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Antagonistic effects of a newly synthesized compound, (E)-2,2-diethyl-3'-[2-[2-(4-isopropyl)thiazolyl]ethenyl]succinanilic+ ++ acid sodium salt (MCI-826) on the contraction of the isolated guinea pig trachea and human bronchus induced by various agonists including peptide leukotrienes (p-LTs), histamine, acetylcholine (ACh), prostaglandin (PG) D2 and others were investigated and compared with the effects of a p-LT antagonist, FPL 55712, in some experiments. MCI-826 potently antagonized LTD4- and LTE4-induced contractions at extremely low concentrations in the isolated guinea pig trachea with pA2 values of 8.3 and 8.9, respectively, on a molar basis. These values indicated that MCI-826 is over 100 times stronger than FPL 55712. Similarly, MCI-826 at 10(-8) g/ml (2.4 x 10(-8) M) markedly antagonized LTD4-induced contractions of the isolated human bronchus. Although FPL 55712 fairly inhibited the 10(-9) g/ml LTC4-induced contraction of the isolated guinea pig trachea, MCI-826 had little effect on the contraction at high concentrations like 3 x 10(-6) g/ml (7.1 x 10(-6) M). MCI-826 modestly affected the other agonist-induced contractions and the resting tonus of the isolated guinea pig trachea at 10(-6) g/ml (2.4 x 10(-6) M) or higher concentrations, but FPL 55712 caused fair inhibition of some of those contractions and gradually lowered the resting tonus with time. These results indicate that MCI-826 is a highly potent and selective antagonist of LTD4 and LTE4 and can be a useful tool for biological and pharmacological experiments on p-LTs.

Anaphylactic histamine release from isolated rat peritoneal mast cells was concentration-dependently blocked by a 5-min treatment with exogenous histamine at 0.9 and 9 microM and enhanced by a 20- to 30-min treatment with thioperamide (H3-antagonist) at 3 microM with significance, but little affected by mepyramine (H1-antagonist) and cimetidine (H2-antagonist) at the cell concentration of 10(6) mast cells/ml. At a low concentration of mast cells (10(4) mast cells/ml), (R)-alpha-methylhistamine (alpha-MH), an H3-agonist, at 0.9-90 microM also inhibited the release in a concentration-dependent fashion. Thioperamide, but neither mepyramine nor cimetidine, significantly restored the decreased release by alpha-MH. However, the complete restoration by thioperamide could not be achieved because the drug itself slightly but concentration-dependently inhibited anaphylactic histamine release. On the other hand, not only betahistine and dimaprit but also alpha-MH did not suppress histamine release from the mast cells induced by compound 48/80. In rat plasma, considerable levels of histamine were detected. From these results, it is strongly suggested that histamine H3-like receptors are largely responsible for the negative feedback regulation of the anaphylactic histamine release from rat peritoneal mast cells.

Whether anaphylactic histamine release from rat peritoneal mast cells is influenced by betahistine, a histamine H1-receptor agonist/H3-antagonist, and dimaprit, an H2-agonist, was examined. Treatment with dimaprit at 6 and 60 microM for 20 min significantly inhibited the anaphylactic histamine release, whereas betahistine at up to 80 microM under the same conditions did not affect it. Treatment with dimaprit at 6 and 60 microM for 1 to 20 min and for 5 to 20 min, respectively, caused a time-dependent inhibition of the release, but up to 30 min treatment with 8 and 80 microM betahistine had no effect. The decreased histamine release induced by dimaprit was recovered by neither mepyramine nor cimetidine. However, thioperamide, an H3-selective antagonist, dose-dependently restored the diminished release. From these results, the inhibition of anaphylactic histamine release by dimaprit is not produced by the stimulation of H2-receptors, but involves the stimulation of H3-like receptors or H3-subtype receptors, which are distinct from the H3-receptors located in brain, and suggests that the receptor plays an important role in the negative feedback regulation of histamine release.

