilin receptors in the stomach is evident from the original work by Brown (19), which showed that duodenal alkalinization stimulated contractile

FIG. 4. Eight-hour changes in contractile activity in the gastric antrum and the small intestine before and after feeding in a conscious dog. Note completely different contractile patterns before and after feeding (86).

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FIG. 5. Effect of synthetic motilin on gastrointestinal contractile activity in a conscious dog. Intravenous infusion of synthetic motilin at a dose of 0.3 mg/kg/h for 20 min induced a band of strong contractions in the stomach, which migrated in the caudad direction along the small intestine. The motilin-induced contractile response is quite similar to that in the spontaneously occurring migrating contractions in the interdigestive state. Contractile activity was measured by means of chronically implanted force transducers (86).

activity in the autotransplanted fundic pouch of the stomach in the dog, and the same mechanism has been reported in studies on the gastric pouch (99,147,191,215–217,223). The Release of Motilin While most of the gastrointestinal hormones are released in response to the ingestion of a meal, motilin has the following specific characteristics: it is released at about 100-min intervals during the interdigestive state when no nutrient is present, at least in the duodenum and the upper jejunum, and moreover the release of motilin is inhibited by feeding in the dog (34,100,174) and man (1,9,84,180,242). It is reported, however, that when the meal is synchronized with phase III, a transient increase in motilin is documented in man (9). As shown in Figure 6, the plasma motilin concentration repeats its fluctuation at about 100 min intervals in the fasted state, and each peak coincides with the end of phase III contractions in the stomach. When Brown et al. (19) reported their initial studies on motilin, they demonstrated that alkalinization of the dog duodenum induced a contractile response in the completely extrinsically denervated fundic pouch, and this evidence encouraged them to start the separation and purification of motilin from the duodenal mucosa. But Bloom’s group reported a study in which the release of motilin in man was not brought about by duodenal alkalinization but by acidification (136,137). This controversy resulted in confusion as to the mechanism of motilin release, particularly in terms of pH change. Our data on the dog (88,235,236) and man (117), however, clearly indicate that changes in pH in the duodenum do not substantially influence the endogenous release of motilin if the pH range remains between 2.0 and 8.5 as shown in Fig. 7 in a dog and Fig. 8 in a patient with a duodenal ulcer (117). It is clear that the presence of nutrient in the duodenum strongly suppresses the endogenous release of motilin (141). What is more important in this connection is that the stimulation of endogenous release of motilin and the occurrence of phase III contractions in the stomach are different issues: as shown in Fig. 8, no phase III contractions were induced with the high plasma concentration of motilin. The observation of occurrence of phase III in the stom-

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FIG. 6. Relation between the plasma motilin concentration and gastrointestinal contractile activity in a conscious dog. During the interdigestive state, the plasma motilin concentration fluctuates at about 100-min intervals and each peak of the motilin concentration coincides with the end of a band of strong contractions (phase III activity) in the gastric antrum (95).

ach is therefore not always a good index of endogenous release of motilin. Details of the mechanisms of motilin release are still a mystery, but fragments of evidence have been revealed little by little. It has been found that atropine or hexamethonium blocks a cyclic increase in the plasma motilin concentration (34,123,242), and electrical stimulation of the cervical vagi in anesthetized dogs results in a significant increase in the plasma motilin concentration (62,119,123), which can be inhibited by atropine or hexamethonium (123). On the other hand, carbachol-induced motilin release is blocked by atropine but not by hexamethonium (62). These findings (62,66,123) indicate that the muscarinic receptors are presumably located in a nonneural structure, perhaps in the motilin cell, and Poitras et al. (169) demonstrated the existence of muscarinic receptors in motilin cells. More recently we found that muscarinic3 receptors are responsible for motilin release from canine motilin cells in the perifusion system, and this has been verified in conscious dogs (183,234). Participation of vagal control in the release of motilin has been controversial, but because chronic truncal vagotomy failed to affect motilin release (35,125,171,241), the release of motilin is likely to be controlled by nonvagal cholinergic innervation. This is further supported by an acute experiment showing that the spontaneous fluctuations in the plasma motilin concentration were not influenced by vagosympathetic nerve blockade by cooling (75). The controversial factor in motilin release is that the release of motilin and contraction of smooth muscle are both controlled by muscarinic receptors. We consider that mechanisms necessary for motilin release are independent of the vagal innervation, and present in the duodenum, in which unknown changes (probably changes in intraluminal pressure or motility) occurring at 100-min intervals are transmitted to motilin cells through muscarinic3 receptors; in other words, motilin cells are innervated by local or intramural cholinergic neurons independently of the central vagal activity. As to the periodic release of motilin, we consider it to occur as follows (102). Even during the interdigestive state, the basal secretion continues without stopping in the stomach, duodenum, and pancreas etc., and though the volume is small, it becomes a fairly large amount with time. If the gastrointestinal tract does not move at all during the interdigestive state, it is overflowed with the basal secretion accumulated in the lumen of the gastrointestinal tract. But, in reality, a band of strong contractions

FIG. 7. Effect of duodenal acidification on motilin release and contractile activity in the stomach and duodenum in conscious dogs. Intraduodenal acidification with pH 2.0 did not interfere with motilin release or the occurrence of phase III in the stomach. And at pH 1.0, endogenous release of motilin was inhibited, and accordingly phase III contractions were not induced in the stomach.

