Kim Byung Joo, Kim Hyungwoo, Lee Guem San, So Insuk, Kim Seon Jeong
Division of Longevity and Biofunctional Medicine, Pusan National University School of Korean Medicine, Yangsan 626-870, Republic of Korea.
Division of Pharmacology, Pusan National University School of Korean Medicine, Yangsan 626-870, Republic of Korea.
J Ethnopharmacol. 2014 Aug 8;155(1):744-52. doi: 10.1016/j.jep.2014.06.024. Epub 2014 Jun 19.
San-Huang-Xie-Xin-Tang (SHXXT) is a traditional Chinese medicinal formula composed of Coptidis rhizoma (Coptis chinesis Franch), Scutellariae radix (Scutellaria baicalensis Georgi), and Rhei rhizoma (Rheum officinale Baill) and is widely used in Eastern Asia, especially to ameliorate the symptoms of gastrointestinal (GI) disorders related to gastritis, gastric bleeding, peptic ulcers, and abnormal GI motility
Interstitial cells of Cajal (ICCs) are pacemaker cells in the GI tract that generate rhythmic oscillations in membrane potentials known as slow waves. Because GI disorders, especially abnormal GI motility, are major lifelong problems, the authors investigated the effects of SHXXT on mouse small intestine ICCs, and sought to identify the receptors and the action mechanisms involved.
Enzymatic digestions were used to dissociate ICCs from small intestines, and the whole-cell patch-clamp configuration was used to record potentials generated by cultured ICCs.
SHXXT produced membrane depolarization in current-clamp mode, and Y25130 (a 5-HT3 receptor antagonist) and RS39604 (a 5-HT4 receptor antagonist) blocked SHXXT-induced membrane depolarizations, whereas SB269970 (a 5-HT7 receptor antagonist) did not. However, during external Ca2+ free conditions or in the presence of thapsigargin, SHXXT did not exhibit membrane depolarization. Furthermore, the application of flufenamic acid (a nonselective cation channel (NSCC) blocker) or DIDS (a chloride channel blocker) abolished pacemaker potential generation and blocked SHXXT-induced membrane depolarizations. In addition, SHXXT-induced membrane depolarizations, which are dependent on G-protein, in ICCs were blocked by PD 98059 (a p42/44 mitogen-activated protein kinase (MAPK) inhibitor), SB203580 (a p38 MAPK inhibitor), and by a c-jun NH2-terminal kinase (JNK) II inhibitor. Regarding the components of SHXXT, Coptidis rhizome and Rhei rhizoma modulated ICC pacemaking activity, whereas Scutellariae radix did not.
SHXXT modulates pacemaker potentials via 5-HT3 and 5-HT4 receptor-mediated pathways, external Ca2+ influx, and Ca2+ release from internal stores. Furthermore, NSCCs and Cl- channels play important roles in the regulation of pacemaking activity in a MAPK dependent manner in ICCs. The regulation of pacemaking activity by SHXXT may be due to the activity of Coptidis rhizome and Rhei rhizome. The study shows SHXXT can modulate the pacemaking activity of ICCs in the GI tract, and thus, suggests SHXXT has potential pharmacological relevance for the treatment of GI motility disorders.
三黄泻心汤（SHXXT）是一种中药方剂，由黄连（Coptis chinesis Franch）、黄芩（Scutellaria baicalensis Georgi）和大黄（Rheum officinale Baill）组成，在东亚地区广泛使用，尤其用于改善与胃炎、胃出血、消化性溃疡和胃肠动力异常相关的胃肠道（GI）疾病症状。
Cajal间质细胞（ICCs）是胃肠道中的起搏细胞，可产生称为慢波的膜电位节律性振荡。由于胃肠道疾病，尤其是胃肠动力异常，是主要的终身问题，作者研究了三黄泻心汤对小鼠小肠ICCs的影响，并试图确定其涉及的受体和作用机制。
采用酶消化法从小肠中分离ICCs，并采用全细胞膜片钳配置记录培养的ICCs产生的电位。
三黄泻心汤在电流钳模式下产生膜去极化，Y25130（一种5-HT3受体拮抗剂）和RS39604（一种5-HT4受体拮抗剂）可阻断三黄泻心汤诱导的膜去极化，而SB269970（一种5-HT7受体拮抗剂）则不能。然而，在无细胞外Ca2+条件下或存在毒胡萝卜素时，三黄泻心汤未表现出膜去极化。此外，应用氟芬那酸（一种非选择性阳离子通道（NSCC）阻滞剂）或DIDS（一种氯通道阻滞剂）可消除起搏电位的产生并阻断三黄泻心汤诱导的膜去极化。此外，三黄泻心汤诱导的ICCs中依赖G蛋白的膜去极化被PD 98059（一种p42/44丝裂原活化蛋白激酶（MAPK）抑制剂）、SB203580（一种p38 MAPK抑制剂）和c-jun NH2末端激酶（JNK）II抑制剂阻断。关于三黄泻心汤的成分，黄连和大黄调节ICCs的起搏活性，而黄芩则无此作用。
三黄泻心汤通过5-HT3和5-HT4受体介导的途径、细胞外Ca2+内流以及从内部储存库释放Ca2+来调节起搏电位。此外，NSCCs和Cl-通道以MAPK依赖的方式在ICCs起搏活性调节中起重要作用。三黄泻心汤对起搏活性的调节可能归因于黄连和大黄的活性。该研究表明三黄泻心汤可调节胃肠道中ICCs的起搏活性，因此提示三黄泻心汤在治疗胃肠动力障碍方面具有潜在的药理学相关性。
