Salvia miltiorrhiza induces depolarization of pacemaker potentials in murine small intestinal interstitial cells of Cajal via extracellular Ca2+ and Na+ influx

Han,Donghun; Kim,Jeong Nam; Kwon,Min Ji; Han,Taewon; Kim,Yun Tai; Kim,Byung Joo

doi:10.3892/mmr.2021.11987

Salvia miltiorrhiza induces depolarization of pacemaker potentials in murine small intestinal interstitial cells of Cajal via extracellular Ca²⁺ and Na⁺ influx

Authors:
- Donghun Han
- Jeong Nam Kim
- Min Ji Kwon
- Taewon Han
- Yun Tai Kim
- Byung Joo Kim
View Affiliations

Affiliations: Division of Longevity and Biofunctional Medicine, Pusan National University School of Korean Medicine, Yangsan, Gyeongsangnam‑do 50612, Republic of Korea, Korea Food Research Institute, Wanju‑gun, Jeollabuk‑do 55365, Republic of Korea
Published online on: March 11, 2021 https://doi.org/10.3892/mmr.2021.11987
Article Number: 348

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Interstitial cells of Cajal (ICCs) are pacemaker cells that control smooth muscle contraction in the gastrointestinal (GI) tract. The present study investigated the effects of Salvia miltiorrhiza (SM) on the pacemaker potentials of ICCs from the mouse small intestine in vitro and on GI motility in vivo. The whole‑cell patch‑clamp configuration was used to record pacemaker potential in ICCs in vitro, and GI motility was investigated in vivo by recording intestinal transit rate (ITR). Using the whole‑cell patch‑clamp configuration, SM depolarized the pacemaker potentials of ICCs in a dose‑dependent manner. Fulvestrant blocked SM‑induced effects but 1,3‑dihydro‑3,3‑bis(4‑hydroxyphenyl)-7-methyl‑2H‑indol‑2‑one did not. Additionally, 4‑[2‑phenyl-5,7‑bis(trifluoromethyl) pyrazolo[1,5‑a]pyrimidin‑3‑yl] phenol blocked SM‑induced effects. Intracellular guanosine 5'‑O‑(2‑thiodiphosphate), and pretreatment with extracellular Ca²⁺‑ and Na⁺‑free solutions also blocked SM‑induced effects. Furthermore, ITR values were increased by SM in vivo and SM elevated the levels of motilin (MTL). The SM‑induced increase in ITR was associated with increased protein expression levels of c‑kit and the transmembrane protein 16A (TMEM16A) channel. In addition, SM induced pacemaker potential depolarization through estrogen receptor β in a G protein‑dependent manner via extracellular Ca²⁺ and Na⁺ regulation in the murine small intestine in vitro. Moreover, SM increased the ITR in vivo through the MTL hormone via c‑kit and TMEM16A‑dependent pathways. Taken together, these results suggested that SM may have the ability to control GI motility and could be used as a GI motility regulator.

