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Pharmacological mechanism responsible for the Atractylodes japonica-induced distal colonic contraction in rats.

ARTICLE INFO

Keywords:

Atractylodes japonica

EtOAc extract

Choline acetyltransferase

Muscarinic receptor

Contractility

Distal colon longitudinal muscle

ABSTRACT

Background and aim: Atractylodes japonica Koidz (Compositae) has been commonly used to treat the gastrointestinal (GI) disorders in Korean traditional medicine, but its pharmacological roles in the regulation of GI motility have not been clarified yet.

Methods: Atractylodes japonica was sequentially partitioned with MeOH, n-hexane, [CHCl.sub.3], EtOAc and n-BuOH saturated with [H.sub.2]O, and the effects of Atractylodes japonica extracts on the spontaneous contractility of GI muscle strips prepared from rats were measured.

Results: Among five different fractionations, EtOAc extracts of Atractylodes japonica (AJEA) dose-dependently increased the low frequency contraction of distal colon longitudinal muscles (DCLM), and the [ED.sub.50] values were revealed to be 1.71 x [10.sup.-9] g/ml. Among GI tracts, a prominent contractile response to AJEA was observed only in the DCLM. The contractile patterns produced by AJEA remarkably differed from those caused by acetylcholine and 5-HT.4-DAMP and methoctramine at 0.5 [micro]M significantly blocked the AJEA (1.0 [micro]g/ml)-induced contraction of DCLM, but ondansetron, GR113808 and methysergide at 1.0 [micro]M in combination did not change the AJEA-induced DCLM contractions. Acetylethylcholine mustard (5.0 [micro]M) significantly diminished the AJEA-induced DCLM contractions, whereas p-chlorophenyl alanine (1.0 [micro]M) did not affect the stimulatory effects of AJEA on the DCLM contractions.

Conclusion: The present results suggest that AJEA may specifically act on the DCLM among GI smooth muscles, and AJEA-induced DCLM contraction is likely mediated, at least, by activation of ChAT and acetylcholinergic muscarinic receptors.

[C] 2010 Elsevier GmbH. All rights reserved.

Introduction

The rhizome of Atractylodes japonica Koidz (Compositae) has been known to reveal a variety of pharmacological properties including anti-oxidant (Choi et al. 2009) and anti-inflammatory Gang et al. 2004) effects and to contain several constituents including atractylon and its derivatives (Hikino et al. 1964; Satoh et al. 1996), sesquiterpenoids (Kitajima et al. 2003), diacetylatractylodiol and its derivatives (Sakurai et al. 1994). It has been demonstrated that atractylon and its derivatives are a major component of Atractylodes japonica and suppress the reabsorption of water and [Na.sup.+] through inhibiting [Na.sup.+], [K.sup.+]-ATPase activity in kidneys (Satoh et al. 1996). Additionally, atractylenolide I and III from the rhizome of Atractylodes macrocephala Koidz inhibit tumor necrosis factor-[alpha] and nitric oxide (NO) production in lipopolysaccharide-stimulated peritoneal macrophages (Li et al. 2007), and the acetylene compounds from Atractylodes rhizome suppress the indometacin-induced formation of gastric ulcer in rats (Sakurai et al. 1994).

In Korean traditional medicine, the rhizome of Atractylodes japonica Koidz (Compositae) has been widely used for centuries as a therapeutic remedy to treat or reduce the symptoms of water retention, arthritis and digestive disorders (Kim et al. 1997). Especially, decoction of Atractylodes japonica is commonly used to treat the dysfunction of GI motility and gastric secretion. Despite the considerable use of Atractylodes japonica for modulating the GI dysfunction including defecation disorder and constipation, as far as we know, its pharmacological roles in the regulation of GI motility have not been understood yet. In view of therapeutic use of Atractylodes japonica in Korean traditional medicine and the functional importance of colonic motility for migrating GI contents into rectum, we hypothesized that pharmacological effects of Atractylodes japonica on the modulation of abnormal colonic motility could be due to increase in the smooth muscle contractility through facilitating release of excitatory neurotransmitters such as acetylcholine (ACh) and serotonin (5-HT). In order to examine this hypothesis, we set out to characterize the contractile responses of distal colon longitudinal muscles (DCLM) to the Atractylodes japonica extracts in rats.

Materials and methods

Plant materials

The fresh roots of Atractylodes japonica Koidz (Compositae) were collected in July 2009 at Jinan, Jeonbuk province, Korea. The plant was authenticated by Prof. Hong Jun Kim, College of Oriental Medicine, Woosuk University. The voucher specimen (JSI0907) was deposited in the Herbarium of College of Oriental Medicine, Woosuk University.

