Since endothelin-1 (ET-1) might regulate insulin secretion and glucose metabolism, we carried out experiments to study the effect of ET-1 in conscious rats by injecting ET-1 (0.5 or 1.0 μg/100 g body weight, i.p.) and examining the plasma glucose (PG) and insulin (PI) concentrations and PG/PI ratios continuously for 3 hours after the injection. Compared to the saline controls, ET-1 increased PG and PG/PI ratios in a dose-dependent manner. Oral glucose tolerance test (OGTT) performed at 30 min after the injection showed that PG levels stayed significantly higher in rats preinjected with ET-1 than rats with saline injection, although the change in PI levels was not different. Simultaneous infusion of glucose and insulin to somatostatin-primed rats with ET-1 or saline injection resulted in significantly higher steady state plasma glucose (SSPG) levels and SSPG/PI ratios in rats injected with ET-1 than control rats with saline. These results unequivocally indicated that intraperitoneally administered ET-1 induces insulin resistance in conscious rats.