Abstract--The present study evaluated the potential mechanism involved in the hypotensive effect induced by ET-1 in rats treated with the NO synthase inhibitor N^G-nitro-L-arginine methyl ester (L-NAME) in the drinking water during 7 days. Hypertension developed in the L-NAME-treated rats (164±3 versus 112±1 mm Hg in untreated control rats), and the hypotensive effect of ET-1 (100 pmol/kg IV) was significantly enhanced compared with control rats (32±2% versus 20±1% fall in mean arterial pressure). The enhanced ET-1 hypotensive effect in L-NAME-treated rats was abolished by the ET_B receptor antagonist BQ-788 but was unaltered by the cyclooxygenase inhibitor diclofenac, the cytochrome P450 inhibitor fluconazole, or the potassium channel blockers apamin, glibenclamide, tetraethylammonium, and 4-aminopyridine. Pretreatment with the cannabinoid CB₁ receptor antagonist SR141716A significantly reduced the hypotensive response to ET-1 in L-NAME-treated rats (20±1%), although it did not modify the response in untreated control rats (17±1%). These findings indicate that in rats under chronic NOS inhibition, the hypotensive effect of ET-1 is unexpectedly enhanced and appears to be mediated by a non-NO/non-prostanoid mechanism and involves an SR141716A-sensitive mechanism triggered by ET_B receptor activation.