ANIMAL CELLS AND SYSTEMS 2020, VOL. 24, NO. 2, 84–90 https://doi.org/10.1080/19768354.2020.1746398 Hesperidin depolarizes the pacemaker potentials through 5-HT receptor in murine small intestinal interstitial cells of Cajal a b b Minwoo Hwang , Jeong Nam Kim and Byung Joo Kim a b Department of Sasang Constitutional Medicine, College of Korean Medicine, Kyung Hee University, Seoul, Republic of Korea; Division of Longevity and Biofunctional Medicine, Pusan National University School of Korean Medicine, Yangsan, Republic of Korea ABSTRACT ARTICLE HISTORY Received 2 December 2019 Hesperidin, a citrus ﬂavonoid, can exert numerous beneﬁcial eﬀects on human health. Interstitial Revised 4 March 2020 cells of Cajal (ICC) are pacemaker cells in the gastrointestinal (GI) tract. In the present study, we Accepted 19 March 2020 investigated potential eﬀects of hesperidin on pacemaker potential of ICC in murine small intestine and GI motility. A whole-cell patch-clamp conﬁguration was used to record pacemaker KEYWORDS potential in ICC, and GI motility was investigated in vivo by recording gastric emptying (GE) and Hesperidin; interstitial cells of intestinal transit rate (ITR). Hesperidin depolarized pacemaker potentials of ICC in a dose- Cajal; gastrointestinal dependent manner. Pre-treatment with methoctramine or 4-DAMP did not inhibit hesperidin- motility; pacemaker potential induced pacemaker potential depolarization. Neither a 5-HT receptor antagonist (Y25130) nor a 5-HT receptor antagonist (SB269970) reduced the eﬀect of hesperidin on ICC pacemaker potential, whereas the 5-HT receptor antagonist RS39604 was found to inhibit this eﬀect. In the presence of GDP–β–S, hesperidin-induced pacemaker potential depolarization was inhibited. Moreover, in the presence of U73122 and calphostin C, hesperidin did not depolarize pacemaker potentials. Furthermore, hesperidin accelerated GE and ITR in vivo. These results imply that hesperidin depolarized ICC pacemaker potential via 5-HT receptors, G protein, and PLC/PKC dependent pathways and that it increased GI motility. Therefore, hesperidin may be a promising novel drug to regulate GI motility. Introduction reduced, GI motility also decreases (Der et al. 2000; Wei et al. 2014). Potential eﬀects of hesperidin on GI Polyphenols occur in various plants and are important for motility have not yet been comprehensively investi- their defense systems; ﬂavonoids are a group of polyphe- gated; therefore, in the current study, we assessed the nols which are particularly common in edible plants that eﬀects of hesperidin on ICC in vitro and on GI motility constitute a large part of human diet (Cho et al. 2018; in vivo. Chung et al. 2018; Stevens et al. 2019). The predominant ﬂavonoid in sweet fruits is hesperidin (Garg et al. 2001) which also occurs frequently in vegetables and bev- Materials and methods erages such as tea and red wine (Orallo et al. 2004; Preparation of cell cultures Bock et al. 2008). Hesperidin is known to exert various eﬀects on humans including anti-inﬂammatory activity Animal experiments were conducted in compliance with (Garg et al. 2001). Moreover, hesperidin has been the stipulations of the animal experiment ethics commit- reported to regulate gastrointestinal (GI) motility by tee of Pusan National University (approval no. PNU-2018- reducing inﬂammatory reactions and stimulating 1832). Small intestines of ICR mice were isolated, and the calcium release (Xiong et al. 2016). mucous membrane was excised. Small-intestinal muscles 2+ GI motility is