Arteries relax to the vasodilators acetylcholine, substance P, ATP and bradykinin only if the endothelium is present. One hypothesis is that these substances stimulate the endothelial cells to release a vasodilator substance which in turn relaxes the underlying smooth muscle. We considered that other hormones which have direct actions on smooth muscle cells may also release the dilator substance. If the hormone contracts smooth muscle cells and also activates the release of the dilator from endothelial cells, the algebraic sum of these stimuli would determine the physiological response. Our preliminary experiments in pig and dog isolated coronary arteries showed that noradrenaline (NA) and serotonin (5-hydroxytryptamine, 5-HT) were significantly more powerful vasoconstrictors in the absence of endothelium. We report here the unexpected finding that these constrictor amines release a vasodilator substance from endothelial cells that can act as a physiological antagonist of the well known smooth muscle contractile responses. We suggest that the potential involvement of the vasodilator signal should be considered in the responses to vasoconstrictors in both normal and diseased blood vessels.