The presence of the endothelin (ET) system was first discovered in 1988.1– The ET system includes ET-1, ET-2, ET-3, and ET-4. ET-1, a 21 amino acid peptide, represents the major isoform of the ET system, as it is the most potent vasoconstrictor known.2– ET-1 is cleaved from its precursor by the action of ET-converting enzyme. ET-1 acts through two receptors, ET-A and ET-B. Activation of the ET-A receptor leads to an increased intracellular calcium concentration inducing vasoconstriction and cellular proliferation. Contrary, ET-B receptors are inhibitory, and are involved in the clearance of ET-1 and inhibition of the ET-converting enzyme. Additionally, activation of ET-B receptors results in release of vasodilatory mediators such as nitric oxide and prostacyclin. Thus, ET-1 has both vasoconstrictive and vasodilatory effects, but the vasoconstrictive effect predominates, more so in the vessels with dysfunctional endothelium; the loss of nitric oxide may augment the vasoconstrictive activity of ET-1. ET-1 plays a role in both the physiologic and pathologic conditions of the cardiovascular system. Human and canine epicardial coronary arteries display a baseline ET-1–dependent tone, which is an ET-A receptor-dependent process.3– In healthy coronary arteries, administration of ET-1 causes biphasic coronary response characterized by a transient dilatation of large and small vessels followed by a sustained constriction. With higher doses, the vasoconstrictive response predominates, both in the coronary as well as the peripheral circulation. In a human experiment4 in which ET-1 was administered IV in doses of 0.2, 1, and 8.0 pmol/kg/min, coronary blood flow was reduced by 23%, coronary vascular resistance increased by 48%, and mean arterial pressure increased from 95 to 106 mm Hg with the highest ET-1 infusion rates. The reduction in coronary blood flow and increase in coronary vascular resistance were parallel to the decrease in coronary sinus oxygen levels. The threshold dose of ET-1 for causing significant coronary effects was 1.0 pmol/kg/min, a dose that raised plasma levels by fourfold. Thus, ET-1 at nonphysiologic plasma levels results in a mismatch between oxygen supply and demand in coronary circulation, although at physiologic levels it plays a major role in maintaining the healthy vascular tone.