Comparison of TRPA1-versus TRPV1-mediated cough in guinea pigs.
Comparison of TRPA1-versus TRPV1-mediated cough in guinea pigs.
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DOI：
10.1016/j.ejphar.2012.05.048
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发表时间：
2012-08-15
影响因子：
5
通讯作者：
Kollarik M
中科院分区：
文献类型：
--
作者：
Brozmanova M;Mazurova L;Ru F;Tatar M;Kollarik M
TRPA 1受体被与呼吸系统疾病相关的内源性炎症介质和外源性污染物分子激活。以前的研究表明TRPA 1是止咳治疗的药物靶点。在这里，我们评估了TRPA 1激活诱发咳嗽的相对功效。在清醒的豚鼠中，TRPA 1激动剂烯丙基异硫氰酸酯（AITC）以10 mM的最大有效浓度诱发咳嗽，该浓度被选择性TRPA 1拮抗剂AP-18消除。AITC（10 mM）诱导咳嗽的效果比辣椒素（50 μM）低约3倍。离体单纤维细胞外记录显示，类似于辣椒素，AITC诱发气道颈静脉C-纤维的激活，但不诱发气道结状Aδ-纤维的激活。与咳嗽研究一致，AITC在引起颈静脉C纤维持续激活方面的有效性比辣椒素低约3倍。另一种TRPA 1激动剂肉桂醛在诱导咳嗽方面比AITC有效约两倍。然而，肉桂醛（10 mM）诱导的咳嗽仅部分地被TRPA 1拮抗剂AP-18抑制，并且被AP-18和TRPV 1拮抗剂I-RTX联合消除。我们的结论是，在幼稚豚鼠中，TRPA 1激活引发的咳嗽与TRPV 1引发的咳嗽相比相对温和，可能是由于TRPA 1刺激诱导气道C纤维持续激活的功效较低。
TRPA1 receptor is activated by endogenous inflammatory mediators and exogenous pollutant molecules relevant to respiratory diseases. Previous studies have implicated TRPA1 as a drug target for antitussive therapy. Here we evaluated the relative efficacy of TRPA1 activation to evoke cough. In conscious guinea pigs the TRPA1 agonist allyl-isothiocyanate (AITC) evoked cough with a maximally effective concentration of 10mM that was abolished by the selective TRPA1 antagonist AP-18. AITC (10mM) was approximately 3-times less effective in inducing cough than capsaicin (50 μM). Ex vivo single fiber extracellular recordings revealed that, similarly to capsaicin, AITC evoked activation in airway jugular C-fibers, but not in airway nodose Aδ-fibers. Consistent with the cough studies, AITC was approximately 3-times less effective than capsaicin in evoking sustained activation of the jugular C-fibers. Another TRPA1 agonist, cinnamaldehyde, was approximately twofold more effective than AITC in inducing cough. However, the cinnamaldehyde (10mM)-induced cough was only partially inhibited by the TRPA1 antagonist AP-18, and was abolished by combination of AP-18 and the TRPV1 antagonist I-RTX. We conclude that in naïve guinea pigs, TRPA1 activation initiates cough that is relatively modest compared to the cough initiated by TRPV1, likely due to lower efficacy of TRPA1 stimulation to induce sustained activation of airway C-fibers.