Effects of 9-[(4-acetyl-3-hydroxy-2-n-propylphenoxy)methyl]-3-(1H-tetrazol -5-yl)-4H-pyrido[1,2-alpha]pyrimidin-4-one (AS-35) on the resting tonus or contractions induced by agonists, such as leukotriene (LT) D4 and specific antigen of isolated guinea pig tracheas or human bronchi, and the in vitro anaphylactic release of histamine and LTs from human lung fragments were investigated and compared with the effects of FPL 55712 and disodium cromoglycate. AS-35 as well as FPL 55712 did not affect the contractions induced by acetylcholine and histamine of the isolated guinea pig trachea. However, the compound at relatively low concentrations obviously inhibited contractions induced by LTD4, and the antagonistic activity was stronger than that of FPL 55712. Treatment of the isolated human bronchus with AS-35 tended to induce the inhibition of both LTD4- and antigen-induced contractions and the relaxation of the resting tonus in a concentration-dependent manner. The inhibitory potency at 10(-6) g/ml was slightly stronger than that of FPL 55712, but this was not statistically significant. The anaphylactic release of histamine and LTs from the lung fragments appeared to be inhibited by the treatment with AS-35 5 min prior to the antigen challenge. From these results, it is suggested that AS-35 is effective against allergic asthma through antagonism towards peptide-LTs released anaphylactically in addition to inhibition of the chemical mediator release.

In the present study, we examined the effects of aging on the pharmacokinetics of 14Cquinupramine in male rats, following the administration to the aged (2 and 1-year old) and young (8 weeks old) rats.1. The concentration of radioactivity in blood of young rats reached the maximum 1hr after oral administration. In the older animals, Tmax was more delayed. The blood concentration of radioactivity declined with the similar half-life times (Tα1/2=0.87-1.66hr., Tβ1/2-19.2 -25.1hr ) in all groups of rats studied. Cmax and the area under the blood concentration-time curve (AUC) in the aged rats were 2.8 and 2.7 times higer, respectively, than those in the young rats.2. Two hours after oral administration of 14C-quinupramine, the tissue levels of radioactivity in the aged (2 years old) rats were 1.6-10.3 times higher than those in the young rats. The difference became more pronounced 24hr after administration. The distribution pattern of radioactivity in the aged rats was similar to that in the young rats. These findings were consistent with the results of whole body autoradiography.3. The in vitro plasma protein binding assay of 14C-quinupramine showed that more than 80% was bound to the protein in every group of animals. In vivo plasma protein binding of radioactivity was 46.5% 2hr and 58.5% lhr after oral administration of 14C-quinupramine in the aged (2 years old) and young rats, respectivery.4.The hepatic microsomal drug metabolizing activities (aminopyrine N-demethylation and aniline p-hydroxylation) and the content of cytochrome P-450 in rats decreased with aging. In vitro metabolic study of 14C-quinupramine with rat liver microsomes revealed that 48.2% and 8.4% of quinupramine remained unchanged in the aged (2 years old) and young rats, respectively.After oral administration of 14C-quinupramine, the aged (2 years old) rats showed higher content of the unchanged form in the urine, faces, plasma, heart, liver and kidney than the young rats.5. Within 24hr after oral administration, the recovery of radioactivity in excreta was 92.4 %, and 66.5% and 51.5% in the young and aged (1 and 2 years old) animals, respectively. The cumulative urinary excretion of radioactivity was 27.5%, 28.1% and 37.2% within 168hr after dosing in the young and aged (1 and 2 years old) rats, respectively.

The mechanisms of endothelin-1-induced histamine release were examined and compared with those responsible for antigen-induced release by using passively sensitized mouse bone marrow-derived mast cells and various drugs that may influence histamine release. The following results were obtained: (1) Although islet-activating protein potently inhibited endothelin-1-induced histamine release, it did not affect the antigen-induced release. (2) Histamine release induced by endothelin-1 was relatively more sensitive to ethylenediaminetetraacetic acid than that induced by antigen, although, extracellular Ca 2+ is a requisite for both types of the release. (3) ( 8R ∗ , 9S ∗ , 11S ∗ )-(−)-9-hydroxy-9-methoxycarbonyl-8-methyl- 2,3,9,10-tetrahydro-8, 11-epoxy-1 H ,8 H ,11 H -2,7b,11a-triazadibenzo[ a,g ]cycloocta[ c,d,e ]trinden-1-one and ( 8R ∗ , 9S ∗ , 11S ∗ )-(−)-9-hydroxy-9-methoxycarbonyl-8-methyl-14- n -propoxy- 2,3,9,10-tetrahydro-8,11-epoxy-1 H ,8 H ,11 H -2,7b,11a-triazadibenzol[ a,g ]cycloota-[ c,d,e ]trinden-1-one, which possibly inhibit protein kinases, strongly inhibited antigen-induced histamine release, while these drugs alone did not inhibit endothelin-1-induced release. (4) Staurosporine, a non-selective protein kinase inhibitor, prevented the elevation of cytosolic Ca 2+ concentrations induced by antigen, whereas that induced by endothelin-1 was not influenced; histamine release induced by either stimulus was greatly inhibited by the drug. These results indicate and/or suggest that some biological events induced by endothelin-1 leading to histamine release are different from those involved in the histamine release induced by antigen.