Preparation of extracts

The air-dried rhizomes of the Atractylodes japonica (120 g) were ground to fine powder and extracted by maceration with MeOH at room temperature for 14 days with occasional shaking. The extract was then concentrated under reduced pressure to afford an extract (32.5 g, yield 27.1%), which was suspended in distilled water and partitioned sequentially with n-hexane, [CHCl.sub.3], EtOAc and n-BuOH saturated with [H.sub.2]O. Each solvent was evaporated in vacuo to yield n-hexane extract (5.3 g, 4.4%), [CHCl.sub.3] extract (5.9 g, 4.9%), EtOAc extract (AJEA, 1.4 g, 1.1%) and n-BuOH extract (6.9 g, 5.8%). All extracts were dissolved with 10% dimethyl sulfoxide (DMSO) to be used in the experiments, and the final concentration of DMSO was less than 0.05%, which did not affect the spontaneous contractility of colonic smooth muscles (data not shown).

Smart LC chromatographic conditions

An LC800 series system equipped with binary solvent delivery pump, auto sampler, degasser system and UV-visible detector was used to achieve Smart LC fingerprints. The chromatographic separation was carried out on a 2.1 mm x 50 mm, 2 [micro]m particle, Innertsil ODS-4 C18 column (GL sciences, Japan) maintained at 40[degrees]C. The mobile phase consisting a mixture 0.05% aqueous phosphoric acid and acetonitrile in the ratio of 34:66 (v/v) with flow rate of 0.5 ml/min was employed. The detector wavelength was monitored at 254 nm. All injection volumes of sample and standards were 1.5 [micro]1. Atractylenolide I, atractylenolide III, diacetyl-atractylodiol and eudesma-4(15),7(11)-dien-8-one used as reference compounds were previously isolated from the roots of Atractylodes japonica (Kim et al. 2009), and their structures were identified according to the previous reports (Kim et al. 2009; Lee et al. 2005). The components were identified by comparison of their retention times to those of authentic standards under identical analysis conditions and the UV spectra with our in-house PDA library. Fig. 1 shows the typical chromatograms of the MeOH extracts of Atractylodes japonica.

[FIGURE 1 OMITTED]

Experimental animals

This study used 8-week old male Sprague-Dawley rats received from the Samtako BioKorea (Kyungki, Korea), and alt animals were acclimated for 1 week with free access to a solid rodent diet (Samyang Co., Kyungki, Korea) and tap water under controlled condition of a temperature 23 [+ or -] 2[degrees]C, relative humidity 50-60% and 12-h dark-light cycle. Animals were deprived of food for 17h before experiments, but they were allowed free access to tap water. Animal experiments were conducted in accordance with the institutional guideline established by the Wonkwang University Committee for the Care and Use of Laboratory Animals.

Preparation of distal colonic strips

Rats were sacrificed by [CO.sub.2] asphyxiation and cervical dislocation, and distal colons in the distance of 2 cm from the anus were dissected, and luminal contents were flushed out using Krebs-Ringer bicarbonate buffer (composition 118 mM NaCl, 4.7 mM KCl, 1.2 mM [KH.sub.2][PO.sub.4], 1.2 mM [MgSO.sub.4], 2.6 mM [CaCl.sub.2], 25 mM [NaHCO.sub.3] and 11.5 mM D-glucose, pH 7.4). The distal colonic strips (approximately 1 cm length) were longitudinally mounted in an organ bath (10 ml) containing Krebs-Ringer bicarbonate buffer bubbled with 5% [CO.sub.2]/95% [O.sub.2] and maintained at 37[degrees]C. One edge of colonic strips tied with suture silk was fixed to the bottom of organ bath, and the other edge was connected to the isometric force transducer (Grass Technologies, West Warwick, RI).

Measurement of smooth muscle contractility

The contractile responses of distal colonic strips to five different organic extracts of Atractylodes japonica were measured as described previously (Jeong et al. 2009). In brief, after strips were allowed to equilibrate for 60-90 min with washout every 10 min, 1 g of tension was slowly applied to the tissues before starting experiments. Antagonistic drugs (Heldman et al. 1996) used were pretreated for 5-10 min before treating 1.0[micro]g/ml of AJEA, and ACh (0.5 [micro]M) and 5-HT(10 [micro]M) were used as positive control drugs in comparison with the extract-induced distal colonic contractility. The mean contractility, tension and amplitude, produced under the resting and drug-treated conditions was measured over period of 10 and 90 min (10 min intervals), respectively. Contractility out-putted from the force transducer was isometrically measured by biological recording system equipped with amplifier (PowerLab 4/25, AD Instruments, Colorado Spring, CO).