controlled by numerous diﬀerent cell were equilibrated using Ca -free Hank’s solution. Cells types in the GI tract, and among these, ICC plays a key were enzymatically isolated using collagenase role (Huizinga et al. 1995;Sanders 1996;Kim et al. (Worthington Biochemical, Lakewood, NJ, USA) and 2005). ICC can generate electrical charges (Huizinga were then cultured in smooth muscle growth medium et al. 1995;Sanders 1996;Kim et al. 2005), and when ([SMGM]; Clonetics, San Diego, CA, USA) inside a CO ICC abundance and intercellular connectivity are incubator and at 37°C. CONTACT Byung Joo Kim firstname.lastname@example.org Division of Longevity and Biofunctional Medicine, Pusan National University School of Korean Medicine, 49 Busandaehakro, Mulgeum-eup, Yangsan 50612, Republic of Korea © 2020 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. TRANSLATIONAL MEDICINE ANIMAL CELLS AND SYSTEMS 85 Patch-clamp experiments ± 0.5 mV at 1 μM, 13.1 ± 0.7 mV (P < 0.01) at 10 μM, and 24.8 ± 1.3 mV (P < 0.01) at 30 μM(Figure 1D), and ampli- Na -Tyrode solution was used in bath, and the solution tude values were 24.3 ± 1.0 mV at 1 μM, 13.0 ± 0.7 mV (P was produced using KCl 140, MgCl 5, K ATP 2.7, 2 2 < 0.01) at 10 μM, and 2.7 ± 0.6 mV (P < 0.01) at 30 μM NaGTP 0.1, creatine phosphate disodium 2.5, HEPES 5, (Figure 1E). and EGTA 0.1. Electrophysiological analyses were con- ducted, and results were analyzed using pClamp (Mol- Hesperidin-induced pacemaker potential ecular Devices, Sunnyvale, CA, USA) and Origin depolarization in ICC and muscarinic receptors software (version 6.0, Microcal, USA). Previous studies suggested that muscarinic receptors aﬀect excitatory nerve transmission in the GI tract (Hui- Assessment of gastric emptying (GE) zinga et al. 1984; Inoue and Chen 1993). Moreover, M2 Twenty minutes after administering phenol red solution, and M3 subtypes of muscarinic receptors occur in cul- stomachs tissue was cut into several pieces which were tured ICC (Epperson et al. 2000). Therefore, we investi- placed in sodium hydroxide. Tissue preparations were gated involvement of M2 and M3 subtypes in then centrifuged with NaOH at 1050 × g for 10 min, hesperidin-induced pacemaker potential depolarization and absorbance was measured using a spectrometer at in ICC. Neither methoctramine (an M2 receptor antagon- 560 nm, according to previously published methods. ist) nor 4-DAMP (an M3 receptor antagonist) produced an eﬀect on hesperidin-induced pacemaker potential depolarization (Figure 2A,B, respectively). Depolarization Intestinal transit rate (ITR) measurements values were 13.5 ± 0.7 mV with methoctramine and 13.1 Mice were administered hesperidin, followed by oral ± 0.8 mV with 4-DAMP (Figure 2C), and amplitude values administration of Evans Blue. Thirty minutes later, were 12.2 ± 0.8 mV with methoctramine and 13.4 ± animals were euthanized, and ITR was measured accord- 0.5 mV with 4-DAMP (Figure 2D). ing to the distance over which Evans Blue had been transported in the intestine (expressed as percentage Involvement of the 5-HT receptor in of the length of the intestine). hesperidin-induced pacemaker potential depolarization in ICC Drugs 5-HT receptors are known to be involved in the function of GI motility, thus we investigated the involvement of 5- 5-HT receptor antagonists were obtained from Tocris HT receptors (Gershon and Tack 2007). Previous studies Bioscience (Bristol, United Kingdom). All other reagents found that only 5-HT R were expressed (Liu et al. including hesperidin were purchased from Sigma- 3,4,7 2011; Shahi et al. 2011). Neither 5-HT receptor antagon- Aldrich (St. Louis, MO, USA). 