替米沙坦通过直接抑制Kv2.1通道促进离体大鼠的胰岛素分泌  

Telmisartan promotes insulin secretion in rats through direct inhibition of Kv2.1 channel

作　　者：刘涛 陈晓琴 郭瑞旺 崔丽娟[2] 刘师伟 LIU Tao;CHEN Xiao-qin;GUO Rui-wang;CUI Li-juan;LIU Shi-wei(Dept of General Surgery,Shanxi Bethune Hospital,Third Hospital of Shanxi Medical University,Taiyuan 030032,China;Dept of Pharmacology,School of Basic Medicine,Shanxi Medical University,Taiyuan 030001,China;Endocrinology Dept,,Shanxi Bethune Hospital,Third Hospital of Shanxi Medical University,,Taiyuan 030032,China;Endocrine and Metabolic Diseases Key Laboratory of Shanxi Province,Taiyuan 030032,China)

机构地区：[1]山西白求恩医院山西医科大学第三医院普通外科,山西太原030032 [2]山西医科大学基础医学院药理教研室,山西太原030001 [3]山西白求恩医院山西医科大学第三医院内分泌科 [4]山西白求恩医院内分泌科内分泌代谢病山西省重点实验室,山西太原030032

出　　处：《中国药理学通报》2024年第5期893-898,共6页Chinese Pharmacological Bulletin

基　　金：内分泌代谢病山西省重点实验室基金(No 202104010910009);山西省卫健委科研项目(No 2021148);山西省基础研究计划资助项目(No 202103021224353);山西省“136”兴医工程建设经费(No 2021YZ06)。

摘　　要：目的研究替米沙坦促进大鼠胰岛素分泌作用相关的信号通路。方法(1)分离成年Wistar大鼠胰腺获得胰岛和胰岛细胞,通过胰岛素分泌实验观察药物对胰岛素分泌的影响,通过钙成像实验和全细胞膜片钳技术观察药物对β细胞内Ca^(2+)浓度的变化和对离子通道的作用。(2)使用过表达电压门控性钾(voltage-gated potassium channel,Kv)通道2.1亚型(Kv2.1)的慢病毒转染中国仓鼠卵巢(Chinese hamster ovary,CHO)细胞构建CHO-Kv2.1细胞系,使用膜片钳技术观察替米沙坦对Kv2.1通道的直接作用。结果缬沙坦和厄贝沙坦无类似替米沙坦的高糖浓度下促胰岛素分泌、升高β细胞内Ca^(2+)浓度和抑制β细胞的Kv通道等作用。过氧化物酶体增殖物激活受体γ(peroxisome proliferator-activated receptorγ,PPARγ)阻断剂GW9662亦未阻断替米沙坦的上述作用。而替米沙坦可以浓度依赖性地抑制CHO-Kv2.1细胞的Kv2.1通道电流。结论替米沙坦的促胰岛素分泌作用可能与血管紧张素Ⅱ-1型(angiotensin II type 1,AT-1)受体和PPARγ无关,但至少与对Kv2.1通道的直接抑制作用有关。Aim To investigate the signaling pathways related to telmisartan-induced insulinotropic effect in rats.Methods(1)Islets and cells were isolated from Wistar rats.Islets were treated with different drugs,then supernatant liquid was collected for insulin secretion.The changes in intracellular Ca^(2+)([Ca^(2+)]i)concentrations ofβ-cells and the effects on ion channel were observed using calcium imaging technology and patch-clamp technology respectively.(2)CHO-Kv2.1 cell line was constructed with lentivirus vector overexpressing Kv2.1 channel,then patch-clamp experiment was performed on CHO-Kv2.1 cells to observe the direct effect of telmisartan on Kv2.1 channel.Results Different from telmisartan,valsartan and irbesartan under high glucose condition did not exhibit insulinotropic effect,elevation of[Ca^(2+)]i levels,and inhibition of Kv channels inβcells.GW9662,a peroxisome proliferator-activated receptorγ(PPARγ)blocker,did not influence the effects of telmisartan on insulin secretion,[Ca^(2+)]i level and Kv channel.CHO cells had no endogenous outward potassium currents,while Kv2.1 channel current and its concentration dependent suppression by telmisartan were both detected on CHO-Kv2.1 cells.Conclusion Neither AT-1 receptors nor PPARγis involved in telmisartan-induced insulinotropic effect,and the effect of telmisartan is partly due to the direct inhibition of kv2.1 channel.

关 键 词：替米沙坦 Β细胞 胰岛素分泌 AT-1受体 PPARΓ Kv2.1通道 

分 类 号：R-332[医药卫生] R322.57R347.8R348.1R392.11R916.4