Effect Of Motilin Research Articles

Motilin activates neurons in the rat amygdala and increases gastric motility

Motilin and motilin receptors have been found in most regions of the brain, including the amygdala, one of the most important parts of the limbic system. Our previous study found that administration of motilin in the hippocampus stimulates gastric motility. We now explore the effect of motilin in the amygdala on gastric motility. In conscious rats, gastric motility was recorded after microinjection of motilin, motilin receptor antagonist (GM-109) or a mixture of the two into the basomedial amygdala nucleus (BMA). In anesthetized rats the changes of spontaneous discharges of gastric distention sensitive neurons (GDSN) in the BMA were recorded after intracerebroventricular (i.c.v.) microinjection of motilin or GM-109. In conscious rats the amplitude of gastric contractions increased dose-dependently after microinjection of motilin in the BMA, and decreased after microinjection of GM-109. The excitatory or inhibitory effects induced by motilin or GM-109 alone, were weakened by microinjection of a mixture solution of both. The spontaneous discharge frequency of gastric distention excitatory neuron (GDEN) was mainly inhibited by i.c.v. microinjection of motilin but excited by GM-109. In contrast, the spontaneous discharge frequency of gastric distention inhibitory neuron (GDIN) was mainly excited by motilin, but inhibited by GM-109. Our findings suggest that motilin may regulate gastric motility by modulating neural pathways in the BMA.

Altered Gastrointestinal and Metabolic Function in the GPR39-Obestatin Receptor–Knockout Mouse

The G-protein-coupled receptor GPR39 is a member of a family that includes the receptors for ghrelin and motilin. Recently the peptide obestatin was identified as a natural ligand for GPR39. The objective of this study was to gain insight into the biological function of the GPR39 receptor. GPR39(-/-) mice were generated and analyzed. Endogenous GPR39 expression was detected in the brain (septum-amygdala) and the gastrointestinal system (parietal cells, enterocytes, neurons, and pancreas). Gastric emptying of a solid meal (measured by the (14)C octanoic breath test) in GPR39(-/-) mice was accelerated significantly with a gastric half-emptying time of 49.5 +/- 2.2 minutes compared with 86.9 +/- 8.4 minutes in GPR39(+/+) mice. A more effective expulsion of distally located pellets (30%-75% of length) was observed in the colon of GPR39(-/-) mice. Four hours after pylorus ligation, the volume of gastric secretion was increased significantly (GPR39(-/-): 638 +/- 336 microL; GPR39(+/+): 225 +/- 170 microL), but gastric acid secretion was unchanged. The mature body weight and body fat composition of GPR39(-/-) mice was significantly higher compared with GPR39(+/+) mice, but this was not related to hyperphagia because 24-hour food intake did not differ between both genotypes. In contrast, deficiency of the GPR39 receptor led to reduced hyperphagia after fasting. The cholesterol levels were increased significantly in the GPR39(-/-) mice. Our data partially confirm and extend the described in vivo effects of obestatin and suggest that this peptide plays a functional role in the regulation of gastrointestinal and metabolic function through interaction with the GPR39 receptor.

Intragastric acidification inhibits motilin‐induced phase III activity in humans

In a randomized, placebo-controlled crossover design we studied the effect of gastric acidification on motilin-induced interdigestive antropyloroduodenal motility. Ten healthy volunteers participated in the study consisting of four experiments. Each experiment started after a spontaneous occurring phase III and consisted of intragastric infusion of either saline or acid (0.08 mol L(-1) HCl) for 90 min and intravenous infusion of either saline or motilin (4 pmol kg(-1) min(-1)) for 30 min. Antropyloroduodenal motility and pH were recorded continuously for 240 min. Reoccurrence of phase III was significantly (P < 0.05) earlier during intragastric saline-intravenous motilin infusion compared with control (intragastric saline-intravenous saline), 52 min (range 25-79) and 113 min (84-141) respectively. This effect was completely abolished during intragastric acid-intravenous motilin infusion, 112 min (82-142). The percentage of phase III of antral origin was significantly (P < 0.05) higher during intragastric saline-intravenous motilin infusion (90%) compared with control (30%). The mean area under the contraction (AUC) for phase II was significantly (P < 0.05) lower during intragastric saline-intravenous motilin infusion and intragastric acid-intravenous saline infusion compared with control. It is concluded that in humans intragastric acidification inhibits the effect of motilin on antroduodenal motility, decreases the AUC of antral phase II contractions and delays the occurrence of phase III of the migrating motor complex.