(phase III) occurs in the stomach at about 100-min intervals and migrates along the small intestine to sweep the accumulated intraluminal contents into the large intestine. The accumulation of the basal secretion seems to be perceived by the enteric nervous system, which then stimulates motilin cells through muscarinic

FIG. 8. Changes in the plasma motilin concentration, pH, and contractile activity in the stomach and duodenum of a 41-year-old male patient with a duodenal ulcer. These 5-h changes were obtained after the patient was fasted for more than 8 h, but no phase III activity was observed in the stomach although the plasma motilin concentration was increased. After an IV bolus injection of famotidine (histamine2 receptor antagonist), typical phase III activity was induced in the stomach and migrated to the duodenum with the return of intragastric and duodenal pH to neutral (117).

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MOTILIN receptors on motilin cells because the initiation of motilin release always coincides with the start of phase II activity in the duodenum (unpublished data). Because the rate of basal secretion during phase I is constant, the time until the basal secretion reaches a certain volume or intraluminal pressure must be constant, and accordingly motilin is released at constant intervals. The plasma motilin concentration reaches its peak and then starts to decrease, but what inhibits motilin release is unknown. The inhibitory mechanism due to nutrients in the duodenum has also not yet been elucidated (36,122,141,191,241). It may not be so simple as direct inhibition through the microvilli of motilin cells, but it may be mediated to motilin cells through neurons after nutrients are absorbed (140,141). Mechanism of Action There is no doubt that peaks of the plasma motilin concentration coincide with the end of phase III contractions in the stomach (100,121) and IV administration of motilin induces phase IIIlike contractions in the lower esophageal sphincter (72,87), stomach, and duodenum in the dog (92,101,211,228) and man (224). Evidence of this is further supported by the fact that neutralization of circulating motilin by giving an antiserum for motilin prevents spontaneous occurrence of phase III activity in the stomach (120,152,168). It is also accepted that spontaneously occurring and motilin-induced phase III contractions in the stomach are completely abolished by pretreatment with atropine and hexamethonium in the dog (55,156,187), and therefore it is concluded that the final mediator of the action of motilin must be acetylcholine in the smooth muscle of the stomach. The question then arises, ‘‘At what site is the action of motilin transmitted to the cholinergic neurons?’’ Motilin is produced in motilin cells, which are scattered in the absorptive epithelial cells covering the villi of the duodenum and upper jejunum with their apical portion covered with microvilli exposed to the lumen and with their basal portion facing blood and lymph capillaries, nerve endings, and muscle fibers, etc., in the villi (111). Motilin as a gastrointestinal hormone has been considered to be released into the blood capillaries and to then enter the general circulation through the portal vein, reaching the stomach to stimulate contraction, but recent studies have revealed that the mechanism is not so simple. On the other hand, there have been quite similar findings on the action of cholecystokinin on gallbladder contractions and enzyme secretion in the pancreas. CCK-induced gallbladder contractions are inhibited by atropine (212), and recent studies suggest that the action of CCK is transmitted to cholinergic neurons through CCK-A receptors on the afferent vagus (127,128,158). There is no evidence to indicate that the action of motilin is also transmitted to the afferent vagal nerve, but it is very important to determine the site(s) where the action of motilin is transmitted to the cholinergic neurons. The other findings supporting the importance of the vagal nerve in the action of motilin are in the report by Miolan and Roman (135), in which the electrical activity of the vagal efferents to the stomach was indirectly measured in conscious dogs, and they found that the discharge frequency of the efferents fluctuated with the various phases of the migrating myoelectric complexes occurring on the gastric antrum. But it is also known that motilin stimulates contractions in the vagally denervated pouch (99,216) and in the stomach after chronic truncal vagotomy in the dog, but the motilin-induced contractions in the vagotomized stomach are quite different from spontaneously occurring phase III in the contractile pattern. These findings indicate that there are motilin receptors within the wall of the stomach. In fact, the existence of motilin receptors in the dog