Construction of concentration-response curves

Cumulative concentration-response curve, increasing the concentration AJEA (1 x [10.sup.-12] to 1 x [10.sup.-5] g/ml), was applied using a "single-dose" protocol. Each strip was used only for one complete concentration-response. The longitudinally mounted distal colonic strips were treated with each concentration of AJEA for 10 min. The contractility (tension and amplitude) produced by each concentration of AJEA was measured, and percentage changes compared to the basal contractility were calculated. The [ED.sub.50] values were interpolated from concentration-response curve by means of personal computer program (GraphPad Prism and Instat 5.5).

Chemical reagents

ACh, 5-HT, methoctramine, 4-diphenyllacetoxy-N(2-chloriethyl)-piperidine (4-DAMP), ondansetron, GR113808, methysergide, acetylethylcholine mustard and p-chlorophenyl alanine were purchased from the Sigma Chemicals (St. Louis, MO). All other chemicals and reagents were of the highest grade from commercial sources.

Statistical analysis

All results are presented as means + S.E. of 7-9 experiments. One-way analysis of variance (ANOVA) was performed, followed by post hoc analysis by Student-Newman-Keuls test. Probability values less than 0.05 were considered statistically significant.

Results

Effects of EtOAc extracts on the distal colonic contractility

AJEA (1 x [10.sup.-12] to 1 x [10.sup.-5] g/ml), an EtOAc extract of Atracty-lodes japonica, dose-dependently stimulated the spontaneous contractility of DCLM (Fig. 2A), and the [ED.sub.50] values in stimulating the low frequency contraction with high amplitude were revealed to be 1.71 x [10.sup.-9] g/ml (Fig. 2B). Interestingly, only AJEA among the five different organic fractionations (MeOH, n-hexane, [CHCl.sub.3], EtOAc and n-BuOH) examined in this study significantly stimulated the magnitude of DCLM contractility. However, it did not affect the spontaneous contractility of the other regions of GI smooth muscles including distal colonic circular muscles (data not shown).

[FIGURE 2 OMITTED]

Contractile pattern and time-course curves

As shown in Fig. 3A, AJEA reproduced a typical pattern of muscle contractility in the DCLM of rats. A gradual increase (magnitude and frequency) of low frequency contraction with high amplitude was recorded from the DCLM after treatment of AJEA (1 [micro]g/ml), whereas AJEA did not significantly change the high frequency contraction with low amplitude. These contractile patterns in magnitude and time-course markedly differed from those produced by ACh (0.5 [micro]M) and 5-HT (10 [micro]M), which cause a tonic contraction immediately after treatment of agnoists, followed by a gradual decline to the resting levels (Fig.3A). Maximal contractile responses of DCLM to AJEA were observed at around 70 min after treatment of agonist (Fig. 3B).

[FIGURE 3 OMITTED]

Antagonistic effects on the AJEA-induced contractions

To understand the pharmacological mechanism responsible for the stimulatory effects of AJEA on the DCLM contractility, a possible involvement of the muscarinic and/or serotoninergic receptors was investigated using pharmacological strategy. The AJEA (1.0 [micro]g/ml)-induced DCLM contractions were significantly abolished by pretreatment of the muscarinic [M.sub.3] receptor-preferring antagonist, 4-DAMP (0.5 [micro]M), for 5 min, but they were not changed by methoctramine (0.5 [micro]M), a muscarinic [M.sub.2] receptor-preferring antagonist (Fig.4A and B). In the presence of the 5-H[T.sub.3] (ondansetron, 1.0 [micro]M) and 5-H[T.sub.4] (GR113808, 1.0 [micro]M) receptor antagonists in combination did not change the AJEA (1.0 [micro]g/ml)-induced DCLM contractions (Fog. 4C), and addition of each antagonist alone to organ bath also did not affect the stimulatory effects of AJEA to organ bath also did not affect the stimulatory effects of AJEA on the spontaneous contractility of DCLM (data not shown).