Influence of Motilin on Gastric Fundus Tone and on Meal-Induced Satiety in Man: Role of Cholinergic Pathways

Motilin agonists are strong gastroprokinetics, but their impact on symptoms in delayed gastric emptying has been disappointing. It has been speculated that it is due to the contractile effect of motilin agonists on the proximal stomach, but the pathway involved and the symptomatic consequences have been incompletely elucidated. To study whether motilin enhances proximal stomach tone and enhances meal-induced satiety and to evaluate whether this effect involves a cholinergic pathway. A gastric barostat was used to study, in healthy subjects, the effect of motilin (300 ng/kg/30 min i.v.) or saline on fasting gastric fundus tone and on post-prandial relaxation. To evaluate the involvement of a cholinergic pathway, atropine (12 microg/kg/h) was administered intravenously simultaneously with or before and during motilin infusion in the fasting state. Finally, a satiety drinking test was performed in 21 subjects twice after pretreatment with placebo or motilin and with placebo or atropine. Administration of motilin caused a significant increase of fasting fundus tone expressed as decrease of the mean balloon volume (324 +/- 60 mL vs 213 +/- 62 mL, p < 0.05). Simultaneous administration of atropine and motilin did not generate a significant volume change (192 +/- 60 mL vs 181 +/- 83 mL, NS), but pretreatment with atropine alone induced a relaxation, and when motilin was added this revealed an ongoing contraction (192 +/- 24 mL vs 136 +/- 21 mL, p < or = 0.05). Motilin infusion also inhibited gastric accommodation (p < or = 0.05 vs placebo) and increased satiety during a satiety drinking test (p < or = 0.05 vs placebo). Administration of motilin causes a contraction of the proximal stomach in humans and increases meal-induced satiety. The effect of motilin is atropine-resistant and involves a direct muscular pathway or a non-cholinergic neural pathway.

New motilin agonists: a long and winding road

New motilin agonists: a long and winding road

Comparison of the gastroprokinetic effects of ghrelin, GHRP-6 and motilin in rats in vivo and in vitro

Ghrelin and motilin form a new family of structurally related peptides. We compared the gastroprokinetic effects of ghrelin, the ghrelin receptor agonist, growth hormone releasing peptide 6 (GHRP-6), and motilin in rats in vivo and in vitro. MethodsGhrelin, GHRP-6 or motilin (10–150 μg/kg) were injected i.p. and the effects on gastric emptying and transit were measured after intragastric application of Evans blue. In antral and fundic strips the effect of motilin, ghrelin or GHRP-6 was studied during electrical field stimulation (EFS) in the absence and presence of NG-nitro-l-arginine methyl ester hydrochloride (l-NAME) (300 μM). ResultsGhrelin and GHRP-6 but not motilin accelerated gastric emptying and transit in rats. Ghrelin was more potent than GHRP-6 and the dose–response relationship for ghrelin but not for GHRP-6 was bell-shaped. In fundic or antral strips, neural responses to EFS consisted of an on-relaxation that was reversed into a cholinergically mediated contraction by addition of the nitric oxide (NO)-synthase blocker, l-NAME. The post-stimulus off-contraction was cholinergically mediated. Under normal conditions, the ghrelin agonists reduced the on-relaxations in fundic strips and increased the cholinergic off-contractions in antral and fundic strips. The concentration response curves in muscle strips of the fundus were bell-shaped with maximal effects for ghrelin at 1.2 μM (on-responses) and 0.66 μM (off-responses) and for GHRP-6 at 0.50 μM (on-responses) and 0.26 μM (off-responses). No effects were observed with motilin between 1 nM and 0.1 μM. Studies in the presence of l-NAME confirmed the effect of the ghrelin agonists on cholinergic excitatory motor responses. No effects were observed with motilin under the different experimental conditions. The presence of growth hormone secretagogue receptor 1a transcripts in the strip preparations was confirmed by reverse transcriptase polymerase chain reaction (RT-PCR). ConclusionGhrelin and GHRP-6 but not motilin accelerate gastric emptying and transit by activating cholinergic excitatory pathways in the enteric nervous system in addition to the known vagal pathways.