597 stomach was confirmed in the isolated perfused stomach (40,69,138): the stomach was completely isolated from all attachments, the celiac artery was perfused with a nutrient solution containing oxygenated human erythrocytes, and then it was found that motilin stimulated strong phasic contractions in the stomach (138). It is now concluded that at least in dogs there are two pathways through which the action of motilin is mediated to the smooth muscle of the stomach: one through the vagus nerve (central, or vagal dependent) and the other through the intramural nervous system in the stomach (peripheral, or vagal independent). At present the best way to prove the existence of a receptor is a direct demonstration of the receptor in various ways or in binding studies of a ligand. In the case of motilin, nobody has successfully cloned or sequenced motilin receptors (163). As to studies on the binding of motilin, many studies have shown the existence of motilin receptors on the smooth muscle of the human (47,163,189) and rabbit (12,44,47,49,77,112,160,163) stomach, as shown in Fig. 9, but not in the dog stomach. Autoradiography in the human (189) and rabbit (185) stomach demonstrates an abundance of motilin receptors mainly in the circular muscle layer of the stomach, but no evidence has been obtained from the dog stomach even though most of the important findings in the physiology of motilin have been obtained in dog experiments. The technique applied to the binding assay for motilin in human and rabbit stomach in our laboratory (189) and others (163) is, however, not considered to be an ideal one because purification of the plasma membrane of the human gastric antrum, for instance, loses its motilin binding activity, and we have to use crude homogenates of smooth muscle tissues for binding studies. The more smooth muscle tissues are purified, the weaker becomes the motilin binding activity. A recent study describes the presence

FIG. 9. Autoradiographic distribution of binding sites of motilin in human gastric antrum. Sections were incubated with 10 010 M [ 125I]motilin for 60 min. b-Sensitive film was exposed for 7 days at 47C. (A) Brightfield photomicrograph showing a section of human gastric antrum stained with H&E. (B) Autoradiograph illustrating the distribution of motilin binding sites as detected by [ 125I]motilin. (C) Illustrations of [ 125I]motilin binding in the presence of 10 08 M EM574 in adjacent sections. (D, E) The labeling disappeared completely after the addition of 10 07 M EM574 and unlabeled motilin. Arrowheads indicate identical positions in each of the sections. S: serosa, SM: submucosa, C: circular muscle layer, L: longitudinal muscle layer. Bar Å 2 mm (189).

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of motilin receptors in nerve tissues isolated from the gastroduodenal tissues (172), but this has not been confirmed. In the rabbit cerebellum, as already mentioned, motilin receptors have been demonstrated by autoradiography (43). On the other hand, we have shown the importance of 5-hydroxytryptamine neurons in the stomach in the control of phase III contractions by motilin in the dog by inactivation of 5-hydroxytryptamine neurons by treatment with parachlorophenylalanine of conscious dogs (73,157) and with 5,6-dihydroxytryptamine in the isolated perfused dog stomach (73). Figure 10 shows that the destruction of 5-hydroxytryptamine neurons by pretreatment with 5,6-dihydroxytryptamine failed to stimulate contraction by motilin in an isolated perfused stomach (73). Complete elimination of the action of motilin with a 5-hydroxytryptamine3 receptor antagonist in conscious dogs (93,240) and the isolated perfused dog stomach (138) further supports our hypothesis that the 5-hydroxytryptamine neuron is indispensable for the manifestation of motilin in the stomach, but the exact site of 5-hydroxytryptamine3 receptors has not been identified. In human studies, on the other hand, the mechanism of inhibition by ondansetron is different from that in the dog; selective antagonism of 5-hydroxytryptamine3 receptors suppresses phase III in the stomach and simultaneously inhibits plasma motilin peaks, namely, the suppression of phase III in the stomach is achieved through the inhibition of endogenous release of motilin in man (227). Putting these findings altogether, we may conclude the mechanism of motilin’s action during the interdigestive state in the dog to be as follows. The schema of this mechanism of action is shown in Fig. 11. 1. Motilin released in the villi of the upper small intestine enters the capillaries on the one hand, and may possibly stimulate nerve terminals in the villi on the other. But the pathway to stimulate nerve terminals as reported in the case of CCK (8)

FIG. 11. A schematic presentation of the action of motilin. Motilin, released into the general circulation from motilin cells in the upper small intestine, seems to act at motilin receptors in 5-hydroxytryptamine neurons in the medulla, and is transmitted to the dorsal motor nucleus of the vagus through 5-HT 3 receptors in the cholinergic vagal efferents. A pathway to stimulate the dorsal motor nucleus of the vagus through the vagal afferents is not likely because exogenous motilin still stimulates typical phase III in the stomach after the duodenum and upper jejunum are completely removed.

