&NA;The vasoconstrictor responses of isolated rat portal vein and aorta to synthetically prepared endothelin are investigated. Both preparations respond to 10−9M levels of the peptide although the aortic response is more sustained than that of the portal vein. Endothelin‐evoked contractions, unlike those evoked by scorpion &agr;‐toxins (which are homologous to endothelin) or by veratridine, are insensitive to tetrodotoxin or to the removal of sodium ions from the tissue‐bathing medium. Contractile responses to endothelin may still be observed in high‐potassium depolarizing medium and are not dependent on the presence of extracellular chloride; however, the responses are dependent on the presence of extracellular calcium and are blocked by nitrendipine, nifedipine, or nickel. Endothelin‐evoked uptake of45Ca into aortic tissue is also independent of extracellular sodium or potassium and is blocked by nifedipine. These data strongly suggest that endothelin acts at a site closely coupled to the calcium channel and that depolarization by sodium influx through voltage‐dependent channels is not involved in endothelin‐induced vasoconstriction. (Circulation Research1989;65:265‐271)