This study investigated the role of endothelin-1 for hyperglycemia, vascular, and pancreatic injury in early type I diabetes in non-obese-diabetic (NOD) mice. Endothelium dependent relaxation to acetylcholine and vascular gene expression of endothelin converting enzyme (ECE) isoforms 1 and 2 were studied as indicators of vascular injury. Endothelial NO bioactivity in the aorta was reduced in diabetic NOD mice while vascular expression of ECE-1 and ECE-2 mRNA was increased compared with controls (all p<0.05). Vascular histology was normal in all animals. Unexpectedly, treatment of prediabetic NOD mice for 6 weeks with the orally active ET(A) receptor antagonist BSF461314 prevented onset of diabetes without affecting insulitis severity. ET(A) receptor blockade also restored abnormal endothelial NO bioactivity and reduced ECE-1 and ECE-2 gene expression in NOD mice to levels comparable with healthy controls (p<0.05). Moreover, secretion of endothelin-1 in a time-dependent fashion was observed by pancreatic islet beta-cells cultured in vitro. These data suggest a critical role for ET(A) receptor signaling in the development of autoimmune forms of diabetes and the early vascular injury associated with it.