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FIG. 10. Effect of 5,6-dihydroxytryptamine on motilin-induced contractions in in situ isolated perfused dog stomach. In (A) intra-arterial infusion of motilin (0.3 mg/kg/h) induced strong contractions in the gastric body and antrum, but after the stomach was perfused with 5,6-DHT for 30 min (B), the contraction-stimulating activity of motilin was completely eliminated, but the 5,6-DHT-treated stomach still reacted to bethanechol in a similar way to before 5,6-DHT (73).

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is not likely to be present because no motilin receptors have been documented in the vagus nerve or nodose ganglion, and the discharge of electrical activity obtained from afferent fibers recorded from the cervical vagus was not affected at all by motilin (unpublished observation). The very characteristic contractile pattern of phase III in the stomach is atropine sensitive and abolished by acute and chronic vagotomy. After truncal vagotomy, the stomach contracts in response to motilin, but the spontaneously occurring contractions and motilin-induced contractions after vagotomy are quite different from those before motilin, so that the final mediator of motilin should be acetylcholine through the vagus nerve. The problem is how the action of motilin is transmitted to the vagal cholinergic neurons. Intracerebroventricular administration of motilin in conscious dogs does not exert any effect on gastrointestinal contractile activity (76). Where then is the site(s) in which the action of motilin is mediated indirectly to the dorsal motor nucleus of the vagus or its vicinity? The area postrema, for instance, is very rich in fenestrated capillaries, and also supplied with numerous neurons including 5-hydroxytryptamine neurons in the perivascular spaces around the capillaries and linked to the dorsal vagal complex (126). These neurons are reported to be able to be excited by many neurotransmitters and peptides including 5-hydroxytryptamine, histamine, gastrin, substance P, VIP, CCK, and somatostatin (29). It is hypothesized that motilin may stimulate motilin receptors in 5-hydroxytryptamine neurons in the area postrema, and stimulation of 5-hydroxytryptamine neurons activates vagal

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efferents through 5-hydroxytryptamine3 receptors. So far, however, the existence of motilin receptors has not been demonstrated in the area postrema or its vicinity. 6. It is hard to consider that the phase III contractions are only controlled by motilin-induced, vagally mediated acetylcholine release in the stomach because local intra-arterial injection of acetylcholine does not mimic motilin. To express the characteristic phase III contractions, the local existence of motilin receptors in the enteric nervous system or in the smooth muscle in the stomach seems to modify acetylcholine-induced contractions. In the case of the dog, motilin receptors are likely to be present in the nervous system, but not in the smooth muscle of the stomach. This is evident from the original work on the autotransplanted fundic pouch by Brown et al. (19) and by our recent work on the isolated stomach (138). Other Actions of Motilin Beside the most well-known action of motilin in inducing phase III contractions in the stomach, it is generally accepted that motilin stimulates enzyme secretion in the stomach (114,146) and the pancreas (107,113,131), and gallbladder contractions (97,133,213) including the sphincter of Oddi (7,144,186,211). All these secretory and motor events are considered to be the common phenomena associated with the increased gastrointestinal activity, especially seen in the interdigestive state in the dog and man. Some investigators explain these cyclic increases in gastrointestinal activity as a series of mechanical and chemical cleanings (225) of the digestive tract—the gastrointestinal housekeeper (39,209). The above-mentioned activity is involved in the gastrointestinal function, but it is known that the plasma concentration of pancreatic polypeptide (PP) is closely related to that of motilin (24,33,74,103,195), but there are very few studies (171) on the effect of motilin on the endogenous release of PP, although it was reported that PP has nothing to do with the initiation of phase III activity in the stomach (103,218). Our recent studies clearly demonstrated that motilin stimulates endogenous release of islet hormones from the endocrine pancreas. It is now clear that both insulin (207) and PP fluctuate with motilin during the interdigestive state, and that IV injection of motilin stimulates dosedependent release of insulin (207) and PP (139) in fasted dogs. Figure 12 shows a dose-dependent increase in PP release in response to motilin in conscious dogs. The motilin-induced endogenous release of insulin and PP is completely abolished by pretreatment of the dog with atropine, hexamethonium, and a 5-hydroxytryptamine3 receptor antagonist, and by truncal vagotomy (139,207). Because there are no motilin receptors in the pancreas, the action of motilin is most likely to be mediated through vagal cholinergic muscarinic receptors including 5-hydroxytryptamine3 receptors. The periodic increase in the plasma motilin concentration during the interdigestive state is therefore considered not merely to induce phase III contractions in the stomach but should be understood to activate (warm up) the general function of the upper digestive organs, including the endocrine pancreas to avoid longterm quiescence of these functions. Motilin and Diseases of the Digestive Organs It is widely known that during the fasted state (generally at night) in healthy adults, the interdigestive migrating phase III contractions occur in the stomach at about 100-min intervals, and the cyclic contractile events are under the control of motilin in the blood (9,11,105,208,224,242). Clinical studies on these

