A small molecule inhibitor of the chloride channel TMEM16A blocks vascular smooth muscle contraction and lowers blood pressure in spontaneously hypertensive rats.
A small molecule inhibitor of the chloride channel TMEM16A blocks vascular smooth muscle contraction and lowers blood pressure in spontaneously hypertensive rats.
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DOI：
10.1016/j.kint.2021.03.025
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发表时间：
2021-08
影响因子：
19.6
通讯作者：
Verkman AS
中科院分区：
文献类型：
--
作者：
Cil O;Chen X;Askew Page HR;Baldwin SN;Jordan MC;Myat Thwe P;Anderson MO;Haggie PM;Greenwood IA;Roos KP;Verkman AS
高血压是心血管疾病发病率和死亡率的主要原因，尽管抗高血压药物具有不同的靶点和作用机制。在这里，我们提供的证据表明，药理学抑制TMEM 16 A（ANO 1），在血管平滑肌细胞中表达的钙激活氯离子通道，阻断钙激活氯离子电流和收缩血管平滑肌在体外，并降低血压在自发性高血压大鼠。在表达TMEM 16 A的Fischer大鼠甲状腺细胞和大鼠血管平滑肌细胞的原代培养物中，酰基氨基环烷基噻吩TMh-23以纳摩尔效力完全抑制钙激活的TMEM 16 A氯电流。TMh-23降低了野生型和自发性高血压大鼠肠系膜阻力动脉中血栓烷模拟物U46619引起的血管收缩，在自发性高血压大鼠中具有更大的抑制作用。通过尾袖和遥测测量的血压显示，在自发性高血压大鼠中，在单剂量的TMh-23后，收缩压降低高达45-mmHg，持续4 - 6小时。在用TMh-23处理的野生型大鼠或小鼠中观察到对血压的最小影响。用TMh-23每天两次治疗自发性高血压大鼠5天，使每日平均收缩压和舒张压持续降低20-25 mmHg。TMh-23的作用是可逆的，在治疗停止后三天，自发性高血压大鼠的血压恢复到基线水平。因此，我们的研究提供了TMEM 16 A作为抗高血压治疗靶点的验证，并证明了TMh-23作为具有新作用机制的抗高血压药的功效。
Hypertension is a major cause of cardiovascular morbidity and mortality, despite the availability of antihypertensive drugs with different targets and mechanisms of action. Here, we provide evidence that pharmacological inhibition of TMEM16A (ANO1), a calcium-activated chloride channel expressed in vascular smooth muscle cells, blocks calcium-activated chloride currents and contraction in vascular smooth muscle in vitro and decreases blood pressure in spontaneously hypertensive rats. The acylaminocycloalkylthiophene TMinh-23 fully inhibited calcium-activated TMEM16A chloride current with nanomolar potency in Fischer rat thyroid cells expressing TMEM16A, and in primary cultures of rat vascular smooth muscle cells. TMinh-23 reduced vasoconstriction caused by the thromboxane mimetic U46619 in mesenteric resistance arteries of wild-type and spontaneously hypertensive rats, with a greater inhibition in spontaneously hypertensive rats. Blood pressure measurements by tail-cuff and telemetry showed up to a 45-mmHg reduction in systolic blood pressure lasting for four-six hours in spontaneously hypertensive rats after a single dose of TMinh-23. A minimal effect on blood pressure was seen in wild-type rats or mice treated with TMinh-23. Five-day twice daily treatment of spontaneously hypertensive rats with TMinh-23 produced sustained reductions of 20–25 mmHg in daily mean systolic and diastolic blood pressure. TMinh-23 action was reversible, with blood pressure returning to baseline in spontaneously hypertensive rats by three days after treatment discontinuation. Thus, our studies provide validation for TMEM16A as a target for antihypertensive therapy and demonstrate the efficacy of TMinh-23 as an antihypertensive with a novel mechanism of action.
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影响因子：
4.8
作者：
Cil, Onur;Anderson, Marc O.;Verkman, Alan S.
通讯作者：
Verkman, Alan S.
TMEM16A 在小鼠平滑肌中的表达谱和蛋白质翻译
影响因子：
5.5
作者：
Davis, Alison J.;Forrest, Abigail S.;Leblanc, Normand
通讯作者：
Leblanc, Normand
影响因子：
15.9
作者：
Heinze, Christoph;Seniuk, Anika;Huebner, Christian A.
通讯作者：
Huebner, Christian A.
DOI：
10.1073/pnas.1415739112
发表时间：
2015-02-17
影响因子：
11.1
作者：
Catalan, Marcelo A.;Kondo, Yusuke;Melvin, James E.
通讯作者：
Melvin, James E.
影响因子：
24.3
作者：
Papp, Rita;Nagaraj, Chandran;Olschewski, Andrea
通讯作者：
Olschewski, Andrea