Endothelin is a peptide with 21 amino acids that is produced by ischemic or injured endothelial cells. As indicated by in vitro and animal studies, endothelin is also a potent constrictor for renal mesangial and coronary vessels, a bronchoconstrictor, and an endocrine regulator. Our laboratory has shown that endothelin is an agonist for monocyte production of interleukins-1, -6, and -8, prostaglandin E2, and substances that trigger superoxide production. Systemic endothelin levels increase in patients with hypoperfusion and sepsis, indicating that endothelin may be yet another important cytokine in critical illness. Though endothelin has been shown to be a potent vasoconstrictor in healthy dogs, systemic vascular resistance does not increase in critically ill patients with high endothelin levels. (We hypothesize that this might be due to prostaglandin E2-mediated vasodilation predominating over endothelin-mediated vasoconstriction.) We questioned whether any changes occur in systemic endothelin levels in patients with major burns (> 20%). Ten hemodynamically stable patients resuscitated by a modified Parkland formula to a urine output greater than 30 ml/hr had endothelin levels drawn on admission and at 1, 6, 12, 24, and 48 hours after admission. Endothelin levels were measured by radioimmunoassay. Mean endothelin levels were elevated at 205 +/- 28 fmol/ml at all time points in contrast to levels of 39 +/- 9 fmol/ml in the healthy control group. In summary, systemic endothelin levels increase significantly in patients with major burns. Endothelin may be yet another cytokine playing a significant role in the immune, inflammatory, and multiorgan dysfunction observed with major burns.