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MOTILIN INDUCED MOTOR COMPLEXES ARE MEDIATED BY NON-VAGAL CHOLINERGIC PATHWAYS

K.E. Hall, N.E. Diamant and G.R. Greenberg. Departments of Physiology and Medicine, University of Toronto, Toronto, Canada.

Whether neural or hormonal mechanisms control the migrating motor complex (MMC) remains controversial. As the vagus nerve and motilin are the two prime candi- dates for MMC modulation, we investigated the relative contribution of each in M~iC initiation and propagation. In 4 fasted dogs the MMC was monitored by recording intralumenal pressure in the LES, stomach and upper small bowehVagal nerve blockade was undertaken by cooling previously isolated vago-sympathetic nerve trunks on each side of the neck. Mean ± SEM plasma motilin (pmol/l) was lowest in late phase I (71 ± 7), gradually increased during phase II (81 ± 6) and reached peak levels in pha~e Ill (109 ± 8) and phase IV (127 ± 9) (P< 0~01). Following vagal blockade phase II of the small bowel MMC and the concomitant increase in plasma motilin was abolished; only phase Ill-like activity remained which was associated with a sharp increment in plasma motilin (165 ± 22). Bolus injections of porcine motilin that achieved peak plasma levels equiva- lent to fasting were also undertaken. Porcine and canine plasma motilin were differentiated by RIA using two separate antibodies. Porcine motilin (lO00 ng) initiated phase Ill motor activity similar to controls within one minute, at peak plasma levels of 137 ± 7. Porcine motilin was undetectable prior to the termination of MMC. A significant (P< O.OOl) peak in canine motilin occurred during phase Ill-IV when the vagus was intact (172 ± 4) or blocked (125 ± 13). Lower doses of porcine motilin (200 to 800 ng) produced a dose-dependant decrease in phase Ill activity and peak levels of canine motilin (69 ± 3 to 142 ± 8). Atropine (40 ~g/kg) abolished porcine motilin induced MMCs in both intact and vagally blocked dogs, however a diminished, but significant (P< O.OOl) peak in canine motilln persisted (92 ± 6). These results suggest that in dogs phase II of the MMC in the small bowel and the associated motilin release is dependent on vagal integrity, while phase Ill is dependent on non- vagal cholinergic innervation. Porcine motilin induces both motor activity and endogenous motilin release, but through a non-vagal cholinergic pathway. Neural rather than hormonal mechanisms appear to dominate in the regulation of MMC activity.

PANCREATICO-BILIARY JUICE BUT NOT ACID STIMULATES MOTILIN RELEASE AND INIT- IATES MIGRATING MOTOR COMPLEX (MMC) IN MAN. C. Owyang, S. Achem-Karam, A. Funakoshi and A.Io Vinik, Department of Internal Medicine, The Universi ty of Michigan, Ann Arbor, Michigan, U.S.A.

The mechanism responsible for the i n i t i a t i o n of the in terd igest ive migrat- ing motor complexes is unknown. The occurrence of MMC in the gastroduodenal area is associated with bursts of secretion of gastr ic acid and pancreatic and b i l i a r y ju ice into the duodenum and a r ise in c i rcu la t ing mo t i l i n - l i ke im- munoreactivity (MLI) and pancreatic polypeptide (PP). We have investigated the role of HCl and pancreat ic -b i l ia ry (PB) secretion in MLI and PP release and the formation of the MMC in 6 healthy subjects using a gastrointest inal intubation and perfusion method with pressure transducers positioned in the antrum, mid duodenum and proximal jejunum. During the control study, a total of 18 MMCs were recorded in 6 subjects. Gastric acid, pancreatic t rypsin, plasma MLI and PP were measured during the 4 phases of gastroduodenal motor ac t i v i t y (Table I ) *p< 0.05 (Di f ferent from Phase I)

Phase I Phase I I Phase I I I Phase IV Gastric acid (mMoles/hr) ~ * 3 - ~ T +0.4 *2.4 +0.3 1.5+0.5 Trypsin output (Ku/hr) 4 . ~ 0 . 8 * 31 ~5.0 *28°7 ¥5.3 7.8¥3.2 Plasma MLI (pg/ml) I0~18 "169 ¥21 "174 ¥26 I0~13 Plasma PP (pg/ml) 26~4 * 93¥14 "108 ~18 18T6

