{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T20:18:03Z","timestamp":1785529083196,"version":"3.56.0"},"reference-count":35,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2015,8,11]],"date-time":"2015-08-11T00:00:00Z","timestamp":1439251200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"intramural funding, provided by the E-Da hospital","award":["EDAHP103008"],"award-info":[{"award-number":["EDAHP103008"]}]},{"name":"intramural funding, provided by the E-Da hospital","award":["EDAHP103036"],"award-info":[{"award-number":["EDAHP103036"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Up to 40% of patients with gastroesophageal reflux disease (GERD) suffer from proton pump inhibitor refractory GERD but clinically the medications to strengthen the lower esophageal sphincter (LES) to avoid irritating reflux are few in number. This study aimed to examine whether Salvia miltiorrhiza (SM) extracts induce tonic contraction of rat LES ex vivo and elucidate the underlying mechanisms. To investigate the mechanism underlying the SM extract-induced contractile effects, rats were pretreated with atropine  (a muscarinic receptor antagonist), tetrodotoxin (a sodium channel blocker), nifedipine  (a calcium channel blocker), and Ca2+-free Krebs-Henseleit solution with ethylene glycol tetraacetic acid (EGTA), followed by administration of cumulative dosages of SM extracts. SM extracts induced dose-related tonic contraction of the LES, which was unaffected by tetrodotoxin, atropine, or nifedipine. However, the SM extract-induced LES contraction was significantly inhibited by Ca2+-free Krebs-Henseleit solution with EGTA. Next, SM extracts significantly induce extracellular Ca2+ entry into primary LES cells in addition to intracellular Ca2+ release and in a dose-response manner. Confocal fluorescence microscopy showed that the SM extracts consistently induced significant extracellular Ca2+ influx into primary LES cells in a time-dependent manner. In conclusion, SM extracts could induce tonic contraction of LES mainly through the extracellular Ca2+ influx pathway.<\/jats:p>","DOI":"10.3390\/molecules200814504","type":"journal-article","created":{"date-parts":[[2015,8,11]],"date-time":"2015-08-11T10:38:57Z","timestamp":1439289537000},"page":"14504-14521","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Salvia miltiorrhiza Induces Tonic Contraction of the Lower Esophageal Sphincter in Rats via Activation of Extracellular  Ca2+ Influx"],"prefix":"10.3390","volume":"20","author":[{"given":"Ching-Chung","family":"Tsai","sequence":"first","affiliation":[{"name":"School of Pharmacy, Kaohsiung Medical University, No. 100, Shih-Chuan 1st Road,  Sanmin District, Kaohsiung City 807, Taiwan"},{"name":"Departments of Pediatrics, E-Da Hospital, I-Shou University, No. 1, Yida Road, Jiaosu Village, Yanchao District, Kaohsiung City 824, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li-Ching","family":"Chang","sequence":"additional","affiliation":[{"name":"Department of Occupational Therapy, I-Shou University, No. 8, Yida Road, Jiaosu Village, Yanchao District, Kaohsiung City 824, Taiwan"},{"name":"Department of Pharmacy, E-Da Hospital, I-Shou University, No.1, Yida Road, Jiaosu Village, Yanchao District, Kaohsiung City 824, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shih-Che","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, E-Da Hospital, I-Shou University, No. 1, Yida Road, Jiaosu Village,  Yanchao District, Kaohsiung City 824, Taiwan"},{"name":"School of Medicine, I-Shou University, No. 8, Yida Road, Jiaosu Village, Yanchao District, Kaohsiung City, 824, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shu-Leei","family":"Tey","sequence":"additional","affiliation":[{"name":"Departments of Pediatrics, E-Da Hospital, I-Shou University, No. 1, Yida Road, Jiaosu Village, Yanchao District, Kaohsiung City 824, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen-Li","family":"Hsu","sequence":"additional","affiliation":[{"name":"Institute of Basic Medical Sciences, Medical College, National Cheng Kung University, No. 1, Dasyue Road, East District, Tainan City 701, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu-Tsun","family":"Su","sequence":"additional","affiliation":[{"name":"Departments of Pediatrics, E-Da Hospital, I-Shou University, No. 1, Yida Road, Jiaosu Village, Yanchao District, Kaohsiung City 824, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ching-Wen","family":"Liu","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Kaohsiung Medical University, No. 100, Shih-Chuan 1st Road,  Sanmin District, Kaohsiung City 807, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tong-Rong","family":"Tsai","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Kaohsiung Medical University, No. 100, Shih-Chuan 1st Road,  Sanmin District, Kaohsiung City 807, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2015,8,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1111\/j.1365-2982.2005.00661.x","article-title":"The lower oesophageal sphincter","volume":"17","author":"Boeckxstaens","year":"2005","journal-title":"Neurogastroenterol. 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