View Figures

View References

1	Kim SY, Moon TC, Chang HW, Son KH, Kang SS and Kim HP: Effects of tanshinone I isolated from Salvia miltiorrhiza bunge on arachidonic acid metabolism and in vivo inflammatory responses. Phytother Res. 16:616–620. 2002. View Article : Google Scholar : PubMed/NCBI
2	Wu YJ, Hong CY, Lin SJ, Wu P and Shiao MS: Increase of vitamin E content in LDL and reduction of atherosclerosis in cholesterol-fed rabbits by a water-soluble antioxidant-rich fraction of Salvia miltiorrhiza. Arterioscler Thromb Vasc Biol. 18:481–486. 1998. View Article : Google Scholar : PubMed/NCBI
3	Guo Y, Li Y, Xue L, Severino RP, Gao S, Niu J, Qin LP, Zhang D and Bromme D: Salvia miltiorrhiza: An ancient Chinese herbal medicine as a source for antiosteoporotic drugs. J Ethnopharmacol. 155:1401–1416. 2014. View Article : Google Scholar : PubMed/NCBI
4	Ji XY, Tan BK and Zhu YZ: Salvia miltiorrhiza and ischemic diseases. Acta Pharmacol Sin. 21:1089–1094. 2000.PubMed/NCBI
5	Chan K, Chui SH, Wong DY, Ha WY, Chan CL and Wong RN: Protective effects of danshensu from the aqueous extract of Salvia miltiorrhiza (Danshen) against homocysteine-induced endothelial dysfunction. Life Sci. 75:3157–3171. 2004. View Article : Google Scholar : PubMed/NCBI
6	Zhang ZY, Chen XP and Lu QP: Effect of Salvia miltiorrhiza pretreatment on the CCK and VIP expression in hepatic ischemia-reperfusion-induced digestive tract congestion. Front Med China. 4:317–322. 2010. View Article : Google Scholar : PubMed/NCBI
7	Wen XD, Wang CZ, Yu C, Zhang Z, Calway T, Wang Y, Li P and Yuan CS: Salvia miltiorrhiza (Danshen) significantly ameliorates colon inflammation in dextran sulfate sodium induced colitis. Am J Chin Med. 41:1097–1108. 2013. View Article : Google Scholar : PubMed/NCBI
8	Xiping Z, Yan P, Xinmei H, Guanghua F, Meili M, Jie N and Fangjie Z: Effects of dexamethasone and Salvia miltiorrhizae on the small intestine and immune organs of rats with severe acute pancreatitis. Inflammation. 33:259–266. 2010. View Article : Google Scholar : PubMed/NCBI
9	Tsai CC, Huang SC, Liu JK, Wang HC, Tsai TR, Tsai PJ, Liu CW and Chang LC: Salvia miltiorrhiza causes tonic contraction in rat ileum through Ca²⁺-calmodulin pathway. J Ethnopharmacol. 142:694–699. 2012. View Article : Google Scholar : PubMed/NCBI
10	Tsai CC, Chang LC, Huang SC, Tey SL, Hsu WL, Su YT, Liu CW and Tsai TR: Salvia miltiorrhiza induces tonic contraction of the lower esophageal sphincter in rats via activation of extracellular Ca²⁺ influx. Molecules. 20:14504–14521. 2015. View Article : Google Scholar : PubMed/NCBI
11	Yang X, Guo Y, He J, Zhang F, Sun X, Yang S and Dong H: Estrogen and estrogen receptors in the modulation of gastrointestinal epithelial secretion. Oncotarget. 8:97683–97692. 2017. View Article : Google Scholar : PubMed/NCBI
12	Zhang JM, Li J, Liu EW, Wang H, Fan GW, Wang YF, Zhu Y, Ma SW and Gao XM: Danshen enhanced the estrogenic effects of qing E formula in ovariectomized rats. BMC Complement Altern Med. 16:1812016. View Article : Google Scholar : PubMed/NCBI
13	Fan G, Zhu Y, Guo H, Wang X, Wang H and Gao X: Direct vasorelaxation by a novel phytoestrogen tanshinone IIA is mediated by nongenomic action of estrogen receptor through endothelial nitric oxide synthase activation and calcium mobilization. J Cardiovasc Pharmacol. 57:340–347. 2011. View Article : Google Scholar : PubMed/NCBI
14	Evans RM: The steroid and thyroid hormone receptor superfamily. Science. 240:889–895. 1988. View Article : Google Scholar : PubMed/NCBI
15	Yasar P, Ayaz G, User SD, Güpür G and Muyan M: Molecular mechanism of estrogen-estrogen receptor signaling. Reprod Med Biol. 16:4–20. 2016. View Article : Google Scholar : PubMed/NCBI
16	Mapplebeck JC, Beggs S and Salter MW: Sex differences in pain: A tale of two immune cells. Pain. 157 (Suppl):S2–S6. 2016. View Article : Google Scholar : PubMed/NCBI
17	Mulak A and Bonaz B: Irritable bowel syndrome: A model of the brain-gut interactions. Med Sci Monit. 10:RA55–RA62. 2004.PubMed/NCBI
18	Sorge RE, Mapplebeck JC, Rosen S, Beggs S, Taves S, Alexander JK, Martin LJ, Austin JS, Sotocinal SG, Chen D, et al: Different immune cells mediate mechanical pain hypersensitivity in male and female mice. Nat Neurosci. 18:1081–1083. 2015. View Article : Google Scholar : PubMed/NCBI
