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Bidirectional Regulation of Human Colonic Smooth Muscle

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Bidirectional Regulation of Human Colonic Smooth Muscle J Pharmacol Sci 117, 106 – 115 (2011) Journal of Pharmacological Sciences © The Japanese Pharmacological Society Full Paper Bidirectional Regulation of Human Colonic Smooth Muscle Contractility by Tachykinin NK2 Receptors Akihiro Nakamura1, Takahiro Tanaka1, Akio Imanishi2, Makiko Kawamoto2, Masao Toyoda3, Gaku Mizojiri3, and Yasuhiro Tsukimi1,* 1Inflammation Drug Discovery Unit, 2Exploratory Research Center, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 17-85, Jusohonmachi 2-Chome, Yodogawa-ku, Osaka 532-8686, Japan 3Department of Surgery, Saiseikai-Nakatsu Hospital, 10-39, Shibata 2-Chome, Kita-ku, Osaka 530-0012, Japan Received July 7, 2011; Accepted September 6, 2011 Abstract. In this study, we attempted to clarify the mechanism of tachykinin-induced motor response in isolated smooth muscle preparations of the human colon. Fresh specimens of normal colon were obtained from patients suffering from colonic cancer. Using mucosa-free smooth muscle strips, smooth muscle tension with circular direction was monitored isometrically. Sub- stance P (SP), neurokinin A (NKA), and neurokinin B (NKB) produced marked contraction. All of these contractions were inhibited by saredutant, a selective NK2-R antagonist, but not by CP122721, 8 a selective NK1-R antagonist or talnetant, a selective NK3-R antagonist. βAla -NKA(4-10) induced concentration-dependent contraction similar to NKA, but Sar9-Met11-SP and Met-Phe7-NKB did not cause marked contraction. Colonic contraction induced by βAla8-NKA(4-10) was completely G blocked by saredutant, but not by atropine. Tetrodotoxin or N -nitro-L-arginine methyl ester pre- treatment significantly enhanced βAla8-NKA(4-10)–induced contraction. Immunohistochemical analysis showed that the NK2-R was expressed on the smooth muscle layers and myenteric plexus where it was also co-expressed with neuronal nitric oxide synthase in the myenteric plexus. These results suggest that the NK2-R is a major contributor to tachykinin-induced smooth muscle con- traction in human colon and that the NK2-R–mediated response consists of an excitatory component via direct action on the smooth muscle and an inhibitory component possibly via nitric oxide neurons. Keywords: NK1 receptor, NK2 receptor, NK3 receptor, human colon, smooth muscle Introduction receptors (3). Since the late 20th century, a number of selective tachykinin receptor agonists and antagonists It is well known that tachykinins such as substance P have been developed and are useful as pharmacological (SP), neurokinin A (NKA), and neurokinin B (NKB) act tools for investigating the role of tachykinins and their as neurotransmitters (1). Three tachykinin receptors have receptors (4 – 8). been identified including neurokinin 1 receptor (NK1-R), Tachykinins and their receptors are abundantly ex- neurokinin 2 receptor (NK2-R), and neurokinin 3 recep- pressed in gut tissues (9), and it is thought that tachyki- tor (NK3-R) (1). These are Gq-coupled receptors and nins play an important role in gut motility. The role of their activation causes Ca2+ influx into the cells (2, 3). tachykinin receptors in gut motility has been intensively SP, NKA, and NKB preferentially bind to NK1-R, NK2- investigated in guinea pigs (10 – 12), rats (13), mice (14), R, and NK3-R, respectively; however their selectivity is and dogs (15). It has been suggested that there are species limited and it has been reported that each tachykinin has differences for each tachykinin receptor (16, 17), human the potential to act as a full agonist to each tachykinin tissue is essential for studies relevant to humans. Al- though excellent reviews (18 – 20) have summarized the *Corresponding author. [email protected] currently available information about tachykinin and Published online in J-STAGE on September 23, 2011 (in advance) their receptors, their role in gut contraction remains doi: 10.1254/jphs.11118FP controversial. Therefore, more evidence is still needed. 106 NK2 Receptor and Motility in Human Colon 107 To better understand the involvement of tachykinins who underwent abdominal surgery for colonic cancer. and their receptors in the human colon we performed the The responses to tachykinin were the same in these two following experiments: evaluated the contribution of preparations, so we combined the data from both of them tachykinin receptor subtypes with selective receptor an- to analyze the data. Isolated colon was immediately im- tagonists on tachykinin-induced smooth muscle contrac- mersed in ice-cold Krebs solution of the following tion in isolated colonic strips; evaluated the effects of composition: 120.7 mM NaCl, 15.5 mM NaHCO3, 5.9 muscarinic receptor blockade, inhibition of nitric oxide mM KCl, 1.2 mM NaH2PO4, 2.5 mM CaCl2, 1.2 mM synthesis, neuronal conductance on NK2-R–mediated MgCl2, and 11.5 mM glucose. The specimens were contraction; and conducted immunohistological studies transferred to the Takeda Pharmaceutical Company to visualize the NK2-R expression on the smooth muscle research center. After washing the tissue with Krebs layers and the myenteric plexus in relation to neuronal solution, mucosa was removed using fine forceps and nitric oxide synthase (nNOS). small pieces of smooth muscle with circular direction (approx. 