Whether endothelin-1 or -3 is capable of inducing histamine release from the peritoneal mast cells of BALB/c mice was investigated in vitro and compared to the release induced by compound 48/80. In contrast to the mouse bone marrow-derived mast cells, which originated from the same strain and have been reported upon previously, the (both crude and purified) peritoneal mast cells potently secreted histamine in response to either endothelin-1 or endothelin-3 in a concentration-dependent fashion. Even at a concentration as low as 10 nM, endothelin-1 induced a histamine release of more than 50% from the peritoneal mast cells. Cyclo(D-Asp-Pro-D-Val-Leu-D-Trp) (BQ-123), an endothelin ETA receptor antagonist, markedly suppressed not only the histamine released induced by endothelin-1 but also that due to endothelin-3 at a similarly low concentration range. Treatment with islet-activating protein (IAP) for 3 h, an inactivator of guanosine triphosphate (GTP) (Gi)-protein, markedly reduced the histamine release induced by endothelin-1. Neomycin at 0.1 and 1 mM or ethylenediaminetetraacetic acid (EDTA) at 0.1 mM in the absence of Ca2+, neither of which affected the histamine release induced by endothelin-1, substantially reduced histamine release caused by compound 48/80. On the other hand, treatment with O-O'-bis(2-aminophenyl)ethyleneglycol-N,N,N',N'-tetraacetic acid, tetraacetoxymethyl ester (BAPTA-AM), an intracellular calcium chelating agent, completely inhibited the release induced by both endothelin-1 and compound 48/80. These results indicate that endothelin-1 is one of the most potent histamine releasers in mouse peritoneal mast cells discovered so far.(ABSTRACT TRUNCATED AT 250 WORDS)

The relationship between the influx of Ca2+ into cells or cytosolic Ca2+ concentration ([Ca2+]i) and the histamine release following antigen stimulation in mouse bone marrow-derived mast cells (BMMC) was examined, and the results were compared with those from human lung mast cells (HLMC) and rat peritoneal mast cells (RPMC) in some experiments. Anaphylactic histamine release from BMMC as well as HLMC, but not that from RPMC, was dependent on the extracellular Ca2+. When BMMC were challenged by antigen following radioactive 45Ca2+ addition, two phases of 45Ca2+ influx into the cells were observed. The first phase, which was initiated and completed within 30 sec and 2 min, respectively, after antigen treatment, appeared to be related to anaphylactic histamine release. The second influx began 30 sec subsequent to the first one and lasted for at least 2 min, and this occurred after the completion of the histamine release; So far, it is not known how this second influx participates in the intracellular event(s). On the other hand, only one sustained elevation of [Ca2+]i occurred that reached its maximum within 2 min after antigen stimulation. Following stimulation of BMMC with antigen in the absence of Ca2+, Ca2+ addition 1 to 5 min later time-dependently enhanced the histamine release, although the release was deteriorated by further extension of Ca2+ addition. In contrast, the releasability of HLMC was rapidly decreased. These results indicate that extracellular Ca2+ not only is prerequisite for anaphylactic histamine release from BMMC, but also may modulate the release and participate in some intracellular event(s) which has yet to be focused upon.

We investigated the effects of ONO-1078, a newly synthesized peptide leukotriene (p-LT) antagonist, on the specific binding of radiolabelled [ 3 H]-LTC 4 , [ 3 H]-LTD 4 and [ 3 H]-LTE 4 to a human lung crude membrane fraction (HLMF). The binding assay was performed under conditions in which [ 3 H]-LTC 4 and [ 3 H]-LTD 4 were not metabolized by HLMF; that is, the metabolism of LTC 4 to LTD 4 or LTE 4 was almost completely prevented by pretreating HLMF with 5 mM acivicin at 37°C for 180 min, and metabolism of LTD 4 to LTE 4 was inhibited by including 5 mM l-cysteine and 5 mM glycine in the assay. [ 3 H]-LTD 4 specific binding was potently and concentration-dependently dissociated by ONO-1078. Its potency was 180-fold stronger than that of FPL 55712, a standardized p-LT antagonist, whereas high concentrations of ONO-1078 similar to those of FPL 55712 were required to inhibit [ 3 H]-LTC 4 specific binding. The rank order of the inhibitory potencies of p-LT agonists and antagonists for [ 3 H]-LTD 4 specific binding was LTD 4 > ONO-1078 > LTE 4 > LTC 4 > FPL 55712. On the other hand, not only high concentrations of ONO-1078 and FPL 55712 but also more than a 100-fold excess of unlabelled LTE 4 was required to inhibit [ 3 H]-LTE 4 specific binding, indicating that the binding sites do not appear to be receptors of LTE 4 . From these results, it is suggested that ONO-1078 is a highly potent LTD 4 antagonist which is expected to be very effective on bronchial asthma.

