The role of the epithelium and cyclooxygenase products was investigated in the responses of isolated airways to sudden stretch. Strips of guinea pig trachea, in some of which the epithelium had been removed mechanically, were suspended in organ chambers; isometric tension was recorded. After rapid stretching to their optimal tension, the preparations (with and without epithelium) relaxed initially and then contracted to a level close to the imposed tension. Afterward, tissues with epithelium maintained this level of tension, but those without epithelium relaxed. After treatment with papaverine or isoproterenol (at concentrations causing maximal relaxation), stretch was followed only by a decrease in tension; a similar response to stretch was also obtained in tissues treated with indomethacin or acetylsalicylic acid (inhibitors of cyclooxygenase). Dazmegrel (an inhibitor of thromboxane synthase) and SQ-29548 (an antagonist of prostaglandin H2 or thromboxane A2 receptors) did not affect the response of tissues with epithelium but abolished the stretch-induced contraction in those without epithelium. Tranylcypromine, which inhibits prostacyclin synthase, and tetrodotoxin, which blocks local reflexes, did not significantly affect the responses of the tissues to stretch. These observations suggest that thromboxane may mediate the epithelium-independent contraction and that another product of cyclooxygenase contributes to the maintenance of tension on stretching observed in tissues with epithelium.