1. To compare the effect of diltiazem and verapamil on the responsiveness of vascular smooth muscle to norepinephrine in the presence and absence of the endothelium, rings of rat aorta were studied in organ chambers. 2. The removal of the endothelium decreased the ED50 to norepinephrine and augmented the maximal response to the catecholamine. 3. The contraction to norepinephrine consisted of a rapid initial (phasic) and a (tonic) part. The tonic part was reduced in the presence of the endothelium. 4. Diltiazem shifted the concentration-response curve to norepinephrine to the right only in rings without endothelium and reduced the difference in maximal response between rings with and without endothelium. 5. Verapamil abolished the difference in sensitivity (ED50) between rings with and without endothelium. 6. Oxyhemoglobin prevented the inhibitory effect of the endothelium on the response to norepinephrine, and unmasked a shift of the ED50 to the catecholamine to the right by diltiazem in rings with endothelium. 7. These experiments suggest that spontaneously released endothelium-derived relaxing factor(s) is a functional antagonist of norepinephrine-induced contractions, presumably by reducing the stimulated influx of extracellular Ca2+.