Whether specific binding sites for endothelin-1 and endothelin-3 exist in mouse bone marrow-derived mast cells (BMMC) and if these endothelins are capable of stimulating chemical mediator release from the cells was investigated. A single component of binding sites for endothelin-1 was found in the cells, but no binding sites for endothelin-3 were observed. Endothelin-1 at 1–100 nM concentration dependently induced release of histamine and immunoreactive leukotriene C 4 from BMMC, while endothelin-3 at up to 100 nM did not stimulate the release of either mediator. Time course experiments revealed that the release of histamine and immunoreactive leukotriene C 4 induced by endothelin-1 occurred rapidly, reaching near maximal levels within 20 s and 2 min, respectively, after the stimulation, while histamine release induced by antigen, at the concentration which induced an extent of release similar to that induced by 100 nM endothelin-1, required comparatively prolonged incubation (approximately 10 min for submaximal levels). Cyclo( D -Asp-Pro- D -Val-Leu- D -Trp) (BQ-123), a selective antagonist of endothelin ET A receptors, not only dissociated [ 125 I] endothelin-1 specifically bound to BMMC but also inhibited the release of both mediators from endothelin-1-induced cells. These results suggested strongly that BMMC have endothelin ET A receptors on their cell membrane, stimulation of which leads to chemical mediator release, probably via a mechanism different from that involved in the antigen-induced release.

The regulation of airway caliber is important for supporting the physiological respiratory function and is considered to be mainly controlled by the central and peripheral nervous systems. In the present review, we discussed the resting tonus of the isolated airway smooth muscle of the guinea pig and compared it with that of the human; the former is similar to the latter because both are well-developed in the airway and well-responsive to a variety of mediators. The resting tonus of the isolated guinea pig trachea is largely decreased by indomethacin, a cyclooxygenase inhibitor, while that of the isolated human bronchus is increased following transient decrease by indomethacin. Furthermore, the human bronchus is markedly decreased by not only a selective peptide leukotriene antagonist, MCI-826, but also 5-lipoxygenase inhibitors, AA 861 and cirsiliol. These results indicate that contractile prostanoid(s) and peptide leukotrienes are possible mediators for the maintaining the resting tonus of the respective preparations. Both preparations still have a small but substantial part of the resting tonus resistant to these drugs, the mediator(s) responsible for which is not clarified yet. In short, arachidonate metabolites are major candidates for the resting tonus of either isolated guinea pig or human airway smooth muscle and may contribute to at least a part of the regulation of the airway caliber as autacoids in vivo.

Whether anaphylactic histamine release from rat peritoneal mast cells is influenced by betahistine, a histamine H1-receptor agonist/H3-antagonist, and dimaprit, an H2-agonist, was examined. Treatment with dimaprit at 6 and 60 microM for 20 min significantly inhibited the anaphylactic histamine release, whereas betahistine at up to 80 microM under the same conditions did not affect it. Treatment with dimaprit at 6 and 60 microM for 1 to 20 min and for 5 to 20 min, respectively, caused a time-dependent inhibition of the release, but up to 30 min treatment with 8 and 80 microM betahistine had no effect. The decreased histamine release induced by dimaprit was recovered by neither mepyramine nor cimetidine. However, thioperamide, an H3-selective antagonist, dose-dependently restored the diminished release. From these results, the inhibition of anaphylactic histamine release by dimaprit is not produced by the stimulation of H2-receptors, but involves the stimulation of H3-like receptors or H3-subtype receptors, which are distinct from the H3-receptors located in brain, and suggests that the receptor plays an important role in the negative feedback regulation of histamine release.

