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

Abstract

Recently attention has been drawn to the role of small airways in asthma. However, little information exists about the responsiveness of small airways to various bronchoconstrictors in comparison to large airways. In this study, 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 microm), medium (250-420 microm) and large (>420 microm) airways. Viable PCLSs were prepared from rat lungs and the bronchoconstriction of differently 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 bronchoconstriction was 6.9 nM in small and 66 nM in large airways, respectively. This finding was corroborated by direct observations in single lung slices containing both a small and a large airway. In such slices, U46619 caused smaller airways to contract to a greater degree than larger ones. ET-1 induced bronchoconstriction was similar in small (EC50 34 nM) and in medium or large (ECso 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 airways to the same extent, whereas thromboxane is ten times more potent in causing small airways to contract than larger ones. Precision-cut lung slices appear to be a valuable model for examining the (patho)physiology of small airways.