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On separate days, O.IM HCI and human PB juice were infused into the duodenum at I0 ml/min for 5 min, 30 min a f te r a previous MMC (Table 2)**p< 0.05

Basal Phase I I I HCI-Phase I I I PB Juice Phase I I I Duodenal pH 6.9+0.5 *'Io2+0o2 7.1+0.3 Trypsin output (Ku/hr) 28.7¥5.3 ** 0 35.4+-11 Plasma MLI (pg/ml) 174¥26 *'110+23 178¥21 Plasma PP (pg/ml) I0~18 17~31 133¥24 MMCs interval (min) 9~8.0 ** 37¥2.0 *'41¥3.0 Intraduodenal perfusion of HCl-had no ef fect on-plasma MLI and i~ i t i a ted duo- denal but not antral MMC. In contrast, PB juice stimulated MLI release and i n i t i a ted both antral and duodenal MMC which were indist inguishable from spon- taneous MMC. This r ise in MLI is known to stimulate MMC. These observations suggest that in terd igest ive secretion of PB juice is causally related to the i n i t i a t i o n of MMC which may be due to the release of mot i l in .

SOMATOSTATIN HAS A PHYSIOLOGICAL ROLE IN THE REGULATION OF THE MIGRATING MOTOR COMPLEX (MMC) IN MAN. T.L.Peeters, G.Vantrappen and J.Janssens. Gastroenterology, Gasthuisberg, K.U.Leuven, B-3000 Leuven, Belgium.

We have shown that pharmacological doses of somatostatin have a striking effect on the MMC : phase 2 activity is completely abolished, phase 3

activity (also called the activity front, AF) in the intestine is normal but its frequency is tripled. We have now examined the relationship between endogenous somatostatin fluctuations and the MMC, and the effect of physiological exogenous doses, using an improved radioimmunoassay for somatostatin. Intestinal motor activity was monitored manometrically at three levels. In 4 volunteers somatostatin was infused in doses of 1.2, 2.4 and 4.8 pM/kg,min over three consecutive periods of 90 min, causing dose dependent increments in plasma somatostatin levels of 7.3, 31.8 and 76.3 pM. In all volunteers and for all doses phase 2 activity was completely abolished. The AF occurred at increased frequency : the mean interval between AF's being 39 ~ 6 min, compared to a normal period length of 92 min (P<O.01). In 4 other volunteers plasma samples were taken at I0 minute intervals and somatostatin levels correlated to the manometric data. The start of an AF in the upper duodenum was accompanied by somatostatin peaks. Peak values, taken as the mean of the levels in the sample obtained after the start of an AF, the preceding sample and the next one, averaged 31.7 ± 3.7 pM compared to 12.2 ± 1.8 pM in the remaining period. As motilin is known to induce AF's, the effect of motilin infusion on somatostatin levels was also studied. Infusion of motilin at a dose of 2.5 pM/kg.min in four volunteers elicited an AF and a somatostatin peak (23.8 ± 4.3 pM, P<0.01). It is concluded that somatostatin has a physiological role in the regulation of the MMC in man and that motilin might elicit AF's via somatostatin.

EFFECT OF PROSTAGLANDIN (PG)-SYNTHETASE-INHIBITORS ON MET-ENKEPHALIN-,ACETYL- CHOLINE- AND GLUCAGON-STIMULATED MOTILITY OF THE ISOLATED RAT COLON. U. Scheurer, E. Drack and F. Halter, GI-Unit, University Hospital Inselspital, 3010 Berne, Switzerland. PG's have been suggested to be modulators of morphine-induced motor actions of the canine intestine.This study was done to investigate the effect of PG-syn- thetase-inhibitors (diclofenac,indomethacin) on the motility of the isolated

rat colon,stimulated by the met-enkephalin analogue FK 33-824 (FK),acetylcho-

line (ACH) Or glucagon (GL).Intraluminal pressure changes were measured by perfusion manometry in organ preparations maintained in a standard organ bath. Results:FK,ACH and GL dose-dependently increased integrated intraluminaltonic