1 The effects of three endothelins: (i) the classical or human/porcine endothelin (ET-1); (ii) [Trp6, Leu7] endothelin (ET-2) and (iii) [Thr2, Phe4, Thr5, Tyr6, Lys7, Tyr'4] endothelin or rat endothelin (ET-3) were tested on the human isolated bronchus. 2 ET-1 produced a concentration-dependent contraction of the human isolated bronchus that proceeded in two different steps. The first step was observed at very low concentrations (pD2 = 11.01 + 0.17, n = 10) but corresponded to a low intrinsic activity (Emax = 15.6 + 1.8% of E,,,X induced by acetylcholine (ACh) 3 x 10-3M, n = 10). This effect was potentiated by Bay K 8644 10-7M (EX = 26.1 + 2.9% of ACh 3 x 10-3M, n = 5, P < 0.05), reduced by nicardipine 10-6M (Ex = 6.0 + 2.6% of ACh 3 x 10-3M, n = 5, P < 0.05) and strongly inhibited in calcium-free medium. The second step of the action of corresponded to a lesser potency (pD2 = 7.90 + 0.17, n = 9) but a higher intrinsic activity (E,,,, = 82.5 + 4.7% of ACh 3 x 10-3M). This effect was not significantly modified by nicardipine 10-6 M or by Bay K 8644 1V-7 M. Neither of the two effects was modified by indomethacin 3 x 10-6 M. 3 The effects of ET-2 and ET-3 were qualitatively similar to those of ET-1 but quantitatively different; for these two steps of contracting activity and for potency and efficacy the ranking was: ET-1 > ET-2 = ET-3. 4 Thus, ET-1 appears to be the most potent of these three substances in its effect on the human isolated bronchus. Its activity seems to involve the action of voltage-dependent calcium channels at low concentrations (10-12 to 10-9M), whereas other mechanisms are involved at higher concentrations (10-8 to 3 x 10-7M).