Abstract--Blockade of angiotensin II type-1 (AT₁) receptors has been shown to reduce the magnitude of the blood pressure response to noradrenaline in pithed rats via an unidentified mechanism. Dose-response curves were established for the noradrenaline-induced (10^-12 to 10^-7 mol/kg) increase of diastolic blood pressure in pithed rats treated with tubocurarine, propranolol, and atropine. Candesartan (1 mg/kg) increased the ED₅₀ of the noradrenaline response (1.3±0.1 nmol/kg) up to 20-fold. Vasopressor responsiveness to noradrenaline was attenuated specifically, whereas the vasopressin-induced increase in diastolic blood pressure was maintained. Specific involvement of AT₁ receptors was confirmed by equivalent actions of losartan. Blockade of norepinephrine transporter or ₂-adrenoceptors using desipramine or rauwolscine reduced the losartan-induced shifts in the ED₅₀ values of noradrenaline by 63% and 21%, respectively. Combined blockade of norepinephrine transporter and ₂-adrenoceptors eliminated the influence of losartan on noradrenaline sensitivity (ED₅₀ 5.5±1.3 versus 5.6±1.2 nmol/kg), a result also observed after sympathetic denervation by reserpine (ED₅₀ 7.1±0.8 versus 7.8±0.8 nmol/kg). Our experiments show that the reduction of vascular noradrenaline sensitivity by AT₁ blockade is dependent on the intact functioning of both neuronal noradrenaline uptake via norepinephrine transporter and presynaptic ₂-mediated autoinhibition, exclusively provided by the sympathetic innervation. These newly identified mechanisms may contribute to the antihypertensive and protective actions of AT₁ blockers.