We measured the release of immunoreactive endothelin-1 (IR-ET-1) by cultured porcine aortic endothelial cells under normoglycemic (5.5 mmol/L) and hyperglycemic (27.5 and 55 mmol/L) conditions. Compared with cells incubated in the presence of a normal glucose concentration, cells incubated in 27.5 mmol/L glucose medium released 52% less IR-ET-1, and those incubated in 55 mmol/L glucose medium released 54% less IR-ET-1. The observed effects of elevated glucose on IR-ET-1 release were both sugar-specific and not due to increased osmolarity. Fetal calf serum (FCS)-stimulated IR-ET-1 release in the presence of elevated glucose was also less than that in the presence of a normal glucose concentration. In addition, the effects of two hormones, insulin and insulin-like growth factor 1 (IGF-1), on IR-ET-1 release were examined. Both insulin and IGF-1 dose-dependently stimulated IR-ET-1 release. Twenty micrograms/mL insulin and 10(-8) mol/L IGF-1 increased IR-ET-1 release by 38% and by 44%, respectively. These results indicate that hyperglycemic condition results in reduction of IR-ET-1 release from cultured porcine aortic endothelial cells and that insulin and IGF-1 stimulate its release. The possible relevance of these observations to physiological regulation of ET-1 release in vivo and pathological processes in diabetes remains to be established.