Endothelin (ET) antagonists do not decrease blood pressure in normal rats. Since angiotensin II (AII) and ET both induce smooth muscle cell contraction through the same transduction pathways we designed experiments to assess whether blockade of the renin angiotensin system would unmask a vasodilatory response to ET receptor antagonists in rats. For this purpose, we tested the effect on arterial blood pressure of the mixed ETA-ETB receptor antagonist bosentan or of the ETA antagonist BQ-123 in the absence or the presence of the AII receptor antagonist losartan. In control conditions bosentan did not affect arterial blood pressure. In contrast, in losartan-pretreated rats, bosentan induced a marked, dose-dependent decrease in arterial pressure (% change after bosentan 10 mg/kg: control -3 +/- 3, losartan -32 +/- 6; cilazapril -28 +/- 3). Similarly, BQ-123 decreased blood pressure in losartan-pretreated but not in control rats. Bosentan also increased the hypotensive effect of losartan in conscious, normotensive rats. The hypotensive effect of the combination of bosentan and losartan was not associated with any changes in cardiac output or heart rate, and thus was entirely due to a decrease in total peripheral resistance. We conclude that blockade of angiotensin II, AT1 receptors unmasks a vasodilator response to ET antagonists. This suggests that endogenous ET plays an active role in the maintenance of arterial blood pressure in rats which can be unmasked by a concomitant inhibition of the renin angiotensin system.