Gallbladder volume as a biomarker for the motilin effect in healthy volunteers and patients with functional dyspepsia

Decreases in gallbladder volume have been suggested as a biomarker for motilin activity in man. Yet, this could not be confirmed in 4 placebo-controlled cross-over studies with 10–12 subjects each. Therefore a meta-analysis was done on the data from these studies to investigate a motilin effect on gallbladder volume in healthy volunteers and patients with functional dyspepsia (FD). Forty-three healthy volunteers and 10 patients with FD received motilin (4 pmol/kg/min) or placebo in four separate double-blind, randomised, placebo-controlled, cross-over studies. Gallbladder volume was measured by ultrasonography. Analysis of variance of the combined data of these studies was performed to allow differentiation between patients and healthy volunteers. Baseline gallbladder volume was similar for placebo and motilin treatment, and between patients and healthy volunteers. Motilin significantly decreased gallbladder volume in healthy volunteers (p=0.003) and patients (p<0.0001) with the decrease being greater in patients (p=0.03). A linear concentration-response relationship was observed. The motilin effect was consistent across the 4 studies. Interdigestive gallbladder volume is a non-invasive endpoint for motilin activity, displaying a consistent response to motilin and a clear concentration-response relationship. However, it is less suitable as biomarker for future pharmacological studies on motilin agonist or antagonists as the effect is probably indirect and as a large study population is required. Clinical Pharmacology & Therapeutics (2004) 75, P57–P57; doi: 10.1016/j.clpt.2003.11.218

Effects of motilin and ursodeoxycholic acid on gastrointestinal myoelectric activity of different origins in fasted rats.

To investigate gastrointestinal migrating myoelectric complex (MMC) and the effects of porcine motilin and ursodeoxycholic acid (UDCA) on MMC of gastrointestinal tract of different origins in fasted rats. Three bipolar silver electrodes were chronically implanted on the antrum, duodenum and jejunum. Seven days later 24 experimental rats were divided into 2 groups. One group was injected with porcine motilin via sublingual vein at a dose of 20 microg/kg, the other group was perfused into stomach with UDCA. The gastrointestinal myoelectric activity was recorded 1 h before and 2 h after the test substance infusions into the rats. In all fasted rats a typical pattern of MMC was observed. Among the totally 68 activity fronts recorded in fasted rats under control, 67% started in duodenum, and 33% in antrum. MMC cycle duration and duration of phase III of antral origin were longer than those of duodenal origin. Administration of 20 microg/kg porcine motilin induced a premature antral phase III of antral origin. But perfusion into stomach with UDCA resulted in shorter MMC cycle duration, longer duration of phase III of duodenal origin, which were followed with shorter cycle duration and duration of antral phase III. In fasted rats, MMC could originate from antrum and duodenum respectively. The characteristics of MMC of different origins may contribute to the large variations within subjects. The mechanisms of different origins of phase III may be different. Porcine motilin and UDCA could affect MMC of different origins of the gastrointestinal tract in fasted state, respectively.

Effect of motilin on endogenous release of insulin in conscious dogs in the fed state.

The aim was to investigate the insulin-releasing activity of motilin during and after feeding. A single intravenous bolus injection of motilin (0.01-0.3 microg/kg) dose-dependently stimulated endogenous release of insulin in the postprandial state. The insulin-releasing activity of motilin in the fed state was completely abolished by pretreatment with atropine or hexamethonium and was partly inhibited by ondansetron. Truncal vagotomy also greatly suppressed the motilin-induced insulin release. While phentolamine significantly enhanced insulin release in response to motilin, propranolol significantly inhibited this response in both states. The motilin-induced insulin release in the fed states was not accompanied by any changes in glucose concentrations. In conclusion, while the physiological significance remains unclear, these results indicate that physiological doses of motilin stimulate endogenous release of insulin via a vagally cholinergic muscarinic pathway, and that adrenergic and 5-hydroxytryptamine3 receptors are also involved in this response, in the dog.