[FIGURE 4 OMITTED]

Involvement of ACh and 5-HT synthe

Regarding in a remarkable difference of contractile patterns produced by AJEA and excitatory neurotransmitters such as ACh and 5-HT (Fig. 3A), this study hypothesized that increase of ACh and/or 5-HT synthesis and release in the enteric nerve systems possibly mediates the stimulatory effects of AJEA on the DCLM contractility and examined this hypothesis using acetylethylcholine mustard, a selective choline acetyl transferase (ChAT) inhibitor (Heldman et al. 1996), and p-chlorophenyl alanine, a selective tryptophan hydroxylase (TPH) inhibitor (Sallanon et al. 1982). Pretreatment of DCLM with acetylethylcholine mustard (5.0 [micro]M) significantly diminished the contractile responses, both tension and amplitude, stimulated by 1.0 [micro]g/ml of AJEA (Fig. 5), whereas inhibition of TPH by p-chlorophenyl alanine (1.0 [micro]M) had no significant effects on the AJEA-induced contraction of DCLM (Fig. 6).

[FIGURE 5 OMITTED]

[FIGURE 6 OMITTED]

Discussion

Although Atractylodes japonica is commonly used as herbal remedy to improve the dysfunctions of GI motility including constipation and defecation disorder in Korean traditional medicine (Kim et al. 1997), its pharmacological role in the regulation of GI contractility has not been clarified yet. So, this study has tried to understand the regulatory effects of Atractylodes japonica on the spontaneous contractility of GI smooth muscles. We fractionated Atractylodes japonica with MeOH, n-hexane, [CHCl.sub.3], EtOAc and n-BuOH and observed that only AJEA, EtOAc fraction, significantly stimulated the spontaneous contractility of DCLM. Moreover, an obvious stimulatory response to AJEA was observed only in the DCLM, but not in the other regions of GI smooth muscles including the distal colon circular muscles. These findings lead us to consider that the effective ingredients of Atractylodes japonica for stimulating GI contractility are likely contained in the EtOAc extracts, a partial non-polar fraction, and AJEA may specifically act on the DCLM in rats.

Interestingly, AJEA gradually increased the low frequency contraction with high amplitude in the DCLM of rats, and a maximal contraction of DCLM was observed at around 70 min after treating AJEA. In contrast, ACh and 5-HT produced a transient tonic contraction of DCLM immediately after treatment of agonists, followed by a gradual decline to the resting levels with a slight increase in low frequency contractions (Fig. 3A). These apparent differences of contractile patterns possibly reflect the unique pharmacological and therapeutical properties of Atractylodes japonica in the regulation of DCLM contractility.

ACh released from the enteric postsynaptic cholinergic neurons is, in fact, the primary stimulant neurotransmitter for contractile activity of GI smooth muscles, and the [M.sub.2] and [M.sub.3] receptors among five different subtypes of muscarinic receptors play a key role in the smooth muscle contraction of GI tracts (Ehlert 2003). Regarding in these information, we examined whether AJEA-induced contraction of DCLM was mediated, at least, by activation of the muscarinic receptors and observed that the muscarinic [M.sub.3] receptor-preferring antagonist, 4-DAMP, significantly blocked the AJEA-induced DCLM contractions, but the muscarinic [M.sub.2] receptor-preferring antagonist, methoctramine, abolished only the later phase of contractile response of DCLM to AJEA (Fig. 4B). Although it has been suggested that the extent of contribution of the muscarinic [M.sub.2] and [M.sub.3] receptors in ACh- or carbachol-mediated GI contractility differs with the type of smooth muscles and the species of animals (Barocelli et al. 1995), we carefully consider that AJEA may have high affinity with the muscarinic [M.sub.3] receptors, and the contractile response of DCLM to AJEA may largely result from activation of the muscarinic [M.sub.3] receptors. However, to understand clearly these speculations, further studies are needed to elucidate the pharmacological affinity of AJEA with the muscarinic receptor subtypes.

In addition, 5-HT is also generally considered as important excitatory neurotransmitter acting on the GI smooth muscles. Among seven different subtypes of 5-HT receptors, the 5-[HT.sub.3] and 5-[HT.sub.4] receptors are known to facilitate ACh release at the myenteric neurons and nerve terminals of GI tracts, followed by producing the smooth muscle contractions (Chetty et al. 2006; Jin et al. 1999; Talley 2001; Taniyama et al. 2000). These cellular events lead us to suppose that activation of serotoninergic receptors also possibly mediates the stimulatory effects of AJEA on the DCLM contractility through enhancing ACh releases. However, this hypothesis was revealed not to be true. The contractile responses of DCLM to AJEA were not affected after application of the 5-HT receptor antagonists, methysergide, ondansetron and GR113808 in combination (Fig. 4C), suggesting that AJEA-induced DCLM contractions are not likely mediated, at least, by a direct action of the serotoninergic receptors. It has been suggested that 5-HT can produce the different responses such as muscle contraction and relaxation depending on the experimental conditions (Kim and Camilleri 2000). Under the condition used in this study, a transient tonic contraction was occurred immediately after treatment of DCLM with 5-HT (Fig. 3A), and these stimulatory effects were remarkably abolished by 5-HT receptor antagonists (data not shown). Therefore, we could consider that a negative effect of 5-HT receptor antagonist on the AJEA-induced DCLM contractions is not likely related with the experimental condition and animal species, and serotoninergic mechanism may be not implicated in the stimulatory effect of AJEA on the DCLM contractility.

