Endothelins constrict guinea pig tracheas by multiple mechanisms.

When tracheal rings isolated from guinea pigs were treated with endothelins (ETs), a dose-dependent constriction was observed and measured isometrically. ET potencies were ET-1 = ET-2 greater than ET-3. Dose-response curves of epithelium-denuded tracheas were shifted to the left by approximately one order of magnitude. Lung tissue contained saturable binding sites to 125I-labeled ET-1. These binding sites were replaced by ET-1 = ET-2 greater than ET-3. Because the airway tissue contained primarily ET-1 as measured by immunoassay after high-performance liquid chromatography separation, we investigated the mechanism of ET-1-induced tracheal constriction. Tracheal constriction induced by ET-1 required Ca++ in the medium. Because suppression of the contractile response by nicardipine and diltiazem was small, Ca++ entry appeared to be gated primarily through Ca++ channels rather than via voltage-dependent ones. FPL55712, SC47014A, indomethacin and OKY046 suppressed the dose-response curves, suggesting that lipid mediators are formed in response to ET-1. Diphenhydramine also altered dose-response curves, suggesting that histamine release from mast cells was partially responsible for the constriction. Pretreatment of tracheas with compound 48/80 resulted in suppression of the contractile responses. Furthermore, the combination of indomethacin, FPL55712 and diphenhydramine gave essentially identical effects. Our observations suggest that ET-1 provokes the contractile response of guinea pig tracheas not only by direct actions on smooth muscle but also by indirect actions through production of chemical mediators in mast cells and other inflammatory cells.