LC Chopra, D Hucks, CH Twort and JP Ward
Department of Allergy and Respiratory Medicine, United Medical and Dental Schools (UMDS), London, United Kingdom.

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.

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