FIG. 12. Effect of graded doses of motilin on endogenous release of pancreatic polypeptide (PP) in conscious dogs. In (A), a single bolus injection of motilin (0.1 mg/kg) significantly stimulated endogenous release of motilin, and in (B), the dose–response relationship between the peak and 15-min integrated values for the PP response. *p õ 0.05 vs. saline, **p õ 0.0 g vs. motilin 0.03 mg/kg (139).

changes in patients, however, impose a great burden on them, and it is therefore difficult to make these investigations serve as common clinical tests, and for this reason there are very few clinical studies on the role of motilin in diseases. In this respect, it is pertinent to refer to the study by Sekiguchi’s group on the duodenal ulcer (117,197). They took long-term simultaneous measurements of contractile activity in the gastroduodenal region and pH changes in the stomach and the duodenum and the plasma motilin concentration in patients with active duodenal ulcer. One of their results is shown in Fig. 8. They found that no phase III contractions occurred, even after the patient fasted for more than 8 h, in spite of the high plasma motilin concentrations. They gave a bolus injection of an H2 receptor antagonist IV and found that typical phase III activity was bought about with the return of the intraluminal pH of the stomach and duodenum to neutral about 30 min after the injection of the H2 receptor antagonist. These clinical findings suggest to us many important facts in the study of motilin as well as in the understanding of the pathogenesis of the duodenal ulcer. First of all, it was found that if the pH of the stomach is very low, phase III contractions are not induced even if the plasma motilin level is increased (117). Similar studies on the duodenal ulcer have been reported by Bortolotti et al. and

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FIG. 13. Comparison of acidification effect of gastric body and antrum on contractile response to exogenous motilin. In (A), when the gastric antrum was perfused with saline at pH 1.0, exogenous motilin did not induce contractions in a vagally innervated fundic pouch, gastric body and antrum, or the duodenum. But when the fundic pouch alone was acidified by perfusing it with saline at pH 1.0, which is seen as a quick decrease in intraluminal pH in the pouch, exogenous motilin induced typical phase III contractions in all parts of the stomach and duodenum (236).

others (13–15,71). In this respect, Yamamoto et al. (235–237) demonstrated in conscious dogs that acidification of the gastric antrum, but not the gastric body and fundus, below pH 2.0 inhibited the action of motilin through a long vago–vagal reflex in the dog, as shown in Fig. 13. In the clinical study shown in Fig. 8, it is most likely that the increase in the pH of the antrum toward neutral due to the cessation of acid secretion by the H2 receptor antagonist and gradual emptying of acidic gastric contents provided a favorable conditions for the stomach to react properly to the increased concentration of motilin. On the other hand, in the pathogenesis of the duodenal ulcer, the results of such studies strongly suggest that acidification of the gastric antrum during the night in duodenal ulcer prevents the regular occurrence of phase III in the stomach, and consequently, gastric contents of very low acidity cannot be emptied properly, but are simply mixed in the stomach by irregular phase II-like contractions as

FIG. 14. Effect of erythromycin on contractile activity in the gastrointestinal tract of a conscious dog. Intravenous continuous infusion of erythromycin (EM) at a dose of 100 mg/kg/h for 20 min induced a series of contractions that are quite similar to the spontaneously occurring interdigestive migrating contractions (94).

seen in Fig. 8. These conditions are closely related to complaints by duodenal ulcer patients of such symptoms as heartburn, nausea, and epigastric pain or unpleasant feelings when the stomach is empty. It is concluded that the cessation of gastric acid secretion at night effected by taking an H2 receptor antagonist before bed is also beneficial in alleviating symptoms in terms of gastrointestinal motility because the cyclic increase in the plasma level of motilin induces phase III contractions in the stomach that strongly empty and clean the stomach. Discovery and Clinical Application of Nonpeptide Motilin Agonist, Motilides As the chemical nature of motilin is that of a polypeptide, it is unstable at room temperature, and it is impossible to expect it to have its pharmacological effect on the gastrointestinal tract when it is taken orally. Clinically, motilin can be utilized only for measuring the plasma motilin concentration by radioimmunoassay or the distribution of motilin cells in immunohistochemistry, but is not suitable for clinical application as a drug. The discovery of nonpeptide motilin agonists has enabled us to develop a new prokinetic. In the early 1980s, we incidentally noticed a strong motor-stimulating activity of an antibiotic erythromycin, which was injected as an antibiotic after force transducers were implanted in the gastrointestinal tract of a dog (96). The IV drip infusion of a vial of erythromycin lactobionate (500 mg/vial) in about 1 h induced severe vomiting and diarrhea in the dog with trains of strong phasic contractions at all transducer sites in the postoperative gastrointestinal tract shown on the recording sheet. This finding was soon confirmed by others (167,178). We then reduced the dose of erythromycin to find its minimum effective dose to activate gastric contractions, and to our surprise we found (94) that the motor stimulating effect of 30-min IV infusion at doses of 50–100 mg/kg/h of erythromycin was quite similar to that of motilin, inducing a band of strong phasic contractions in the stomach, which stopped spontaneously in the stomach after about 20-min infusion and migrated along the small intestine, as shown in Fig. 14. Studies thereafter in vitro including the receptor binding for motilin in our laboratory