Excitatory effects of motilin in the hippocampus on gastric motility in rats

Intestinal motilin is known to stimulate gastrointestinal motility. Recently, it was shown that the motilin gene and the motilin receptor are expressed in various regions of the brain. We studied whether motilin can activate pathways in the rat hippocampus to stimulate gastric motility. Gastric motility was monitored in conscious rats, whereas extracellular electrical activity recordings of the hippocampus were performed on anaesthetized rats to measure the influence of microinjection of motilin and CCK-8 into the hippocampus and into the cerebral ventricles. We found that neurons in the CA3 region of the hippocampus are sensitive to gastric distension, and that injection of motilin into the hippocampus increased the amplitude of gastric contractions by 35.3±6.8%, while CCK-8 injection inhibited motility by −27.3±6.8%. The hippocampal motilin-induced stimulation of gastric motility (30.6±5.5%) was completely abolished by subdiaphragmal vagotomy (−2.8±4.4%) but unaffected by the intravenously applied receptor blockers atropine, phentolamine and propranolol. In vivo extracellular recordings of gastric distension-responsive CA3 neurons revealed that intracerebroventricular administration of motilin increased firing while CCK-8 inhibited firing. These opposite effects of motilin and CCK-8 fit with the nature of the actions of these gut–brain peptides on gastric motility. Our findings suggest that the stimulation of gastric motility by motilin administered in the hippocampus reflects the existence of a functional interaction between the hippocampus and a vago–vagus reflex running via a noncholinergic and nonadrenergic efferent pathway.

Interaction of the Growth Hormone-Releasing Peptides Ghrelin and Growth Hormone-Releasing Peptide-6 with the Motilin Receptor in the Rabbit Gastric Antrum

The structural relationship between the motilin and the growth hormone secretagogue receptor (GHS-R), and between their respective ligands, motilin and ghrelin, prompted us to investigate whether ghrelin and the GHS-R agonist growth hormone-releasing peptide-6 (GHRP-6), could interact with the motilin receptor. The interaction was evaluated in the rabbit gastric antrum with binding studies on membrane preparations and with contraction studies on muscle strips in the presence of selective antagonists under conditions of electrical field stimulation (EFS) or not. Binding studies indicated that the affinity (pK(d)) for the motilin receptor was in the order of ghrelin (4.23 +/- 0.07) < GHRP-6 (5.54 +/- 0.08) < motilin (9.13 +/- 0.03). The interaction of ghrelin with the motilin receptor requires the octanoyl group. Motilin induced smooth muscle contractile responses but ghrelin and GHRP-6 were ineffective. EFS elicited on- and off-responses that were increased by motilin already at 10(-9) M, but not by 10(-5) M ghrelin. In contrast, GHRP-6 also enhanced the on- and off-responses. The motilin antagonist Phe-cyclo[Lys-Tyr(3-tBu)-betaAla-] trifluoroacetate (GM-109) blocked the effect of GHRP-6 on the off-responses but not on the on-responses. Under nonadrenergic noncholinergic conditions, the effects of motilin and GHRP-6 on the on-responses were abolished; those on the off-responses were preserved. All responses were blocked by neurokinin (NK)(1) and NK(2) antagonists. In conclusion, ghrelin is unable to induce contractions via the motilin receptor. However, GHRP-6 enhances neural contractile responses, partially via interaction with the motilin receptor on noncholinergic nerves with tachykinins as mediator, and partially via another receptor that may be a GHS-R subtype on cholinergic nerves that corelease tachykinins.

Effect of Duodenectomy on Gastric Motility and Gastric Hormones in Dogs

To test the hypothesis that the duodenum is required to coordinate interdigestive insulin secretion with gastrointestinal motility and to determine whether duodenectomy alters the interdigestive cycles of plasma motilin and insulin levels and their relations to insulin secretion and motility. Adult mongrel dogs were chronically implanted with force transducers in the stomach, duodenum, and upper jejunum to monitor contractile activity. Eight healthy mongrel dogs were divided into control and duodenectomized dogs. Insulin secretion, gastrointestinal motility, and plasma concentrations of motilin during the interdigestive period were measured in normal and duodenectomized dogs. After duodenectomy, no obvious phase III contractions were seen in the gastric antrum, but migrating phase III contractions were seen in the upper jejunum. The plasma motilin concentration did not fluctuate as it does in normal dogs, and remained low. After duodenectomy, insulin secretory cycles were not coordinated with either cycles of interdigestive motility or the plasma concentration of motilin. Exogenous motilin administration stimulated endogenous insulin release significantly compared with saline-treated controls. The contractile response of the stomach to exogenous motilin after duodenectomy was similar to that of intact dogs. Duodenectomy disrupts the relation between cycles of both interdigestive gastrointestinal motility and insulin secretion. These effects of duodenectomy may be attributable to interruption of the duodenopancreatic neural connections, hormonal abnormalities, or loss of vagus-sensitive humoral factors. The duodenum, which stores motilin, seems to play an important role in the relations between gastric migrating motor complexes and the concomitant increase of insulin secretion in fasted dogs. The mechanism responsible for the effect of motilin in both duodenectomized and normal dogs may involve a cholinergic pathway.

