Huang Shih-Che, Chang Bee-Song
Department of Internal Medicine, Tzu Chi General Hospital and Tzu Chi University, 707, Section 3, Chung-Yang Road, Hualien 970, Taiwan.
Regul Pept. 2004 Mar 15;117(3):179-86. doi: 10.1016/j.regpep.2003.10.016.
Endothelin (ET) causes contraction of the muscularis mucosae in the guinea pig esophagus, but its role in the human esophagus remains unknown. To investigate effects of ET in the human esophagus, we measured contraction of isolated human esophageal muscularis mucosae strips caused by ET related peptides and binding of 125I-ET-1 to cell membranes prepared from the human esophageal muscularis mucosae. Autoradiography demonstrated specific binding of 125I-ET-1 to the muscularis mucosae and muscularis propria (muscularis externa) of the human esophagus. ET-1 caused tetrodotoxin and atropine-insensitive contraction of muscularis mucosae strips. In terms of the maximal tension of contraction, ET-1 and ET-2 were equal in efficacy. The relative potencies for ET related peptides to cause contraction were ET-1=ET-2>ET-3>sarafotoxin S6c (SX6c), an ETB receptor agonist. ET-1 caused contraction was mildly inhibited by BQ-123, an ETA receptor antagonist, and not by BQ-788, an ETB receptor antagonist. It was moderately inhibited by the combination of both antagonists, indicating synergistic inhibition. Furthermore, desensitization to SX6c with SX6c pretreatment failed to abolish the contractile response to ET-1, which was completely inhibited by BQ-123. These indicate the involvement of both ETA and ETB receptors in the contraction. Binding of 125I-ET-1 to cell membranes of the muscularis mucosae was saturable and specific. Analysis of dose-inhibition curves demonstrated the presence of ETA and ETB receptors. This study demonstrates that, the muscularis mucosae of the human esophagus, similar to that of the guinea pig esophagus, possesses both ETA and ETB receptors mediating muscle contraction.
内皮素（ET）可引起豚鼠食管黏膜肌层收缩，但其在人类食管中的作用尚不清楚。为研究ET在人类食管中的作用，我们测定了ET相关肽引起的人离体食管黏膜肌层条带收缩以及125I-ET-1与人食管黏膜肌层制备的细胞膜的结合情况。放射自显影显示125I-ET-1与人食管黏膜肌层和固有肌层（外肌层）有特异性结合。ET-1引起黏膜肌层条带对河豚毒素和阿托品不敏感的收缩。就收缩的最大张力而言，ET-1和ET-2的效力相当。ET相关肽引起收缩的相对效价为ET-1=ET-2>ET-3>沙拉新（SX6c），一种ETB受体激动剂。ET-1引起的收缩被ETA受体拮抗剂BQ-123轻度抑制，而不被ETB受体拮抗剂BQ-788抑制。两种拮抗剂联合使用则产生中度抑制，表明存在协同抑制作用。此外，用SX6c预处理使细胞对SX6c脱敏并不能消除对ET-1的收缩反应，而ET-1的收缩反应可被BQ-123完全抑制。这些结果表明ETA和ETB受体均参与了收缩过程。125I-ET-1与人食管黏膜肌层细胞膜的结合具有饱和性和特异性。剂量抑制曲线分析表明存在ETA和ETB受体。本研究表明，人类食管黏膜肌层与豚鼠食管黏膜肌层相似，具有介导肌肉收缩的ETA和ETB受体。