3 ist Y25130 nor 5-HT receptor antagonist SB269970 showed any eﬀect on hesperidin-induced responses Statistical analyses (Figure 3A,C); however, 5-HT receptor antagonist RS39604 inhibited the eﬀect of hesperidin on pacemaker Results are shown as means ± standard error. We potentials of ICC (Figure 3B). In the presence of hesperi- employed an ANOVA to test eﬀects of hesperidin on din and 5-HT receptor antagonists, depolarization values the respective parameters using Prism 6.0 software were 14.0 ± 0.8 mV with Y25130, 13.4 ± 0.6 mV (P < 0.01) (La Jolla, CA, USA). Statistical signiﬁcance is reported at with RS39604, and 13.1 ± 0.8 mV with SB269970 (Figure P < 0.05. 3D), and mean amplitude values were 12.1 ± 1.4 mV with Y25130, 19.5 ± 1.3 mV (P < 0.01) with RS39604, and Results 13.0 ± 0.7 mV with SB269970 (Figure 3E). Eﬀect of hesperidin on pacemaker potentials in ICC Involvement of G proteins in hesperidin-induced pacemaker potential depolarization in ICC Spontaneous pacemaker potentials were observed in ICC. The membrane potential was −56.3 ± 1.7 mV, and GDP–β–S were used to inactivate G–protein (Komori the amplitude was 26.6 ± 1.2 mV. Hesperidin depolarized et al. 1992; Ogata et al. 1996). When GDP–β–S occurred pacemaker potentials in a dose-dependent manner (1– in the cell, hesperidin-induced pacemaker potential 30 μM; Figure 1A–C). Values of depolarization were 1.7 depolarization was inhibited (Figure 4A). In presence of 86 M. HWANG ET AL. Figure 1. Eﬀects of hesperidin on pacemaker potentials of murine small intestine ICC. (A–C) Hesperidin depolarized pacemaker poten- tials of ICC. (D and E) Summaries of pacemaker potential depolarization and amplitude changes due to hesperidin. Bars indicate mean values ± SEs. **P < 0.01. CTRL: Control. GDP–β–S, a depolarization value of 1.7 ± 0.5 mV was controls (55.4 ± 1.9%). GE values in hesperidin treatments observed (P < 0.01; Figure 4B), and the mean amplitude were 58.9 ± 3.4% at 10 mg/kg and 63.9 ± 2.8% at 20 mg/ value was 22.6 ± 1.1 mV (P < 0.01) (Figure 4C). kg (P < 0.01; Figure 6A). The GE values of mosapride and domperidone were 65.7 ± 2.0% (P < 0.01) and 63.1 ± 1.4% (P < 0.01; Figure 6A), respectively. Involvement of phospholipase C (PLC), protein kinase A (PKA), and protein kinase C (PKC) in Eﬀects of hesperidin on ITR hesperidin-induced pacemaker potential depolarization in ICC The mean ITR value in untreated mice, 10 mg/kg hesper- idin treatment, and 20 mg/kg hesperidin treatment was To investigate the involvement of PLC, PKA, and PKC 52.7 ± 2.7%, 54.1 ± 2.3%, and 62.3 ± 1.6%, respectively pathways, we used U73122 (a PLC inhibitor), KT5720 (a (P < 0.01; Figure 6B). PKA inhibitor), and calphostin C (a PKC inhibitor). Neither U73122 nor calphostin C produced an eﬀect on hesperidin-associated responses (Figure 5A,C); however, Discussion in the presence of KT5720, hesperidin was depolarized We investigated eﬀects of hesperidin on pacemaker (Figure 5B). In the presence of U73122, KT5720, or cal- potential in ICC and on GI motility. Hesperidin depolar- phostin C, depolarization values were 1.3 ± 0.4 mV (P < ized pacemaker potentials through 5-HT receptors via 0.01) with U73122, 13.4 ± 1.7 mV with KT5720, and 1.1 G protein and PLC/PKC dependent pathways but not ± 0.2 mV (P < 0.01) with calphostin C (Figure 5D), and through muscarinic receptors, indicating that hesperidin amplitude values were 2.1 ± 0.7 mV (P < 0.01) with can modulate