Effects of the thromboxane receptor agonist U46619 and endotherin-1 on large and small airways

Recently attention has been drawn to the role of small airways in asthma, H owever, Little information exists about the responsiveness of small airways to various bronchoconstrictors in comparison to large airways. Tn this stu dy, the model of precision-cut lung slices (PCLSs) was used to investigate the effects of the thromboxane receptor agonist U46619 and endothelin (ET)- 1 on small (diameter <250 mu m), medium (250-420 mu m) and large (>420 mu m ) airways, Viable PCLSs were prepared from rat lungs and the bronchoconstriction of di fferently. sized airways inducible by U46619 and ET-1 was observed by means of a microscope and analysed by digital imaging techniques. The median effective concentration (EC50) of U46619 for inducing bronchocon striction was 6.9 nM in small and 66 nM in large airways, respectively. Thi sfinding was corroborated by direct observations in single lung slices cont aining both a small and a large airway. In such slices, U46619 caused small er airways to contract to a greater degree than larger ones. ET-1 induced b ronchoconstriction was similar in small (EC50 34 nM) and in medium or large (EC50 22 nM) airways, This was again confirmed by direct observation of ET -1-treated PCLSs, It is concluded that, in rat lungs, endothelin-1 affects small and large ai rways to the same extent, whereas thromboxane is ten times more potent in c ausing small airways to contract than larger ones. Precision-cut lung slice s appear to be a valuable model for examining the (patho)physiology of smal l airways.