19	Meleine M and Matricon J: Gender-Related differences in irritable bowel syndrome: Potential mechanisms of sex hormones. World J Gastroenterol. 20:6725–6743. 2014. View Article : Google Scholar : PubMed/NCBI
20	Huizinga JD, Thuneberg L, Klüppel M, Malysz J, Mikkelsen HB and Bernstein A: W/kit gene required for interstitial cells of cajal and for intestinal pacemaker activity. Nature. 373:347–349. 1995. View Article : Google Scholar : PubMed/NCBI
21	Kim BJ, Lim HH, Yang DK, Jun JY, Chang IY, Park CS, So I, Stanfield PR and Kim KW: Melastatin-Type transient receptor potential channel 7 is required for intestinal pacemaking activity. Gastroenterology. 129:1504–1517. 2005. View Article : Google Scholar : PubMed/NCBI
22	Sanders KM, Ward SM and Koh SD: Interstitial cells: Regulators of smooth muscle function. Physiol Rev. 94:859–907. 2014. View Article : Google Scholar : PubMed/NCBI
23	Chen X, Guo J, Bao J, Lu J and Wang Y: The anticancer properties of Salvia miltiorrhiza Bunge (Danshen): a systematic review. Med Res Rev. 34:768–794. 2014. View Article : Google Scholar : PubMed/NCBI
24	National Research Council (US) Committee for the Update of the Guide for the Care Use of Laboratory Animals: Guide for the Care and Use of Laboratory Animals, 8th edition. National Academies Press (US); Washington, DC: 2011
25	Kim JH and Kim BJ: Depolarization of pacemaker potentials by caffeic acid phenethyl ester in interstitial cells of cajal from the murine small intestine. Can J Physiol Pharmacol. 98:201–210. 2020. View Article : Google Scholar : PubMed/NCBI
26	Hwang M, Kim JN, Lee JR, Kim SC and Kim BJ: Effects of Chaihu-Shugan-san on small intestinal interstitial cells of Cajal in mice. Biol Pharm Bull. 43:707–715. 2020. View Article : Google Scholar : PubMed/NCBI
27	Koh SD, Sanders KM and Ward SM: Spontaneous electrical rhythmicity in cultured interstitial cells of cajal from the murine small intestine. J Physiol. 513:203–213. 1998. View Article : Google Scholar : PubMed/NCBI
28	Komori S, Kawai M, Takewaki T and Ohashi H: GTP-Binding protein involvement in membrane currents evoked by carbachol and histamine in guinea-pig ileal muscle. J Physiol. 450:105–126. 1992. View Article : Google Scholar : PubMed/NCBI
29	Ogata R, Inoue Y, Nakano H, Ito Y and Kitamura K: Oestradiol-Induced relaxation of rabbit basilar artery by inhibition of voltage-dependent Ca channels through GTP-binding protein. Br J Pharmacol. 117:351–359. 1996. View Article : Google Scholar : PubMed/NCBI
30	Ward SM: Interstitial cells of cajal in enteric neurotransmission. Gut. 47:40–43. 2000. View Article : Google Scholar
31	Liao QS, Du Q, Lou J, Xu JY and Xie R: Roles of Na⁺/Ca²⁺ exchanger 1 in digestive system physiology and pathophysiology. World J Gastroenterol. 25:287–299. 2019. View Article : Google Scholar : PubMed/NCBI
32	Kim H, Kim I, Lee MC, Kim HJ, Lee GS, Kim H and Kim BJ: Effects of hwangryunhaedok-tang on gastrointestinal motility function in mice. World J Gastroenterol. 23:2705–2715. 2017. View Article : Google Scholar : PubMed/NCBI
33	Huang F, Rock JR, Harfe BD, Cheng T, Huang X, Jan YN and Jan LY: Studies on expression and function of the TMEM16A calcium-activated chloride channel. Proc Natl Acad Sci USA. 106:21413–21418. 2009. View Article : Google Scholar : PubMed/NCBI
34	Zhu MH, Kim TW, Ro S, Yan W, Ward SM, Koh SD and Sanders KM: A Ca(2+)-activated Cl(−)conductance in interstitial cells of cajal linked to slow wave currents and pacemaker activity. J Physiol. 587:4905–4918. 2009. View Article : Google Scholar : PubMed/NCBI
35	Sanders KM, Koh SD, Ro S and Ward SM: Regulation of gastrointestinal motility-insights from smooth muscle biology. Nat Rev Gastroenterol Hepatol. 9:633–645. 2012. View Article : Google Scholar : PubMed/NCBI
36	Lam FFY, Deng SY, Ng ESK, Yeung JHK, Kwan YW, Lau CBS, Loon JCM, Zhou L, Zuo Z, Leung PC and Fung KP: Mechanisms of the relaxant effect of a danshen and gegen formulation on rat isolated cerebral basilar artery. J Ethnopharmacol. 132:186–192. 2010. View Article : Google Scholar : PubMed/NCBI
