Mechanistic studies of acid-evoked coughing in anesthetized guinea pigs
Mechanistic studies of acid-evoked coughing in anesthetized guinea pigs
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DOI：
10.1152/ajpregu.00862.2005
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发表时间：
2006-08-01
影响因子：
2.8
通讯作者：
Mori, Nanako
中科院分区：
文献类型：
--
作者：
Canning, Brendan J.;Farmer, David G.;Mori, Nanako
在清醒的豚鼠身上进行的实验表明，柠檬酸诱发的咳嗽部分是由瞬时受体电位香草样物质1型(TRPV1)受体依赖的含有速激肽的辣椒素敏感C纤维的激活所介导的。然而，体外电生理分析表明，酸也通过TRPV1不依赖的机制激活辣椒素敏感和不敏感的迷走神经，在麻醉豚鼠的研究表明，酸引起的咳嗽是通过激活辣椒素敏感的迷走神经介导的。在本研究中，我们对麻醉豚鼠柠檬酸诱发咳嗽的机制进行了研究。将药物直接注入胸腔外气管的克雷布斯缓冲液。柠檬酸局部应用于气管粘膜，以增加浓度和1分钟的间隔直接进入气管灌流液。柠檬酸剂量依赖性地引起麻醉豚鼠咳嗽。这是模拟的盐酸，但不是柠檬酸钠。TTX或切断喉返神经可使酸引起的咳嗽几乎或完全消失。用低氯缓冲液灌流气管可增强酸诱导的咳嗽反射。相比之下，在辣椒素脱敏之前，10亩M辣椒素，无钙灌流液，0.1亩M黄连毒素，1亩M阿托品，10亩M异丙肾上腺素，10亩M沙丁胺醇，3亩M吲哚美辛，0.1亩M HOE-140，神经激肽(1)(NK1；NK2(SR-99994)、NK2(SR-48968)和NK3(SB-223412)受体拮抗剂(各0.1mU)、组胺H-1(3mU吡咯胺)和CysLT(1)(1mU ICI-198615)受体拮抗剂的组合、喉上神经切断或去除上皮均不能抑制柠檬酸诱发的咳嗽。这些和其他数据表明，麻醉豚鼠的柠檬酸诱发咳嗽是通过直接激活辣椒素不敏感的迷走神经传入神经介导的，可能是通过依次激活酸敏感离子通道和氯离子通道。
Experiments carried out in conscious guinea pigs suggest that citric acid-evoked coughing is partly mediated by transient receptor potential vanilloid type 1 (TRPV1) receptor-dependent activation of tachykinin-containing, capsaicin-sensitive C fibers. In vitro electrophysiological analyses indicate, however, that acid also activates capsaicin-sensitive and -insensitive vagal afferent nerves by a TRPV1-independent mechanism, and studies in anesthetized guinea pigs show that coughing evoked by acid is mediated by activation of capsaicinin-sensitive vagal afferent nerves. In the present study, we have characterized the mechanisms of citric acid-evoked coughing in anesthetized guinea pigs. Drugs were administered directly to the Krebs buffer perfusing the extrathoracic trachea. Citric acid was applied topically to the tracheal mucosa, directly into the tracheal perfusate in increasing concentrations and at 1-min intervals. Citric acid dose dependently evoked coughing in anesthetized guinea pigs. This was mimicked by hydrochloric acid but not by sodium citrate. The coughing evoked by acid was nearly or completely abolished by TTX or by cutting the recurrent laryngeal nerves. Perfusing the trachea with a low Cl- buffer potentiated the acid-induced cough reflex. In contrast, prior capsaicin desensitization, 10 mu M capsazepine, Ca2+ free perfusate, 0.1 mu M iberiotoxin, 1 mu M atropine, 10 mu M isoproterenol, 10 mu M albuterol, 3 mu M indomethacin, 0.1 mu M HOE-140, a combination of neurokinin(1) (NK1; CP-99994), NK2 (SR-48968), and NK3 (SB-223412) receptor antagonists (0.1 mu M each), a combination of histamine H-1 (3 mu M pyrilamine) and cysLT(1) (1 mu M ICI-198615) receptor antagonists, superior laryngeal nerve transection, or epithelium removal did not inhibit citric acid-evoked coughing. These and other data indicate that citric acid-evoked coughing in anesthetized guinea pigs is mediated by direct activation of capsaicin-insensitive vagal afferent nerves, perhaps through sequential activation of acid-sensing ion channels and chloride channels.