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FIG. 15. Displacement of [ 125I]motilin binding to human gastric antrum smooth muscle homogenates by unlabeled motilin EM574 and EMA. Crude homogenates (1 mg of protein) were incubated with 10 010 M [ 125I]motilin and various concentrations of unlabeled motilin, EM574, and EMA. Results are presented as the percentage inhibition of maximal [ 125I]motilin specific binding. Kd values for motilin, EM574, and EMA were 4.5 1 10 09 , 7.8 1 10 09 , and 9.1 1 10 07 M, respectively (189).

(112,189,190) and others (47,48,160–162) strongly suggested that erythromycin is a motilin agonist, and now the hypothesis has been proved. Displacement of [ 125I]motilin binding to smooth muscle homogenate obtained from human stomach is shown in Fig. 15. We subsequently started collaboration with S. Omura of the Kitasato Institute, Tokyo in the study of the structure–activity relationship of erythromycin, and his group newly synthesized about 300 derivatives of erythromycin in order to find out the chemical structure necessary for expressing motilin-like activity and for reducing antibacterial activity. As a result, it was found (154,155,205,219) that to manifest motilin activity macrolide compounds must be a 14-membered lactone ring with a neutral sugar attached at C3 and an amino sugar at C5 with a glycosidic linkage. In addition to these fundamental structures, various side chains of the lacton ring at C11 and C12 and the neutral sugar were found to influence motilin-like activity, but the effect remained to a small degree. The most significant effects were brought about by the 6.9-hemiacetal structure of the lactone ring, namely the addition of an oxygen bridge between the C6 and C9 of the lactone ring, and by modifications in the dimethyl amino group of the amino sugar desosamine. The greatest increase in motilin-like activity could be obtained from a compound (EM536) in which an oxygen bridge was inserted into the lactone ring between C6 and C9 and the propagyl moiety was added to the nitrogen atom of the dimethyl amino group of desosamine to produce a quaternary ammonium. The motilin-like activity of this compound reached 2890 times that of erythromycin. We then named these compounds ‘‘motilides,’’ meaning motilin-like macrolides (154). The antibacterial activity of motilides was reduced to a less than 100 mg/ml in MIC (minimum inhibitory concentration) value. The reduction in antibacterial activity is indispensable particularly when these compounds are considered to be developed as a safe prokinetic because the continuous intake of them for a couple of weeks as a prokinetic may produce a resistance to macrolide antibiotics in microorganisms.

601 Among motilides, a number of derivatives were found to be suitable for the development of an entirely new type of a prokinetic, and EM574 are now undergoing clinical trials by Takeda Chemical Industries in Japan (85,189). In Fig. 16, the chemical structures of erythromycin (EMA) and EM574 are shown. The birth of motilides enabled us to develop the ‘‘orally effective motilin’’ for the treatment of delayed gastric emptying in various diseases. In addition to Takeda, another new compound of 12membered macrolides (LY267108) was synthesized by Lilly Research Laboratories, and this compound is reported to increase the lower esophageal sphincter pressure in cats and believed to be useful in treating gastroesophageal reflux diseases (70). More recently, Abbott laboratories reported that a derivative of erythromycin (ABT229), which is very similar to EM574, increased gastric motility in healthy male subjects at oral doses of 4–128 mg, and in particular, doses of 8 and 16 mg produced the most significant changes. They concluded that ABT-229 is a promising candidate for the treatment of gastric motility disorders (142). In Europe, some other pharmaceutical companies are said to have entered in this field. These worldwide activities in developing new macrolide compounds as a gastroprokinetic have been brought about by a study by Vantrappen’s group in Belgium in 1990, reporting that delayed gastric emptying in diabetic neuropathy was dramatically improved by oral and IV erythromycin (104). Similar effectiveness in patients with diabetic gastroparesis was reported with motilin by the same group (164), supporting the hypothesis that erythromycin’s effect is mediated through motilin receptors. It is reported that as many as 30% of diabetics have demonstrable gastric motor disorders, such as early satiety, abdominal distention, nausea, vomiting, and anorexia. Gastric stasis may result in

FIG. 16. Chemical structures of erythromycin A (EMA) and its derivative EM574. In (A), the chemical structure of erythromycin A is shown: it is constructed of three major parts, a 14-membered lactone ring, an amino sugar (desosamine), and a neutral sugar (cladinose). In (B), the chemical structure of EM574 is shown, and the chemical structures different from that of EMA are surrounded by circles.