37	Eyster KM: The estrogen receptors: An overview from different perspectives. Methods Mol Biol. 1366:1–10. 2016. View Article : Google Scholar : PubMed/NCBI
38	Li Y, Xu J, Jiang F, Jiang Z, Liu C, Li L, Luo Y, Lu R, Mu Y, Liu Y and Xue B: G protein-coupled estrogen receptor is involved in modulating colonic motor function via nitric oxide release in C57BL/6 female mice. Neurogastroenterol Motil. 28:432–442. 2016. View Article : Google Scholar : PubMed/NCBI
39	Vivacqua A, Bonofiglio D, Recchia AG, Musti AM, Ando DPS and Maggiolini M: The G protein-coupled receptor GPR30 mediates the proliferative effects induced by 17beta-estradiol and hydroxytamoxifen in endometrial cancer cells. Mol Endocrinol. 20:631–646. 2006. View Article : Google Scholar : PubMed/NCBI
40	Zielińska M, Fichna J, Bashashati M, Habibi S, Sibaev A, Timmermans JP and Storr M: G protein-coupled estrogen receptor and estrogen receptor ligands regulate colonic motility and visceral pain. Neurogastroenterol Motil. 29:1–11. 2017. View Article : Google Scholar
41	Zhu MH, Sung IK, Zheng H, Sung TS, Britton FC, O'Driscoll K, Koh SD and Sanders KM: Muscarinic activation of Ca²⁺-activated Cl⁻ current in interstitial cells of cajal. J Physiol. 589:4565–4582. 2011. View Article : Google Scholar : PubMed/NCBI
42	Zhu MH, Sung TS, O'Driscoll K, Koh SD and Sanders KM: Intracellular Ca(2+) release from endoplasmic reticulum regulates slow wave currents and pacemaker activity of interstitial cells of cajal. Am J Physiol Cell Physiol. 308:C608–C620. 2015. View Article : Google Scholar : PubMed/NCBI
43	Drumm BT, Hennig GW, Battersby MJ, Cunningham EK, Sung TS, Ward SM, Sanders KM and Baker SA: Clustering of Ca²⁺ transients in interstitial cells of cajal defines slow wave duration. J Gen Physiol. 149:703–725. 2017. View Article : Google Scholar : PubMed/NCBI
44	Jun JY, Choi S, Yeum CH, Chang IY, You HJ, Park CK, Kim MY, Kong ID, Kim MJ, Lee KP, et al: Substance P induces inward current and regulates pacemaker currents through tachykinin NK1 receptor in cultured interstitial cells of cajal of murine small intestine. Eur J Pharmacol. 495:35–42. 2004. View Article : Google Scholar : PubMed/NCBI
45	Zheng H, Drumm BT, Zhu MH, Xie Y, O'Driscoll KE, Baker SA, Perrino BA, Koh SD and Sanders KM: Na⁺/Ca^{2 +} exchange and pacemaker activity of interstitial cells of cajal. Front Physiol. 11:2302020. View Article : Google Scholar : PubMed/NCBI
46	Ahmed M and Ahmed S: Functional, Diagnostic and Therapeutic Aspects of Gastrointestinal Hormones. Gastroenterology Res. 12:233–244. 2019. View Article : Google Scholar : PubMed/NCBI
47	Thomas PA, Akwari OE and Kelly KA: Hormonal control of gastrointestinal motility. World J Surg. 3:545–552. 1979. View Article : Google Scholar : PubMed/NCBI
48	Peeters TL: Gastrointestinal hormones and gut motility. Curr Opin Endocrinol Diabetes Obes. 22:9–13. 2015. View Article : Google Scholar : PubMed/NCBI
49	Rehfeld JF: The new biology of gastrointestinal hormones. Physiol Rev. 78:1087–1108. 1998. View Article : Google Scholar : PubMed/NCBI
50	Dockray GJ: Gastrointestinal hormones and the dialogue between gut and brain. J Physiol. 592:2927–2941. 2014. View Article : Google Scholar : PubMed/NCBI
51	Hirst GD, Bramich NJ, Teramoto N, Suzuki H and Edwards FR: Regenerative component of slow waves in the guinea-pig gastric antrum involves a delayed increase in [Ca(2+)](i) and Cl(−) channels. J Physiol. 540:907–919. 2002. View Article : Google Scholar : PubMed/NCBI
52	Hwang SJ, Blair PJ, Britton FC, O'Driscoll KE, Hennig G, Bayguinov YR, Rock JR, Harfe BD, Sanders KM and Ward SM: Expression of anoctamin 1/TMEM16A by interstitial cells of cajal is fundamental for slow wave activity in gastrointestinal muscles. J Physiol. 587:4887–4904. 2009. View Article : Google Scholar : PubMed/NCBI
53	Maeda H, Yamagata A and Nishikawa S, Yoshinaga K, Kobayashi S, Nishi K and Nishikawa S: Requirement of c-kit for development of intestinal pacemaker system. Development. 116:369–753. 1992.PubMed/NCBI
54	Torihashi S, Ward SM, Nishikawa S, Nishi K, Kobayashi S and Sanders KM: C-Kit-Dependent development of interstitial cells and electrical activity in the murine gastrointestinal tract. Cell Tissue Res. 280:97–111. 1995. View Article : Google Scholar : PubMed/NCBI