TRPA1 activation leads to neurogenic vasodilatation: involvement of reactive oxygen nitrogen species in addition to CGRP and NO.
TRPA1 activation leads to neurogenic vasodilatation: involvement of reactive oxygen nitrogen species in addition to CGRP and NO.
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DOI：
10.1111/bph.13519
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发表时间：
2016-08
影响因子：
7.3
通讯作者：
Brain SD
中科院分区：
文献类型：
--
作者：
Aubdool AA;Kodji X;Abdul-Kader N;Heads R;Fernandes ES;Bevan S;Brain SD
已知瞬时受体电位锚蛋白-1（TRPA 1）激活介导神经源性血管舒张。我们使用TRPA 1激动剂肉桂醛在体内研究了TRPA 1介导的外周血管舒张的机制。用激光多普勒血流仪测量麻醉小鼠耳血管血流的变化。肉桂醛局部应用于小鼠耳部导致麻醉野生型（WT）小鼠皮肤中的血流量显著增加，但在TRPA 1敲除（KO）小鼠中则没有。肉桂醛诱导的血管舒张被有效的微血管舒张剂神经肽CGRP和神经元NOS衍生的NO通路的药理学阻断所抑制。肉桂醛介导的血管舒张作用通过活性氧氮类（RONS）清除剂（如过氧化氢酶和SOD模拟物TEMPO）处理显著降低，支持RONS在下游血管舒张剂TRPA 1介导的反应中的作用。用非选择性NOS抑制剂L-NAME和抗氧化剂夹竹桃苷共同治疗进一步抑制TRPA 1介导的血管舒张。肉桂醛处理诱导过氧亚硝酸根的产生，其被过氧亚硝酸根清除剂FeTPPS阻断，并且显示依赖于TRPA 1，如WT皮肤中蛋白酪氨酸硝化的增加所反映的，但在TRPA 1 KO小鼠中没有。这项研究提供了体内证据，证明由肉桂醛介导的TRPA 1诱导的血管舒张除了传统的神经肽成分外，还需要神经元NOS衍生的NO。揭示了过氧亚硝酸盐的新作用，其产生于肉桂醛激活TRPA 1的下游。TRPA 1介导的血管舒张的机制途径可能对理解TRPA 1在病理生理学情况中的作用很重要。
Transient receptor potential ankyrin‐1 (TRPA1) activation is known to mediate neurogenic vasodilatation. We investigated the mechanisms involved in TRPA1‐mediated peripheral vasodilatation in vivo using the TRPA1 agonist cinnamaldehyde. Changes in vascular ear blood flow were measured in anaesthetized mice using laser Doppler flowmetry. Topical application of cinnamaldehyde to the mouse ear caused a significant increase in blood flow in the skin of anaesthetized wild‐type (WT) mice but not in TRPA1 knockout (KO) mice. Cinnamaldehyde‐induced vasodilatation was inhibited by the pharmacological blockade of the potent microvascular vasodilator neuropeptide CGRP and neuronal NOS‐derived NO pathways. Cinnamaldehyde‐mediated vasodilatation was significantly reduced by treatment with reactive oxygen nitrogen species (RONS) scavenger such as catalase and the SOD mimetic TEMPOL, supporting a role of RONS in the downstream vasodilator TRPA1‐mediated response. Co‐treatment with a non‐selective NOS inhibitor L‐NAME and antioxidant apocynin further inhibited the TRPA1‐mediated vasodilatation. Cinnamaldehyde treatment induced the generation of peroxynitrite that was blocked by the peroxynitrite scavenger FeTPPS and shown to be dependent on TRPA1, as reflected by an increase in protein tyrosine nitration in the skin of WT, but not in TRPA1 KO mice. This study provides in vivo evidence that TRPA1‐induced vasodilatation mediated by cinnamaldehyde requires neuronal NOS‐derived NO, in addition to the traditional neuropeptide component. A novel role of peroxynitrite is revealed, which is generated downstream of TRPA1 activation by cinnamaldehyde. This mechanistic pathway underlying TRPA1‐mediated vasodilatation may be important in understanding the role of TRPA1 in pathophysiological situations.