Motilides accelerate regional gastrointestinal transit in the dog

Motilides have prokinetic effects on the upper gut during fasting, increasing the strength of antral contractions and stimulating gastroduodenal phase 3 sequences. Effects on the distal gut, and postprandially, are less well documented. To evaluate dose-response effects of motilin and erythromycin on gastric emptying, small bowel and colonic transit in the dog using a validated scintigraphic technique. For gastric emptying and small bowel transit, 99mTc labelled beads were added to a meal of dog chow (450 kcal). Regional colonic transit was measured by 111In labelled beads placed in a capsule which dissolved and released radiation into the proximal colon. Scintiscans were taken at regular intervals and indices of whole-gut transit were calculated. Drugs were given by slow intravenous administration. In the doses used, motilin accelerated regional colonic transit but did not hasten gastric emptying or small bowel transit. Single or repeated doses of motilin had similar effects on colonic transit. Erythromycin accelerated gastric emptying, small bowel transit and regional colonic transit. Motilin receptors are apparently present in the canine small bowel and colon. Postprandially, motilides accelerate transit in the distal gut.

The effect of motilin on the regulation mechanism of intestinal motility in conscious horses.

Laparotomy was performed on seven thoroughbreds to attach a force transducer to the proximal jejunum, distal jejunum, and ileum, as well as to the serous membrane of the cecum. Following observation of intestinal motility in conscious horses, they were intravenously injected with motilin (0.6 microgram/kg) to examine its effect on intestinal motility. Strong contractions peculiar to horses were observed in small intestine. Further, motilin caused strong contractions in the proximal jejunum. The results suggested the involvement of motilin in the regulation mechanism of intestinal motility.

Motilin increases food intake in mice

The effect of motilin on food intake was investigated in nonfood-deprived mice. A significant increase in food intake was observed 1 h after ICV administration of motilin (3 nmol/mouse) and continued for 2 h. This effect was attenuated markedly by the motilin receptor antagonist GM-109 (0.3–3 nmol/mouse) in a dose-related manner. GM-109 alone had no effect on food intake. These results indicate that motilin receptors are present in the brain and may have a role in the regulation of food intake.

Effect of motilin and erythromycin on calcium-activated potassium channels in rabbit colonic myocytes

Background & Aims: Motilin and erythromycin are prokinetic agents that act on the same receptor in gastrointestinal smooth muscle to cause contraction. Both agonists may also cause an increase in outward current. The aim of this study was to determine whether motilin and erythromycin activate calcium-activated potassium (K Ca) channels. Methods: Freshly dispersed longitudinal smooth muscle cells of the rabbit colon were used to measure whole-cell outward current and single-channel activity using patch clamp recording methods. Results: Erythromycin and motilin increased a calcium-dependent outward potassium current and increased the open probability of K Ca channels of cell-attached patches. Conclusions: Erythromycin and motilin activate K Ca channels via an intracellular second messenger system. This effect may modulate the increase in contractility caused by these agonists. GASTROENTEROLOGY 1998;114:748-754

Anxiolytic effect of motilin and reversal with GM-109, a motilin antagonist, in mice

There have been few reports on the effects of the brain-gut peptide motilin on the central nervous system (CNS). We administered motilin intracerebroventricularly to mice and investigated the effect of motilin on anxiety using an elevated plus-maze. Motilin produced a significant decrease in anxiety with an inverted U-shaped dose response. To determine whether the anxiolytic effect of motilin was mediated via motilin receptors in the brain, the effect of GM-109, a novel motilin receptor antagonist, was investigated. GM-109 showed a significant and dose-dependent antagonism on the motilin-induced anxiolytic effect. GM-109 administered alone had no effect on anxiety. These results suggest that motilin receptors are present in the brain and may have a role in anxiety and emotion.

Motilin controls cyclic release of insulin through vagal cholinergic muscarinic pathways in fasted dogs.

