Endothelins-1 and 3 (ET-1 and 3) were evaluated for angiogenesis in the rat cornea. Bisected 2 mm pellets containing 20-1000 ng of ET-1 or ET-3 in Hydron were placed in corneal micro-pockets. Murine vascular endothelial growth factor (VEGF) and human interleukin-8 (IL-8) were positive controls. No angiogenesis occurred in 32 corneas with pellets containing only saline. With 200 ng VEGF pellets, 27/52 corneas (52%) demonstrated angiogenesis. With 200 ng IL-8 pellets, 32/51 corneas (63%) demonstrated angiogenesis. With 20-1000 ng ET-1 pellets, angiogenesis occurred in 65/91 corneas (71%); with ET-3 pellets, 84/116 (72%). ET-1- and ET-3-mediated angiogenesis was unaffected by cyclophosphamide-induced leukopenia. ET-1-mediated angiogenesis was inhibited by an ET(A)-receptor antagonist (ra) (BQ610) and a combined ET(A)/ET(B) ra (bosentan). However, ET-1-mediated angiogenesis was not inhibited by an ET(B) ra(BQ788) and a weak ET(A) ra(BQ123). Thus, ET-1 and -3 are angiogenic in the rat cornea; this effect appears to be direct, not leukocyte-mediated, and ET(A)-receptor-dependent.