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deterioration of glucose control secondary to decreased delivery of nutrients for absorption to the small intestine. In fact, improvement of these gastric abnormalities with gastroprokinetics, including metoclopramide, domperidone, and cisapride, has become a new area of clinical research interest. Beneficial effects of erythromycin on delayed gastric emptying in diabetes have been reported since then (50,106,134,145,193,210,221). When metoclopramide and erythromycin were compared in the treatment of diabetic gastroparesis, Erbas et al. (56) reported more pronounced improvement with erythromycin. In addition, the pathogenesis of idiopathic gastroparesis is of great variety, and benzamides including cisapride acting through 5-HT 4 receptors in the enteric nervous system of the stomach are not always effective in improving all types of delayed gastric emptying. We now need a new type of drug that acts through different receptors from 5-HT 4 or dopamine2 and accelerates delayed gastric emptying. The rediscovery of some macrolides as a motilin agonist has just answered the requirements of the times. In both idiopathic and diabetic gastroparesis, it is generally accepted that EM has a strong gastric prokinetic effect and may represent a useful new therapeutic approach to gastroparesis (181). To elucidate the motor pattern that accounts for accelerated gastric emptying, Annese et al. (4) investigated the effect of 200 mg of EM vs. a placebo on postprandial motility of the stomach and the upper small intestine in 13 normal subjects, and they found that EM significantly increased the amplitude of the antral contractions during the 2-h postprandial study period (123 { 17 vs. 44 { 12 mmHg), and that antroduodenal coordination was significantly improved during the first postprandial hour. These changes in postprandial motility induced by erythromycin may well account for its accelerating effect on gastric emptying. On the other hand, gastric emptying is known to be partially controlled by intraduodenal nutrients by suppressing antral contractions and stimulating localized pyloric contractions. Fraser et al. (64) investigated the effect of erythromycin (3 mg/kg) on intraduodenal intralipid-induced changes in gastroduodenal and pyloric motility. They found that EM overcomes the effects of intraduodenal lipid on gastro–pyloro–duodenal motor response, suppresses localized phasic and tonic pyloric pressure waves and stimulates antral and duodenal pressure waves. Erythromycin is reported to increase LES pressure (220) and duodeno–caecal transit time (118) and gastric emptying of both liquids and solids (132) in healthy subjects. Stacher et al. (200) investigated whether emptying of a test meal and antral contractility were enhanced by intravenous EM (200 mg) in anorexia nervosa patients, and found that EM noticeably accelerated gastric emptying and in most patients induced an antral motor activity characterized by long duration contractions occurring at often irregular intervals. Erythromycin also accelerated gastric and gallbladder emptying in normal (5) and scleroderma patients (53,58,59). Narchi et al. (148) reported their interesting study showing that the IV administration of erythromycin (500 mg) before outpatient laparoscopy decreased residual gastric volume and increased gastric pH without affecting recovery from general anesthesia. There are many studies describing beneficial effect of erythromycin on postoperative gastroparesis. The delayed gastric emptying after esophagogastrectomy with pyloric drainage procedure (25) and after esophagectomy (80) is significantly improved by IV erythromycin. A case study by Hocking (81) demonstrated a beneficial effect of erythromycin from a different angle; a patient after truncal vagotomy and gastroenterostomy had an acute postoperative delayed gastric emptying associated with persistent tachygastria, and the gastric rhythm was only transiently slowed by several attempts at electroversion but re-

