The interactions of leukotriene C4 (LTC4) and D4 (LTD4) with histamine and acetylcholine in contracting guinea pig isolated tracheal smooth muscle have been investigated. In a bathing solution containing 2.5 mM Ca2+, threshold concentrations of the leukotrienes did not affect contractile responses of the smooth muscle to other agonists. However, at a low extracellular Ca2+ concentration (0.1 mM), LTD4 (10(-8) M and 10(-7) M) significantly enhanced contractions induced by histamine or acetylcholine. LTD4 (10(-7) M) shifted the concentration-response curves of these agents leftward by 0.27 and 0.46 log units respectively. The potentiating action of LTD4 was inhibited by the leukotriene antagonist FPL 55712 (3 X 10(-6) M), and was only partially reversible by washing. A subthreshold concentration of potassium chloride (1.5 X 10(-2) M) also increased the sensitivity of the tracheal muscle to acetylcholine in low Ca2+ medium, and this effect was not additive to that of LTD4. These results demonstrate that leukotrienes can alter the in vitro reactivity of airways smooth muscle to other bronchoconstrictor agents. The mechanism of this action may involve altered membrane binding or fluxes of Ca2+, associated with decreased resting potential of the plasma membrane of smooth muscle cells.