5 mm × 1.5 cm) were prepared. These were Materials and Methods placed in a thermostated (35°C) glass-made organ bath filled with 10 mL of Krebs solution bubbled with Binding assay: tachykinin receptor binding assay 95% O2 / 5% CO2 and arranged for isometric recording For the NK1-R binding assay, cell membrane of IM9 of circular muscle mechanical activity with 1 g of ten- cells, a human lymphoblastoma cell line, which expresses sion. The signal was delivered to an electric recorder 125 the NK1 receptor (21), and [ I]-Bolton-Hunter–labeled (MLT-870; ADInstruments, Colorado Springs, CO, Lys3 Substance P (GE Healthcare Japan, Tokyo) were USA) via an amplifier (MLT-119, ADInstruments). All used as a source of NK1-R and its radio-labeled ligand, experiments were conducted according to the protocol respectively. Briefly, various concentrations of test approved by the ethical committees of Saiseikai-Nakatsu compounds and radiolabeled ligand (130 pM) were incu- Hospital and Takeda Pharmaceutical Company. bated with IM9 membranes (12.5 μg) in a final volume of 0.2 ml buffer [50 mM Tris-HCl (pH 7.4) containing Reagents 0.5% DMSO, 2.3 mM MnCl2, 0.02% BSA, 1.5 μg/mL The following substances were used: Substance P (SP; chymostatin, 30 μg/mL bacitracin, and 30 μg/mL Peptide Institute, Inc., Osaka); neurokinin A (NKA, APMSF] at room temperature for 30 min. The reactions Peptide Institute); neurokinin B (NKB, Peptide Institute); were terminated by rapid filtration through a GF/C filter Sar9-Met11-SP (American Peptide Company Inc., 8 plate (PerkinElmer Japan, Yokohama) presoaked with Sunnyvale, CA, USA), a selective NK1-R agonist; βAla - 0.3% polyethyl eneimine, following by ten washes with NKA(4-10) (Bachem, Bubendorf, Switzerland), a selec- 7 washing buffer [50 mM Tris-HCl (pH 7.4) containing tive NK2-R agonist; Met-Phe -NKB (Bachem), a selective 0.02% BSA]. Filters were dried and soaked in 20 μl/well NK3-R agonist. These were dissolved in dimethylsulfox- of Microscint 0 (PerkinElmer Japan) and receptor-bound ide (DMSO; Wako, Osaka) to prepare a 10 mM stock radioactivity was then measured using TopCount liquid solution, which was then diluted with distilled water to Scintillation counter (PerkinElmer Japan). working concentrations immediately prior to experimen- For NK2-R binding assay, various concentrations of tal use. The following selective tachykinin receptor an- test compounds and [125I]Neurokinin A (100 pM, GE tagonists were synthesized by Takeda Pharmaceutical Healthcare Japan) were incubated with the cell membrane Company and used for pharmacological analysis of of CHO cells expressing human NK2-R (2 μg) in a final tachykinin-induced smooth muscle contraction: volume of 0.2 ml reaction buffer at room temperature for CP122721, (2S,3S)-2-phenyl-3-[(5-trifluoromethoxy-2- 30 min. For the NK3-R binding assay, various concentra- methoxy) benzylamino]piperidine (6), an NK1-R antago- tions of test compounds and [125I]His, MePhe7-Neurokinin nist; saredutant (SR48968), [(S)-N-methyl-N-[4-acetyl- B (130 pM, PerkinElmer Japan) were incubated with the amino-4-phenylpiperidino-2-(3,4-dichlorophenyl) butyl] cell membrane of CHO cells expressing human NK3-R benzamide] (7), an NK2-R antagonist; and talnetant (15 μg) in a final volume of 0.2 ml reaction buffer at (SB223412), (S)-(−)-N-(alpha-ethylbenzyl)-3-hydroxy- room temperature for 30 min. 2-phenylquinoline-4-carboxamide (8), an NK3-R antago- nist. The antagonists were dissolved in DMSO. The an- Preparation of smooth muscle preparation of human tagonists were added to the organ baths to give a final colon DMSO concentration of 0.1%. Carbachol (CCh; Sigma, All studies were conducted on normal smooth muscle St. Louis, MO, USA), atropine (Wako), tetrodotoxin G strips of human descending or sigmoidal colon obtained (TTX, Wako), and N -nitro-L-arginine methyl ester (L- from 43 patients (age, 28 – 87 years; female:male, 26:17) NAME, Wako) were dissolved in distilled water. All 108 A Nakamura et al other reagents were of analytical grade. Tokyo). In another series of experiments, double-immunostain- Experimental protocol ing against NK2-R and nNOS was performed. Further- In the first series of experiments, natural tachykinins more, PGP 9.5 was also stained in order to visualize the or selective tachykinin receptor agonists were added to neuronal cells. The section (10 μm) was incubated with the organ bath in a cumulative manner from 0.001 to 10 rabbit anti–NK2-R antibody (1:200, LS-1288; MBL) and μM. The maximum contractile force from baseline was mouse anti-nNOS antibody (1:200, MONX10768; determined for each concentration. In this case, the con- SANBIO BV, Uden, Netherlands), or rabbit anti–PGP 9.5 tractile force measurements were determined after inves- antibody (1:200, RB-9202-R7; Thermo Scientific, tigating the response to CCh (1 μM) and maximum Fremont, CA, USA) and mouse anti-nNOS antibody contractile force was used as an internal control.
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