The effect of motilin on insulin release has not been studied in the interdigestive state. Adult mongrel dogs were chronically implanted with force transducers in the stomach and duodenum to monitor contractile activity, and the plasma motilin and insulin concentrations were measured by a specific radioimmunoassay and enzyme immunoassay, respectively. The concentration of insulin in plasma was found to fluctuate in close association with that of motilin and phase III of the interdigestive migrating contractions in the stomach. This spontaneous release of insulin was mimicked by intravenous infusion of motilin at a dose of 0.3 microgram.kg-1.h-1. Exogenous motilin (0.01-0.3 microgram/kg) dose dependently stimulated insulin release, which was abolished by atropine, hexamethonium, ondansetron, and truncal vagotomy. Phentolamine significantly enhanced, whereas propranolol inhibited, motilin-induced insulin release. In a perifusion system using islet cells from the canine pancreas, motilin did not affect insulin release. In conclusion, motilin stimulates insulin release through vagal cholinergic, muscarinic receptors on pancreatic beta-cells, and the effect appears to be modulated by adrenergic nerves.

Concentration-dependent stimulation of cholinergic motor nerves or smooth muscle by [Nle 13]motilin in the isolated rabbit gastric antrum

In man, rabbit and cat, the effects of motilin and motilides are neurally mediated in vivo, whereas in vitro binding and contractility studies suggest the presence of a smooth muscular receptor. The aim of this study was to investigate in vitro interactions of motilin with the enteric excitatory neurotransmission in the gastric antrum of the rabbit. Circular muscle strips from the pre-pyloric antrum were subjected to electrical field stimulation (1 ms, 1–32 Hz, 10 s train) and muscle twitch responses were recorded isometrically. Induced twitch responses were frequency dependent (1–32 Hz) and entirely neurogenic (tetrodotoxin sensitive). [Nle 13]motilin dose-dependently (10 −9–10 −8 M) enhanced the amplitude of, atropine sensitive, evoked contractions. At 4 Hz the response, expressed as a % of the response to 32 Hz, increased from 15.5±4.1% (control) to 28.1±5.8% (motilin 10 −9 M), and to 45.8±3.6% (motilin 10 −8.5 M) ( P<0.05). This effect was not inhibited by hexamethonium (10 −3.3 M) but was abolished by the motilin receptor antagonist GM-109 (10 −5 M). In unstimulated strips, motilin induced phasic-tonic contractions with a threshold concentration of 10 −8 M and an pEC 50 of 7.48, which were also inhibited by GM-109 (10 −5 M) but not by tetrodotoxin (10 −5.5 M). The maximal tension, frequency and dose-dependency of carbachol-induced contractions were not influenced by motilin (pEC 50, carbachol: 6.48±0.06 (control), 6.49±0.07 (motilin)). In conclusion, motilin enhances contractions induced by electrical field stimulation in the rabbit antrum by a post-ganglionic interaction with the cholinergic neurotransmission in vitro at low doses and interacts directly with antral smooth muscle at high doses. This model is an accurate reflection of the in vivo effects of motilin and provides a tool to study neurogenic and myogenic actions of motilin and motilides in vitro.

Motilin and OHM-11526 activate a calcium current in human and canine jejunal circular smooth muscle.

Motilin is a potent agonist for gastrointestinal smooth muscle contraction and has been proposed to regulate the onset of phase III of the migrating motor complex in dogs and humans. The effects of motilin and OHM-11526, a motilin antagonist in rabbit smooth muscle strips, were examined in isolated canine and human jejunal circular smooth muscle cells using whole cell patch-clamp techniques with Ba2+ as the charge carrier. Effects of both drugs on inward current through L-type Ca2+ channels (ICaL) in both canine and human cells were first observed at 10(-3) M. At 10(-6) M, motilin increased ICaL in canine and human jejunal circular smooth muscle cells by 43 +/- 20 and 45 +/- 11%, respectively, and OHM-11526 increased ICaL by 54 +/- 8 and 54 +/- 14%, respectively. The increase in inward current was blocked by nifedipine and by guanosine 5'-O-(2-thiodiphosphate) but not by pertussis toxin. Washout of both drugs resulted in a further increase in ICaL. These data suggest that both motilin and OHM-11526 activate and ICaL in human and canine jejunal circular smooth muscle cells through a G protein-coupled mechanism.