ICC. Furthermore, hesperidin increased GE U73122, 12.8 ± 1.5 mV with KT5720, and 23.7 ± 0.8 mV and ITR. (P < 0.01) with calphostin C (Figure 5E). Hesperidin is commonly found in highly nutritious fruits such as oranges, tangelos, tangerines, grapefruits, Eﬀects of hesperidin on GE and other citrus fruits (Suzuki et al. 2014). Hesperidin Eﬀects of hesperidin were compared with those of mosa- has been shown to exert numerous biological functions pride and domperidone. Mice treated with hesperidin (Hou et al. 2012); therefore, hesperidin has been com- (10 and 20 mg/kg) showed higher GE values than monly used to treat various disorders including ANIMAL CELLS AND SYSTEMS 87 Figure 2. Eﬀects of muscarinic receptor antagonists on hesperidin-induced pacemaker potential depolarization in ICC. (A) In presence of methoctramine, hesperidin depolarized pacemaker potentials of ICC. (B) With 4-DAMP, hesperidin depolarized pacemaker potentials of ICC. (C and D) Summaries of pacemaker potential depolarization and amplitude changes due to hesperidin with muscarinic receptor antagonists. Bars indicate mean values ± SEs. **P < 0.01. CTRL: Control. Methoc.: Methoctramine. Figure 3. Eﬀects of 5-HT receptor antagonists on hesperidin-induced pacemaker potential depolarization in ICC. (A) In presence of Y25130 (5-HT receptor antagonist), hesperidin depolarized pacemaker potentials of ICC. (B) In presence of RS39604 (a 5-HT receptor 3 4 antagonist), hesperidin did not depolarize pacemaker potential of ICC. (C) In presence of SB269970 (a 5-HT receptor antagonist), hesperidin depolarized pacemaker potential of ICC. (D and E) Summaries of pacemaker potential depolarization and amplitude changes due to hesperidin with 5-HT receptor antagonists. Bars indicate mean values ± SEs. **P < 0.01. CTRL: Control. Y.: Y25130. RS.: RS39604. SB.: SB269970. 88 M. HWANG ET AL. Figure 4. Eﬀects of GDP–β–S on hesperidin–induced pacemaker potential depolarization in ICC. (A) In presence of GDP–β–S (1 mM), hesperidin had no eﬀects. (B and C) Summaries of pacemaker potential depolarization and amplitude changes due to hesperidin with GDP–β–S. Bars indicate mean values ± SEs. **P < 0.01. CTRL: Control. neurological, psychiatric, and cardiovascular diseases (Li rikkunshito (Li and Schluesener 2017). Rikkunshito is a and Schluesener 2017). Furthermore, hesperidin is traditional herbal remedy to promote appetite and is being used in combination with other drugs such as commonly used in Japan to treat indigestion (Arai et al. Figure 5. Eﬀects of phospholipase C (PLC), protein kinase A (PKA), and protein kinase C (PKC) inhibitors on hesperidin-induced pace- maker potential depolarization in ICC. (A) In the presence of U73122 (a PLC inhibitor), hesperidin showed no eﬀect. (B) In the presence of KT5720 (a PKA inhibitor), hesperidin depolarized pacemaker potential of ICC. (C) In the presence of calphostin C (a PKC inhibitor), hesperidin showed no eﬀect. (D and E) Summaries of pacemaker potential depolarization and amplitude changes due to hesperidin with PLC, PKA, or PKC inhibitors. Bars indicate mean values ± SEs. **P < 0.01. CTRL: Control. ANIMAL CELLS AND SYSTEMS 89 Figure 6. Eﬀect of hesperidin on gastric emptying (GE) and intestinal transit rates (ITR). (A) For comparison, we used mosapride and domperidone. Hesperidin increased GE values. (B) Hesperidin accelerated ITR. Bars indicate mean values ± SEs. **P < 0.01. CTRL: Control. Mosa.: Mosapride; Dom.: Domperidone. i.g.: intragastric. 