Continuous release of nitric oxide (NO) from endothelial cells permanently inhibits the synthesis and the vasoconstrictor effects of endothelin (ET). Thus, inhibition of NO synthesis might unmask a vasopressor response to endogenous ET. We tested whether bosentan (bos), a non-peptide antagonist of ET A and ET B receptors, affects the hypertensive response induced by acute of chronic administration of the NO synthase inhibitor L-NAME. In acute experiments, anesthetized rats received L-NAME (3 mg/kg i.v.), in the absence or the presence of bos (3 mg/kg i.v. 15 min before L-NAME). In chronic experiments, rats were treated for 2 months with L-NAME (50mg/kg/day in drinking water) or L-NAME + bos (100mg/kg/day in rat chow), and systolic arterial pressure (plethysmography) was measured in the conscious state. In anesthetized rats, bos did not affect blood pressure, heart rate or cardiac output (Doppler), but reduced the L-NAME - induced increase in arterial pressure (% increase in MAP: control 29+/-5; bos 15+/-4%; p<0.05) and total peripheral resistance (control 126+/-38; bos 62+/-11%; p<0.01), as well as the L-NAME induced decrease in cardiac output (control -36+/-6; bos -26+/-4%; p<0.05), without affecting the decrease in heart rate (control -17+/-2; bos -17+/-2%). The pressor response to L-NAME was also reduced by the specific ET A antagonist BQ-123 (3mg/kg; control 25+/-5; BQ-123 14+/-5%; p<0.05). Bos also reduced the pressor response to L-NAME in ganglion-blocked rats (% increase in MAP after L-NAME: control 89+/-10; bos 45+/-7%; p<0.01). Chronic treatment with L-NAME also induced a marked increase in systolic blood pressure (from 123+/-4 to 212+/-7 mm Hg after 2 months; p<0.01) and this was reduced by chronic treatment with bos (systolic blood pressure after 2 months: 185+/-7 mm Hg; p<0.02). Thus, both acute and chronic inhibition of NO synthesis unmask an ET-induced vasopressor response. This suggests that ET may play a major role in pathophysiological situations associated with an impaired formation of NO.