sponded dramatically to IV erythromycin. Significant improvement of gastroparesis by vagotomy and antrectomy (179) and vagotomy (143,232) by erythromycin 200–250 mg has been reported. Yeo et al. (239) reported that erythromycin is a safe, inexpensive drug that significantly accelerates gastric emptying after pancreaticoduodenectomy and reduces the incidence of delayed gastric emptying by 37%. On the other hand, Strum et al. (204) reported a case study on a 75-year-old woman, describing dramatic improvement by erythromycin of gastroparesis caused by radiotherapy for postoperative endometrial carcinoma. This result suggests that erythromycin acts even when the enteric nervous system is damaged. As a different application, erythromycin may help patients in intensive care units suffering from needless loss of body fluid through a nasogastric tube. For instance, IV erythromycin (200 mg over 30 min) increases indices of antral motility and accelerates liquid gastric emptying in mechanically ventilated critically ill patients in intensive care unit (51). Gastroparesis has been reported as the second most frequent cause of hospitalization in diabetic patients on continuous ambulatory peritoneal dialysis. In this respect, a study reported by Gallar et al. (67) is of great interest; the effect of erythromycin (100 mg/2 l bag of dialysate) improved symptoms in all their patients that could not be controlled with cisapride and metoclopramide. So far, erythromycin has been applied to emptying the stomach in various fields and in different ways in the treatment of patients. This is really a clinical application of the original idea that motilin is a biosignal to induce the ‘‘housekeeper.’’ As to the mechanism of action of erythromycin, many attempts have been made to clarify this in human subjects; Bruley des Varannnes et al. (22) noted the stimulatory action of erythromycin on proximal gastric tone in humans by a mechanism that does not seems to involve endogenous release of motilin or a cholinergic pathway. Fiorucci et al. (60) found that in an erythromycin-induced increase in gastric motility and gallbladder emptying nitric oxide is implicated. Camilleri and his group studied gastric emptying in human subjects in relation to axial forces and found that erythromycin significantly increases the number of axial forces in functional and organic upper gut dysmotility (26,206). Stern and Wolf (201) and Keshavarzian and Isaac (108) used the strong axial forces induced by erythromycin in the gastric antrum, and describe successful transpyloric passage of a nasogastric tube in 20 patients, but as reported by Lin et al. because the percentage of chyme collected through a duodenal fistula in the ú 0.5 mm fraction in dogs was much greater in the EM-treated dogs (63 { 9%) than the controls (7 { 1%), it can be concluded that erythromycin, particularly in large doses, accelerates gastric emptying at the expense of gastric sieving. This study gives us a warning on the use of erythromycin as a prokinetic, and needs further analysis. In dog experiments, EM574 has been found to restore delayed gastric emptying of a solid meal that was pretreated with clonidine, as shown in Fig. 17. As mentioned above, motilin is active in the fasted state, and does not stimulate gastric contractile activity in the fed stomach. To explore erythromycin’s mechanism of action, Carlson et al. (27,28) studied gastric emptying and myoelectric activity in a canine Roux model. Tachyphylaxis was also evaluated following 3 mg/kg PO tid for 1 week. As a result, they demonstrated unchanged response to erythromycin after 1 week’s administration, and a cholinergic pathway involved in accelerating activity in gastric emptying by erythromycin. A recent study in our laboratory, however, revealed that a motilide at a dose three times or more greater than the dose that was originally appropriate for

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603 said to stimulate motor activity by releasing the endogenous acetylcholine through 5-HT 4 receptors, whereas motilides stimulate it through motilin and 5-HT 3 receptors in addition to acetylcholine (85,198). FUTURE PROBLEMS

FIG. 17. Effect of EM574, an erythromycin derivative, on clonidinetreated delayed gastric emptying of a solid meal in a conscious dog. Open circles indicate normal control, and close circles indicate delayed gastric emptying by clonidine. Triangles show restored gastric emptying after treatment with EM574. T 1 / 2 for clonidine alone was 4.5 { 0.5 h, but after treatment with EM574 T 1 / 2 shortened to 3.3 { 0.3 h, which was similar to the value for the saline control, 3.2 { 0.3 h.

inducing phase III contractions in the fasted stomach, significantly and dose-dependently stimulates the amplitude of the existing contractions in the fed stomach (198) and enhances gastric emptying in the dog (214). Postprandial receptors activated by motilides include neurokinin1 receptors, serotonin1/2 and serotonin3 receptors in addition to muscarinic receptors. The mechanism of motilides is therefore different from that of the present prokinetics of the benzamide group. Cisapride, for instance, is

It has become evident that motilin exerts its effect in the period after digestion and absorption have finished, and induces strong phasic contractions in the stomach, and stimulates enzyme secretion from the stomach and pancreas, and also stimulates the endocrine pancreas to release somatostatin (3,38,192), insulin and PP. The physiological significance of phase III activity in the gastrointestinal tract has been considered to be mechanical and chemical cleansing of the empty stomach and intestine in preparation for the next meal, but these periodic increases in gastrointestinal and pancreatic function may be manifestations of periodic increases in the fundamental life phenomenon in a broader sense, that is, a periodic warming-up of function may be necessary to maintain homeostasis, and therefore disturbance of rhythmicity may mean significant disorder of homeostasis. We should therefore be more concerned about the disorder of rhythmicity of body functions. On the other hand, the advent and clinical application of nonpeptide agonists and antagonists of physiologically active substances are awaited. Among numerous substances produced by microorganisms, there are many that it may be possible to develop as useful agonists and antagonists of regulatory peptides, because the original motilide compound is a product of Streptomyces erythraeus, and the specific cholecystokinin A receptor antagonist, asperleicin, is also produced by Aspergillus alliaceus (31,32,57,129). We have been focusing our attention on antibacterial activity in products of microorganisms, but in the future we must look for other useful activities for medical use in these products.

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