Endothelin, a newly discovered vasoconstrictor peptide, when added to isolated cat papillary muscles, induced a direct positive inotropic effect that was slow in onset but of long duration. The magnitude of the developed force was concentration dependent. Endothelin exerted a marked concentration-dependent vasoconstriction in isolated cat carotid arteries and rabbit aortic rings. In both the carotid arteries and the aortic rings, endothelin induced a similar vasoconstrictor effect in the presence or absence of an intact endothelium. Addition of propyl gallate, a 5-lipoxygenase inhibitor, ibuprofen, a cyclooxygenase inhibitor, or SKF-525A, a cytochrome P450 inhibitor, at 2 microM did not significantly attenuate the ability of endothelin to vasoconstrict aortic rings in the presence or absence of an intact endothelium. These results demonstrate that the vasoconstrictor activity of endothelin operates independently of all three pathways of arachidonic acid metabolism (i.e., lipoxygenase, cyclooxygenase, or cytochrome P450 pathways) and is not dependent upon other endothelium-derived mediators (e.g., endothelium-derived relaxing factor, or eicosanoids) in these preparations. Moreover, endothelin exerts a direct positive inotropic effect in isolated cat ventricular myocardial tissue.