2012; Takiguchi et al. 2013). Hesperidin stimulates suggested that 5-HT can control pacemaker activity ghrelin secretion, thus synergistic eﬀects of mixing through 5-HT , 5-HT , and 5-HT receptors (Shahi et al. 3 4 7 hesperidin with rikkunshito produced promising good 2011). In the present study, RS39604 blocked hesperidin results. In addition, hesperidin is readily available and eﬀects, whereas Y25130 and SB269970 showed no inexpensive, therefore it can be manufactured and com- respective eﬀect. Thus, 5-HT receptors were apparently mercialized for therapeutic purposes as well as in the involved in hesperidin-induced eﬀects on ICC (Figure 3). food industry. In the present study, we found that Furthermore, G-protein and PLC/PKC pathways are hesperidin modulated pacemaker potentials in ICC. involved in hesperidin-induced eﬀects in ICC (Figures 4 Therefore, we suggest that hesperidin may regulate GI and 5). In addition, we found that hesperidin increased motility via ICC pacemaker potential. GE and ITR (Figure 6). GI motility disorders are very common and occur Polyphenols occur naturally in various fruits and veg- throughout the GI tract, and the associated symptoms etables. However, potential eﬀects of polyphenols on can substantially aﬀect the quality of life (Pare et al. human health remain to be elucidated. Our results 2001; El-Serag and Talley 2003; Lacy and Weiser 2006; suggest that polyphenols such as hesperidin may be Lacy et al. 2018). Moreover, these disorders are of sub- an option for prevention and treatment of GI disorders. stantial economical concern (Sandler et al. 2002; Lacy Taken together, our results show that hesperidin et al. 2018). ICC are important for GI motility (Huizinga depolarizes pacemaker potentials of ICC via 5-HT recep- et al. 1995; Sanders 1996; Kim et al. 2005). ICC spon- tors, G protein, and PLC/PKC dependent pathways, and taneously generate active pacemaker potential, causing increases GE and ITR. electrical and mechanical activity of smooth muscles (Huizinga et al. 1995; Sanders 1996; Kim et al. 2005). In Acknowledgements 2+ − ICC, a Ca -activated Cl channel and a non-selective cation channel are required for pacemaking activity, MH and BJK conceived of and designed the experiments. JNK performed the experiments. MH and BJK wrote and edited and the ether-a-go-go-related K channel is also one of + the paper. This study was supported by a Korean National the most important K channels for maintaining and acti- Research Foundation (NRF) grant funded by the Korean govern- vating stable membrane voltage in ICC (Zhu et al. 2003; ment (MSIP) (grant No. 2014R1A5A2009936). Kim et al. 2005; Zhu et al. 2009). Further studies on the involvement of ion channels in hesperidin-related eﬀects are required. Disclosure statement Muscarinic receptors are important receptors for reg- No potential conﬂict of interest was reported by the author(s). ulating GI motility (Hirst et al. 2002). In the present study, both methoctramine and 4-DAMP produced no eﬀects on hesperidin reactions. Thus, muscarinic receptors References were apparently not involved in hesperidin eﬀects on Arai M, Matsumura T, Tsuchiya N, Sadakane C, Inami R, Suzuki T, ICC (Figure 2). Furthermore, 5-HT plays a crucial role in Yoshikawa M, Imazeki F, Yokosuka O. 2012. Rikkunshito regulating GI motility (Baker 2005). 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Animal Cells and Systems
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Published: Mar 3, 2020
Keywords: Hesperidin; interstitial cells of Cajal; gastrointestinal motility; pacemaker potential