Staurosporine inhibits the effects of leukotrienes C4 and D4 in isolated guinea pig heart and trachea.

Isolated hearts from guinea pigs were perfused at 37 degrees C with Tyrode's solution according to the technique of Langendorff. Coronary flow, left ventricular pressure amplitude and heart rate were measured. Bolus injection of 30 ng leukotriene C4 caused a long-lasting decrease in coronary flow and left ventricular pressure amplitude while heart rate was not affected. A similar but shorter lasting effect was induced by 100 ng leukotriene D4. The effects of the leukotrienes were completely blocked by 1 microM staurosporine. Staurosporine at concentrations of 100 and 10 nM, in contrast to 1 microM, influenced basic cardiac function slightly or not at all, but antagonized the effects of 30 ng leukotriene C4. In isolated tracheal muscle preparations, leukotriene C4 and D4 induced concentration-dependent contractures. Staurosporine at concentrations of 25-100 nM antagonized the effects of leukotriene C4 and D4 in a noncompetitive manner with inhibitor constants of 47.6 and 75.9 nM, respectively. The results indicate that staurosporine is a potent noncompetitive antagonist of the effects of leukotriene C4 and D4 in smooth muscle.