Effects of a tiaramide derivative, 5-chloro-3-(4-hydroxypiperadinocarbonylmethyl)benzothiazoline++ +-2-one (HPR-611), on anaphylactic chemical mediator release from rat peritoneal exudate cells (RPEC), guinea pig lung fragments (GPLF) and human lung fragments (HLF) were investigated in comparison with those of tiaramide and disodium cromoglycate (DSCG). HPR-611 at 10(-6) - 10(-4) g/ml showed a concentration-dependent inhibition of the histamine release from RPEC regardless of its pretreatment time. Tiaramide also inhibited the release with slightly less potency than HPR-611. The treatment of DSCG 1 min before antigen challenge markedly prevented the release but the inhibitory potency was clearly deteriorated by prolongation of the pretreatment time. Tiaramide tended to influence the anaphylactic release of histamine from GPLF with only 20% inhibition of the release at either 10(-5) or 10(-4) g/ml, whereas HPR-611 at 10(-5) and 10(-4) g/ml significantly suppressed the release in a concentration-dependent fashion. DSCG was not effective on that even at higher concentrations. Anaphylactic release of not only histamine but also immunoreactive leukotriene B4 (i-LTB4) and i-LTC4 from HLF was markedly inhibited by 10(-8) - 10(-4) g/ml of HPR-611. Tiaramide inhibited the release to a somewhat less extent than HPR-611, while nominal or no inhibitions by DSCG were found. From these results, it is clearly apparent that anti-allergic actions of HPR-611 are quite different from those of DSCG.

Arachidonate 5-lipoxygenase plays a pivotal role in the biosynthesis of leukotrienes. Cirsiliol (3',4',5-trihydroxy-6,7-dimethoxyflavone), a selective inhibitor of the enzyme, was derivatized by introducing alkyl groups of various chain lengths at positions 5, 6, 7, and 8 of the A ring of the flavone skeleton. Modification of the positions 5 and 6 with an alkyl group of 5-10 carbons markedly decreased the IC50 values for 5-lipoxygenase inhibition to the order of 10 nM. As tested with 5- or 6-hexyloxy derivatives, a relatively selective inhibition of 5-lipoxygenase was shown. Inhibition of 12-lipoxygenase required much higher concentrations of these compounds, and cyclooxygenase was not inhibited. Modification of positions 7 and 8 did not increase the inhibitory effect of most flavone compounds.

The antiallergic effects of 10-(3-quinuclidinylmethyl)phenothiazine (mequitazine) were investigated in vitro. The results obtained were as follows: 1) In the isolated trachea and lung parenchyma of guinea pigs, mequitazine showed a fairly potent antagonistic action against contractions induced by both histamine (Hi) and acetylcholine (ACh). Mequitazine was much less potent in antihistaminic action and slightly more potent in anticholinergic action than ketotifen. The contractions of the preparation by leukotriene (LT) D4 were antagonized by mequitazine, although the potency was moderate, showing an IC50 value of 2.3 x 10(-5) g/ml in the trachea and 5.1 x 10(-5)g/ml in the lung parenchyma. Mequitazine had no effect on the contraction of the trachea by PGF2 alpha, but inhibited that of the lung parenchyma with pA2 = 7.0. 2) Mequitazine (10(-6) g/ml) slightly inhibited the Schultz-Dale reaction of the isolated guinea pig trachea, while ketotifen at the same concentration did not show any effect. 3) The contraction of the isolated guinea pig trachea by Ca2+ influx was slightly inhibited by mequitazine (10(-5) g/ml). 4) Mequitazine competitively inhibited the cyclic AMP-dependent phosphodiesterase activity from the rat lung with a potency of 10 times and 5 times more than those of ketotifen and theophylline, respectively. 5) Mequitazine (10(-6) to 10(-5) M) suppressed both the anaphylactic and phospholipase A2-induced histamine release from the peritoneal cells of rats. 6) Mequitazine (10(-5) g/ml) also inhibited the anaphylactic and Ca ionophore-induced histamine release from the leukocytes of the atopic patients and normal subjects. 7) The anaphylactic releases of histamine, LTB4 and peptide LT from the human lung fragments were dose-dependently inhibited by mequitazine (10(-7) approximately 10(-5) g/ml).

