The roles of endothelin-1 (ET-1) and its receptors (ET A , ET B ) in mediating altered arterial reactivity in arteries undergoing atherosclerotic changes and/or collateral hyperperfusion, processes of occlusive arterial disease, were evaluated in isolated arteries. Use of normo- (C-) and hypercholesterolemic rabbits (C+) with normal (F-) or high carotid artery flows (F+) induced by contralateral carotid transection yielded 4 groups (C-F-, C-F+, C+ F-, C+ F+; 30 arteries from 6 rabbits per group). Contractions induced by ET-1 (10 pM-50 nm) were 100% inhibited by ET A -selective antagonist BQ123 at 10 μM (IC 5 0 = 200 nm). No inter-group differences were demonstrated. Non-selective antagonist bosentan induced similar but less potent inhibitions (IC 5 0 = 500 nM). ET B -selective antagonist BQ788 (10 μM) was inhibitory at low ET-1 (< 3 nM), but paradoxically potentiated contractions at higher ET-1 concentrations. Paradoxical responses were uninfluenced by blockade of nitric oxide synthesis with nitroarginine (1 mM). In aortas from streptozotocin-diabetic rats (n = 4) and atherosclerotic human coronary arteries (n = 4), BQ123, bosentan, and BQ788 exerted similar effects as in rabbits. Thus, constrictor responses to ET-1 were mediated predominantly by ET A in all arteries tested. Efficacy of BQ123 was not modified by high flow, hypercholesterolemia, atherosclerosis, or diabetes. Paradoxical potentiations of ET-1-induced contractions by BQ788 suggest direct smooth muscle relaxing effects of ET-1 acting on ET B receptors.