Autoradiographic study of motilin binding sites in the rabbit gastrointestinal tract

Sakai, Takafumi; Satoh, Minoru; Sonobe, Koichi; Nakajima, Masami; Shiba, Yoshihiro

doi:10.1016/0167-0115(94)90173-2

Cited by 20 publications

(8 citation statements)

References 19 publications

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“…It has been confirmed by receptor-binding assays that motilin receptors are located on gastrointestinal smooth muscle tissue in humans, rabbits and cats [13,14,19]. It has also been confirmed by autoradiographic studies that motilin receptors in humans and rabbits are specifically recognized in the smooth muscle layer and are densely distributed in circular muscle tissue rather than in longitudinal muscle [20,21]. It has been reported that the Ki values of [Leu 13 ]motilin for human and rabbit motilin receptors are 3.6 B 1.6 and 1.1 B 0.3 nmol/l, respectively [13,14].…”

Section: Discussionsupporting

confidence: 54%

In vitro Pharmacological Profile of SK-896, a New Human Motilin Analogue

Tsukamoto¹,

Kuboyama²,

Yamano³

et al. 2000

Pharmacology

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SK-896 ([Leu¹³]motilin-Hse) is a new human motilin analogue synthesized by Escherichia coli using a biotechnological method. We investigated the binding of SK-896 to motilin receptors and the contractile effect of SK-896 on smooth muscle preparations isolated from the gastrointestinal tract and various regional organs in order to clarify its in vitro pharmacological profile. SK-896 inhibited the binding of ¹²⁵I-human motilin to rabbit gastroduodenal motilin receptors with the same potency as unlabeled human motilin. The IC₅₀ values of SK-896 and human motilin were 3.5 ± 1.5 and 3.1 ± 1.8 nmol/l, respectively. The K_d of human motilin was 3.0 ± 1.5 nmol/l, and the Ki of SK-896 was 3.4 ± 1.5 nmol/l. SK-896 induced contraction of smooth muscle preparations isolated from rabbit duodenum in a concentration-dependent manner. However, there was no effect of SK-896 on duodenal preparations isolated from the dog and the rat. SK-896 thus exhibited species specificity in its contractile effect. We next investigated the effect of SK-896 on various smooth muscle preparations isolated from rabbit gastrointestinal tract, trachea, bladder, gallbladder, uterus, vas deferens and artery. Results showed that SK-896 induced contraction of smooth muscle preparations isolated from gastrointestinal tract, with potencies in the order duodenum > gastric pylorus = jejunum = descending colon > ascending colon ≥ ileum. However, there was no effect of SK-896 on smooth muscle preparations from gastric fundus and other regional organs. SK-896 thus exhibited regional specificity in its contractile effect. Moreover, the effects of SK-896 on smooth muscle preparations from rabbit duodenum were the same as those of human motilin, and were not inhibited by pretreatment with tetrodotoxin and atropine but were inhibited by verapamil. These findings indicate that SK-896 has the same pharmacological profile as human motilin. They suggest that SK-896 acts on gastrointestinal smooth muscle isolated from rabbit directly and specifically.

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Section: Discussionsupporting

confidence: 54%

In vitro Pharmacological Profile of SK-896, a New Human Motilin Analogue

Tsukamoto¹,

Kuboyama²,

Yamano³

et al. 2000

Pharmacology

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“…Binding of 125 I-motilin to tissue sections was carried out by a modification of Sakai et al's protocol, 5 which was optimized in our laboratory. In brief, slides were airdried for 30 minutes and preincubated in 50 mM Tris-HCl (pH 8.0) containing 0.05% PMSF and 0.4% BSA for 20 minutes.…”

Section: Storage Phosphor Autoradiographymentioning

confidence: 99%

Motilin receptor expression in smooth muscle, myenteric plexus, and mucosa of human inflamed and noninflamed intestine

