BACKGROUND Endothelin is an oligopeptide of endothelial origin with potent vasoconstrictive and mitogenic properties, implicated in the pathogenesis of cyclosporine-induced hypertension, graft vasculopathy, and renal failure. Experimental animal data suggest a role for endothelin in allograft rejection also. METHODS To determine the role of endothelin in acute graft rejection after heart transplantation, we determined endothelin plasma levels in 165 blood samples from 79 cardiac allograft recipients (2 to 81 months after the operation) with normal graft function and correlated our findings with the histologic severity of acute graft rejection according to International Society for Heart and Lung Transplantation grading. For comparison endothelin levels were determined in 30 healthy controls and in 22 early postoperative transplant recipients (< 2 months after the operation). RESULTS Endothelin plasma levels were significantly higher in transplant recipients than in controls (early postoperative: 7.97 = 7.53 pg/ml; late postoperative: 3.68 +/- 1.72 pg/ml; controls: 1.55 +/- 0.89 pg/ml). Endothelin plasma levels were not significantly different between groups of rejection grades 0 to 4. In the comparison of two groups of no rejection or lower (International Society for Heart and Lung Transplantation grade 0 and 1, n = 134) and higher (International Society for Heart and Lung Transplantation grade > or = 2, n = 31) rejection severity or comparing patients requiring rejection therapy (n = 20) with those not requiring therapy (n = 145), endothelin levels did not differ significantly between the groups. In 22 patients with three to six available consecutive biopsy scores and endothelin levels, intraindividual longitudinal analysis did also not show any significant correlation. The only positive correlation of endothelin levels with other laboratory parameters was found with serum creatinine concentrations (p < 0.001). In the early postoperative recipients, no correlation of endothelin plasma levels with rejection severity was seen; furthermore the only significant association was found with time after operation. CONCLUSIONS In this study endothelin plasma levels were not influenced by acute allograft rejection after heart transplantation. Therefore endothelin levels do not appear to be a useful marker for noninvasive rejection diagnosis. Furthermore, a relevant pathogenetic role of endothelin in the rejection process cannot be derived from these data.