Chopra L C, Hucks D, Twort C H, Ward J P
Department of Allergy and Respiratory Medicine, United Medical and Dental Schools (UMDS), London, United Kingdom.
Am J Respir Cell Mol Biol. 1997 Apr;16(4):372-8. doi: 10.1165/ajrcmb.16.4.9115747.
The role of protein tyrosine kinases (PTK) in modulating contractility has not been investigated in airway smooth muscle (ASM). We have examined the effects of the PTK inhibitors ST638, genistein, and tyrphostin A47 on contractions induced by carbachol, serotonin, ionomycin, and 75 mM KCl in isolated bronchioles of the rat with internal diameters of 614 +/- 16 microm (small, n = 143), and 1,433 +/- 39 microm (large, n = 57). ST638 caused a dose-dependent decrease in the maximum response to carbachol, and shifted the carbachol concentration-response curve to the right. This effect was greater in small bronchioles. Tyrphostin A47 (100 microM) and genistein (74 microM) had a similar effect to ST638. ST638 caused a concentration-dependent relaxation (EC50 approximately 7.2 microM) in bronchioles precontracted with 0.5 microM carbachol, and was maximally effective at 50 microM when tone was reduced by 82.5 +/- 3.8% in small bronchioles, and 57.2 +/- 2.8% in large bronchioles. ST638 also reduced the maximal response to serotonin, and caused a large shift to the right of the serotonin concentration-response curve. Pretreatment with ST638 (50 microM) reduced the response to 75 mM KCl in both small and large bronchioles in the presence of atropine (small: by 88.9 +/- 5.6%, n = 11; large: by 90.1 +/- 4.4%, n = 11). Tyrphostin A47 (100 microM) had a similar effect (91%). ST638 (50 microM) and tyrphostin A47 (100 microM) substantially relaxed small bronchioles contracted with 1.5 microM ionomycin (ST638: by 86.7 +/- 1.8%, n = 6; tyrphostin: by 89.3 +/- 1.7%, n = 5). We have therefore demonstrated that PTK inhibitors can suppress contraction induced by a number of different mechanisms in ASM. These results suggest that PTK signaling pathways are not only important for proliferation of ASM, but also fon contractile function.
蛋白酪氨酸激酶（PTK）在调节气道平滑肌（ASM）收缩性方面的作用尚未得到研究。我们研究了PTK抑制剂ST638、染料木黄酮和 tyrphostin A47对卡巴胆碱、5-羟色胺、离子霉素和75 mM氯化钾在大鼠离体细支气管中诱导的收缩的影响，这些细支气管内径分别为614±16微米（小，n = 143）和1433±39微米（大，n = 57）。ST638导致对卡巴胆碱的最大反应呈剂量依赖性降低，并使卡巴胆碱浓度-反应曲线右移。这种作用在小细支气管中更明显。Tyrphostin A47（100 microM）和染料木黄酮（74 microM）具有与ST638类似的作用。ST638在预先用0.5 microM卡巴胆碱预收缩的细支气管中引起浓度依赖性舒张（EC50约为7.2 microM），在50 microM时效果最佳，此时小细支气管张力降低82.5±3.8%，大细支气管张力降低57.2±2.8%。ST638还降低了对5-羟色胺的最大反应，并使5-羟色胺浓度-反应曲线大幅右移。在阿托品存在的情况下，用ST638（50 microM）预处理可降低小细支气管和大细支气管对75 mM氯化钾的反应（小细支气管：降低88.9±5.6%，n = 11；大细支气管：降低90.1±4.4%，n = 11）。Tyrphostin A47（100 microM）有类似作用（降低91%）。ST638（50 microM）和tyrphostin A47（100 microM）可使由1.5 microM离子霉素收缩的小细支气管显著舒张（ST638：舒张86.7±1.8%，n = 6；tyrphostin：舒张89.3±1.7%，n = 5）。因此，我们证明PTK抑制剂可抑制ASM中多种不同机制诱导的收缩。这些结果表明，PTK信号通路不仅对ASM的增殖很重要，而且对收缩功能也很重要。
