Grandordy B M, Frossard N, Rhoden K J, Barnes P J
Department of Clinical Pharmacology, Brompton Hospital, London, United Kingdom.
Mol Pharmacol. 1988 May;33(5):515-9.
We have studied the contractile response and phosphoinositide hydrolysis induced by substance P (SP), neurokinin A (NKA), neurokinin B (NKB), and Alp-Phe-Phe(R)-Gly[ANC-2]-Leu-Met-NH2 (L 363851), a selective NK2-receptor agonist, in guinea pig tracheal smooth muscle. The four tachykinins elicited a concentration-dependent contraction in tracheal smooth muscle devoid of epithelium, with the following order of potency: NKA greater than L 363851 greater than NKB greater than SP, (EC50 1.0 x 10(-9) M, 3.2 x 10(-9) M, 7.5 x 10(-9) M and 1.2 x 10(-7) M, respectively), which suggests that NK2 receptors predominate in airway smooth muscle. In the presence of epithelium, the sensitivity of airway smooth muscle to tachykinins was decreased, and the concentration response curves to tachykinins were shifted rightward by 30-fold for SP, 9-fold for NKA, and 5-fold for NKB. The concentration response curve to L 363851 was not significantly shifted in the presence of epithelium. This suggests that epithelium may release a relaxant factor in response to tachykinins via an NK1 receptor. In airway smooth muscle, we found that tachykinins elicited phosphoinositide breakdown with an order of potency similar to that for contractile response (EC50 2.2 x 10(-5) M, 3.6 x 10(-5) M, 4.4 x 10(-5) M, and 5.9 x 10(-5) M). In epithelium, SP alone elicited a significant phosphoinositide breakdown, suggesting that epithelial receptors to tachykinins may be of the NK1 subtype. Since it is established that phosphoinositide derivatives can elicit mobilization of intracellular calcium, our results suggest that phosphoinositide breakdown is the coupling mechanism for tachykinin-induced contraction of airway smooth muscle.
我们研究了P物质（SP）、神经激肽A（NKA）、神经激肽B（NKB）以及选择性NK2受体激动剂Alp-Phe-Phe(R)-Gly[ANC-2]-Leu-Met-NH2（L 363851）在豚鼠气管平滑肌中诱导的收缩反应和磷酸肌醇水解。这四种速激肽在无上皮的气管平滑肌中引起浓度依赖性收缩，其效力顺序如下：NKA＞L 363851＞NKB＞SP（EC50分别为1.0×10⁻⁹ M、3.2×10⁻⁹ M、7.5×10⁻⁹ M和1.2×10⁻⁷ M），这表明NK2受体在气道平滑肌中占主导地位。在上皮存在的情况下，气道平滑肌对速激肽的敏感性降低，并且对速激肽的浓度反应曲线向右移动，SP移动30倍，NKA移动9倍，NKB移动5倍。在有上皮存在时，对L 363851的浓度反应曲线没有明显移动。这表明上皮可能通过NK1受体对速激肽释放一种舒张因子。在气道平滑肌中，我们发现速激肽引起磷酸肌醇分解，其效力顺序与收缩反应相似（EC50分别为2.2×10⁻⁵ M、3.6×10⁻⁵ M、4.4×10⁻⁵ M和5.9×10⁻⁵ M）。在上皮中，单独的SP引起显著的磷酸肌醇分解，这表明上皮对速激肽的受体可能是NK1亚型。由于已经确定磷酸肌醇衍生物可以引起细胞内钙的动员，我们的结果表明磷酸肌醇分解是速激肽诱导气道平滑肌收缩的偶联机制。
