We previously showed that chronic insulin infusion induces insulin resistance, hyperendothelinemia, and hypertension in rats (Juan et al. Metabolism 48: 465-471, 1999). Endothelin-1 (ET-1), a potent vasoconstrictor, is suggested to play an important role in maintaining vascular tone and regulating blood pressure, and insulin increases ET-1 production in vivo and in vitro. In the present study, BQ-610, a selective endothelin A receptor antagonist, was used to examine the role of ET-1 in insulin-induced hypertension in rats. BQ-610 (0.7 mg/ml; 0.5 ml/kg body weight) or normal saline was given intraperitoneally twice daily for 25 days to groups of rats infused with either saline or insulin (2 units per day via subcutaneously implanted osmotic pumps), and changes in plasma levels of insulin, glucose, and ET-1 and the systolic blood pressure were measured over the experimental period, while changes in insulin sensitivity were examined at the end of the experimental period. Plasma insulin and ET-1 levels were measured by radioimmunoassay, plasma glucose levels using a glucose analyzer, the systolic blood pressure by the tail-cuff method, and insulin sensitivity by an oral glucose tolerance test. Our studies showed that insulin infusion caused sustained hyperinsulinemia in both saline- and BQ-610-injected rats over the infusion period. Two weeks after pump implantation, the systolic blood pressure was significantly higher in insulin-infused rats than in saline-infused rats in the saline-injected group (133±3.1 versus 113±1.1 mmHg, p<0.05) but not in the BQ-610-injected group (117±1.2 versus 117±1.8 mmHg). Plasma ET-1 levels in both sets of insulin-infused rats were higher than in saline-infused controls (2.5±0.6 & 2.5±0.8 versus 1.8±0.4 & 1.7±0.3 pmol/L, p<0.05). Oral glucose tolerance tests showed that BQ-610 treatment did not prevent the insulin resistance caused by chronic insulin infusion. No significant changes were found in insulin sensitivity and blood pressure in saline-infused rats treated with BQ-610. In a separate experiment, insulin infusion induced the increase in arterial ET-1 content, hypertension and subsequent plasma ET-1 elevation in rats. These results suggest that, in the insulin-infusion rat model, ET-1 plays a mediating role in the development of hypertension, but not of insulin resistance.