Inhibitory effects of the muscarinic [M.sub.3] receptor antagonist can not be account for solely on the basis of pharmacological mechanism involved in the AJEA-induced contraction of DCLM, because there are significant differences of contractile patterns between ACh- and AJEA-induced DCLM contractility (Fig. 3A). It has been reported that TPH expressed in the nerve cell bodies and fibers of human and rat GI tracts has the ability to synthesize 5-HT (Yu et al. 1999), and 5-HT enhances the ACh release at the myenteric neuron and nerve terminal of GI smooth muscles (Jin et al. 1999; Talley 2001). So, we have considered that in addition to the muscarinic receptors, the de novo cellular pathway possibly mediates the stimulatory effect of AJEA on the spontaneous contractility of DCLM in rats and made a hypothesis as following: AJEA activates the ChAT and TPH activity at presynaptic enteric nerves, and their activation can stimulate the ACh release at the myenteric neurons and nerve terminals, results in producing the DCLM contractions. We observed that the contractile responses of DCLM on AJEA were significantly abolished by blockade of ChAT with acetylethyl-choline mustard, whereas they were not affected by inhibition of TPH with p-chlorophenyl alanine. These results are well consistent with results, indicating that AJEA-induced DCLM contraction is remarkably diminished by application of the muscarinic [M.sub.3] receptor blockade using 4-DAMP, and suggest that ChAT activation likely mediates the AJEA-induced DCLM contractions. This speculation can be supported by the previous report (Majcen and Brzin 1979), suggesting that ChAT in rat ileum regulates the longitudinal muscle contractility with connection with calcium movement and intrinsic cholinergic mechanisms.

Collectively, the present results suggest that EtOAc extracts of Atractylodes japonica, AJEA, dose-dependently stimulate the spontaneous contractility of DCLM in rats, and the stimulatory activity of AJEA is likely mediated, at least, by increase of ACh synthesis and sequential activation of the acetylcholinergic muscarinic receptors, primarily the [M.sub.3] receptor. To our knowledge, this study provides for the first time the scientific evidences to understand the therapeutic property of Atractylodes japonica for modulating the dysfunction of GI motility in Korean traditional medicine.

Acknowledgements

The authors thank Prof. Hong Jun Kim, College of Oriental Medicine, Woosuk University for authentication of plant materials and Mr. Koji Suzuki (GL Sciences, Tokyo, Japan) for technical assistance with the chromatographic Smart LC analysis. This study was financially supported by Wonkwang University Research Grant in 2009.

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Keun Han Choi (a), (1), Seung Il Jeong (b), (1), Jun Ho Lee (a), (1), Byung Soon Hwang (b), Sang Jun Kim (b), Seoul Lee (a), Bong Kyu Choi (a), Kyu Yong Jung (a), *

(a) Department of Pharmacology, Wonkwang University School of Medicine, 344-2 Shinyong-dong, Iksan, Jeonbuk 570-749. Republic of Korea

(b) Jeonju Biomaterials Institute. Jeonbuk 561-360. Republic of Korea

* Corresponding author. Tel.: +82 63 850 6796; fax: +82 63 851 0879. E-mail address: wkuniv@wonkwang.ac.kr(K.Y. Jung).

(1) Shared first author ship because they contributed equally to this work.

0944-7113/$ - see front matter [c] 2010 Elsevier GmbH. All rights reserved.

doi:10.1016/j.phymed.2010.08.010
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Author:Choi, Keun Han; Jeong, Seung Il; Lee, Jun Ho; Hwang, Byung Soon; Kim, Sang Jun; Lee, Seoul; Choi, Bo
Publication:Phytomedicine: International Journal of Phytotherapy & Phytopharmacology
Article Type:Report
Geographic Code:9SOUT
Date:Mar 15, 2011
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