TMEM16A blockers T16Ainh‐A01 and benzbromarone do not modulate the regulation of sweating and cutaneous vasodilatation in humans in vivo
TMEM16A blockers T16Ainh‐A01 and benzbromarone do not modulate the regulation of sweating and cutaneous vasodilatation in humans in vivo
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TMEM16A 阻滞剂 T16Ainh-A01 和苯溴马隆不会调节人体体内出汗和皮肤血管舒张的调节
DOI：
10.1113/ep090521
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发表时间：
2022
影响因子：
2.7
通讯作者：
Nishiyasu Takeshi
中科院分区：
文献类型：
--
作者：
Fujii Naoto;Amano Tatsuro;Kenny Glen P.;M?ndel Toby;Lei Tze‐Huan;Honda Yasushi;Kondo Narihiko;Nishiyasu Takeshi
新发现本研究的中心问题是什么？跨膜元件16 A（TMEM 16 A）阻断剂调节出汗和皮肤血管舒张的热损失反应的激活吗？主要发现及其重要性是什么？相对于溶剂对照部位，TMEM 16 A阻断剂T16 Ainh-A01和苯溴马隆在全身加热期间对出汗率或皮肤血管传导性没有影响，导致核心温度高于基线静息水平1.1 ± 0.1°C。这些结果表明，TMEM 16 A阻滞剂T16 Ainh-A01和苯溴马隆不调节出汗和皮肤血管舒张的调节在全身热stress.AbstractAnimal和体外研究表明，跨膜成员16 A（TMEM 16 A），钙离子激活的Cl−通道，有助于调节外分泌出汗。然而，缺乏直接证据支持这种可能性。我们评估了TMEM 16 A阻滞剂在人体全身发热过程中减少出汗的假设。此外，我们评估了皮肤血管舒张热损失反应的相关变化，以确定TMEM 16 A是否可能存在功能作用。12名年轻（24 ± 2岁）成年人（6名女性）使用注水服进行全身加热，使核心温度升高至基线以上1.1 ± 0.1°C。出汗率与皮肤血管传导性（通过施用硝普钠标准化为最大电导）在通过皮内微透析连续处理的四个前臂皮肤部位进行连续评价，所述皮内微透析用（1）乳酸林格氏溶液（对照），（2）5%二甲基亚砜（DMSO）作为载体对照，或（3）溶解于5%DMSO溶液中的TMEM 16 A阻断剂ImM T16 Ainh-A01或2 mM苯溴马隆。所有药物均通过皮内微透析连续给药。全身加热使核心温度逐渐升高，这被所有皮肤部位的出汗率和皮肤血管传导性的增加所抵消。然而，相对于TMEM 16 A阻断剂处理部位，溶媒对照部位之间的出汗率（所有P> 0.318）和皮肤血管传导性（所有P ≥ 0.073）没有差异。总的来说，我们的研究结果表明，TMEM 16 A阻滞剂T16 Ainh-A01和苯溴马隆不会调节体内年轻人全身加热期间出汗和皮肤血管舒张的调节。
New FindingsWhat is the central question of this study?Do transmembrane member 16A (TMEM16A) blockers modulate the activation of heat loss responses of sweating and cutaneous vasodilatation?What are the main finding and its importance?Relative to the vehicle control site, TMEM16A blockers T16Ainh‐A01 and benzbromarone had no effect on sweat rate or cutaneous vascular conductance during whole‐body heating inducing a 1.1 ± 0.1°C increase in core temperature above baseline resting levels. These results suggest that TMEM16A blockers T16Ainh‐A01 and benzbromarone do not modulate the regulation of sweating and cutaneous vasodilatation during whole‐body heat stress.AbstractAnimal and in vitro studies suggest that transmembrane member 16A (TMEM16A), a Ca2+‐activated Cl−channel, contributes to regulating eccrine sweating. However, direct evidence supporting this possibility in humans is lacking. We assessed the hypothesis that TMEM16A blockers attenuate sweating during whole‐body heating in humans. Additionally, we assessed the associated changes in the heat loss response of cutaneous vasodilatation to determine if a functional role of TMEM16A may exist. Twelve young (24 ± 2 years) adults (six females) underwent whole‐body heating using a water‐perfused suit to raise core temperature 1.1 ± 0.1°C above baseline. Sweat rate and cutaneous vascular conductance (normalized to maximal conductance via administration of sodium nitroprusside) were evaluated continuously at four forearm skin sites treated continuously by intradermal microdialysis with (1) lactated Ringer's solution (control), (2) 5% dimethyl sulfoxide (DMSO) serving as a vehicle control, or (3) TMEM16A blockers 1 mM T16Ainh‐A01 or 2 mM benzbromarone dissolved in 5% DMSO solution. All drugs were administered continuously via intradermal microdialysis. Whole‐body heating increased core temperature progressively and this was paralleled by an increase in sweat rate and cutaneous vascular conductance at all skin sites. However, sweat rate (allP> 0.318) and cutaneous vascular conductance (allP≥ 0.073) did not differ between the vehicle control site relative to the TMEM16A blocker‐treated sites. Collectively, our findings indicate that TMEM16A blockers T16Ainh‐A01 and benzbromarone do not modulate the regulation of sweating and cutaneous vasodilatation during whole‐body heating in young adults in vivo.
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