Beek

Muller

Berg

et al. 2008

Inflammatory Bowel Diseases

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“…Motilin binding sites have been found on the smooth muscle layers of the gastric antrum, duodenum and colon, but no positive binding reaction has been detected in the cecum. Specific binding sites are particularly abundant in the circular muscle layers, with low concentrations in the longitudinal muscle layers of the gastric antrum, duodenum and colon (130). Specific motilin receptors have been identified on the GI muscle (including the colonic one) of several animal species (111,131).…”

Section: Motor-stimulating Drugsmentioning

confidence: 99%

Management of Irritable Bowel Syndrome: Novel Approaches to the Pharmacology of Gut Motility

Scarpignato

Pelosini

1999

Canadian Journal of Gastroenterology and Hepatology

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Although it is unclear to what extent irritable bowel syndrome (IBS) symptoms represent a normal perception of abnormal function or an abnormal perception of normal function, many believe that IBS constitutes the clinical expression of an underlying motility disorder, affecting primarily the mid- and lower gut. Indeed, transit and contractile abnormalities have been demonstrated with sophisticated techniques in a subset of patients with IBS. As a consequence, drugs affecting gastrointestinal (GI) motility have been widely employed with the aim of correcting the major IBS manifestations, ie, pain and altered bowel function. Unfortunately, no single drug has proven to be effective in treating IBS symptom complex. In addition, the use of some medications has often been associated with unpleasant side effects. Therefore, the search for a truly effective and safe drug to control motility disturbances in IBS continues. Several classes of drugs look promising and are under evaluation. Among the motor-inhibiting drugs, gut selective muscarinic antagonists (such as zamifenacin and darifenacin), neurokinin2 antagonists (such as MEN-10627 and MEN-11420), beta3-adrenoreceptor agonists (eg, SR-58611A) and GI-selective calcium channel blockers (eg, pinaverium bromide and octylonium) are able to decrease painful contractile activity in the gut (antispasmodic effect), without significantly affecting other body functions. Novel mechanisms to stimulate GI motility and transit include blockade of cholecystokinin (CCK)A receptors and stimulation of motilin receptors. Loxiglumide (and its dextroisomer, dexloxiglumide) is the only CCKA receptor antagonist that is being evaluated clinically. This drug accelerates gastric emptying and colonic transit, thereby increasing the number of bowel movements in patients with chronic constipation. It is also able to reduce visceral perception. Erythromycin and related 14-member macrolide compounds inhibit the binding of motilin to its receptors on GI smooth muscle and, therefore, act as motilin agonists. This antibiotic accelerates gastric emptying and shortens orocecal transit time. In the large bowel a significant decrease in transit is observed only in the right colon, which suggests a shift in fecal distribution. Several 'motilinomimetics' have been synthesized. Their development depends on the lack of antimicrobial activity and the absence of fading of the prokinetic effect during prolonged administration. 5-hydroxytryptamine (5-HT)4 agonists with significant pharmacological effects on the mid- and distal gut (such as prucalopride and tegaserod) are available for human use. These 'enterokinetic' compounds are useful for treating constipation-predominant IBS patients. 5-HT3 receptor antagonists also possess a number of interesting pharmacological properties that may make them suitable for treatment of IBS. Besides decreasing colonic sensitivity to distension, these drugs prolong intestinal transit and may be particularly useful in diarrhea-predominant IBS. Finally, when administered in small ...

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Autoradiographic study of motilin binding sites in the rabbit gastrointestinal tract

Cited by 20 publications

References 19 publications

In vitro Pharmacological Profile of SK-896, a New Human Motilin Analogue

In vitro Pharmacological Profile of SK-896, a New Human Motilin Analogue

Motilin receptor expression in smooth muscle, myenteric plexus, and mucosa of human inflamed and noninflamed intestine

Management of Irritable Bowel Syndrome: Novel Approaches to the Pharmacology of Gut Motility

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