The effects of tricyclic antidepressant drugs on cardiac receptor binding sites and Ca2+ binding to cardiac sarcoplasmic reticulum were investigated in rats. 1) Quinupramine was found to possess higher affinity for muscarinic cholinergic receptor binding sites in brain and heart, compared with imipramine. 2) Repeated quinupramine treatment induced a significant increase in the Bmax value in cardiac muscarinic cholinergic receptors. 3) In imipramine treated heart, isoproterenol-induced stimulation of ornithine decarboxylase activity was significantly decreased compared with that in the vehicle control. 4) Repeated quinupramine and imipramine treatment caused a significant reduction of Bmax of 45Ca2+ binding in cardiac sarcoplasmic reticulum fractions. 5) After single quinupramine treatment, its concentrations in heart were higher than those in brain and plasma. 6) After the repeated quinupramine treatment, its concentration in heart was 2.4 times higher than that after single treatment. These results demonstrate that repeated tricyclic antidepressant drug treatment caused a functional impairment in Ca2+ binding sites of cardiac sarcoplasmic reticulum and adaptive changes of receptor binding sites.

Possible chemical mediators contributing to 48 hour passive cutaneous anaphylaxis (PCA) in rats were investigated. Forty-eight hour PCA was inhibited considerably by mepyramine and methysergide given intravenously, a finding suggestive of a major role for histamine and serotonin in the reaction. AA-861, a selective 5-lipoxygenase inhibitor did not inhibit the PCA, and leukotriene (LT)D4 or LTE4 and the combination with prostaglandin (PG)E2 had no significant skin reaction. In addition, only small amounts of slow reacting substance of anaphylaxis (SRS-A) were detected in skin fragments, in vitro. Although CV-3988, a selective platelet activating factor (PAF) antagonist, dose-dependently inhibited the PAF-induced skin reaction, the PCA was not affected by treatment with this compound. Indomethacin also had no inhibitory activity on PCA. Thus, sulfidopeptide LTs, PAF and arachidonate cyclooxygenase metabolites probably do not contribute to PCA, at least in rats.

Various tricyclic diterpenoid derivatives of totarol, abietane and pimarane groups were found to have serum cholesterol lowering action in rats. Inhibition of intestinal cholesterol absorption was suggested to be involved in the main mechanism of hypocholesterolemic action of totarol and abietic acid.

The experiments were performed to study the effects of Flavoxate hydrochloride on the gastrointestinal motility and its underlying mechanism. Gastrointestinal motility was inhibited at first and then accelerated markedly after the intravenous injection of Flavoxate hydrochloride (10 mg/kg) in the experiments of anesthetized dogs. For analyzing the underlying mechanism of this response the following experiments were executed. 1) The pendular movements of isolated ileum of rabbits were accelerated with administration of low concentration of Flavoxate hydrochloride less than 10(5) g/ml, while these were reduced with administration of high concentration more than 10(4) g/ml. Because the tetrodotoxin (2.5 times 10(7) g/ml) has no essential effect on these responses, it could be postulated that Flavoxate hydrochloride has direct effect on intestinal smooth muscle itself. 2) Flavoxate hydrochloride (10 mg/kg) induced the differentiated regional response of the sympathetic outflow, that is, the parallel decrease of cutaneous and cardiac sympathetic activities, and the converse increase of splanchnic activity. Therefore, Flavoxate hydrochloride is thought to have an effect on the integrating mechanism of the sympathetic nervous system. This view was also supported by the experiments with neuromuscular preparation of lobster (Panulirus japonicus). It is concluded from these results, that the change of gastrointestinal motility induced by intravenous injection of Flavoxate hydrochloride (10 mg/kg) is influenced both by its effect on the gastrointestinal smooth muscle itself and by its effect via the autonomic nervous system.

Effects of the clathrate compound of mobenzoxamine (MBX) with beta-cyclodextrin (MBX-CD), a new gastro-intestinal function modulator, on the digestive system were studied in comparison with those of metoclopramide, domperidone and trimebutine. MBX-CD showed inhibitory effects that were approximately 1/4 times as potent as metoclopramide on both apomorphine- and copper sulfate-induced emesis and about 1/40 times as potent as domperidone on apomorphine-induced emesis in dogs. In rats, MBX-CD enhanced gastric emptying as potently as metoclopramide, and only MBX-CD showed a clear amelioration of the delayed gastric emptying induced by BaCl2. Similarly, only MBX-CD showed an ameliorative effect on small intestinal transport accelerated by BaCl2 in mice. Though both MBX and trimebutine inhibited spontaneous contractions of the isolated guinea pig stomach and rabbit intestine, it seemed that the properties of these effects were different from those of papaverine. On isolated guinea pig ileum, MBX inhibited contractions induced by various agonists equally to or more potently than trimebutine or papaverine. The results suggest that MBX-CD or MBX acts extensively on the gastro-intestinal system for the reason that it has not only the respective properties of the gastro-intestinal function modulators used as the standards, but also its own characteristic effects.