Reduction of Vascular Noradrenaline Sensitivity by AT 1 Antagonists Depends on Functional Sympathetic Innervation

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Abstract
Blockade of angiotensin II type-1 (AT 1 ) 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 ED 50 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 AT 1 receptors was confirmed by equivalent actions of losartan. Blockade of norepinephrine transporter or α 2 -adrenoceptors using desipramine or rauwolscine reduced the losartan-induced shifts in the ED 50 values of noradrenaline by 63% and 21%, respectively. Combined blockade of norepinephrine transporter and α 2 -adrenoceptors eliminated the influence of losartan on noradrenaline sensitivity ( ED 50 5.5±1.3 versus 5.6±1.2 nmol/kg), a result also observed after sympathetic denervation by reserpine ( ED 50 7.1±0.8 versus 7.8±0.8 nmol/kg). Our experiments show that the reduction of vascular noradrenaline sensitivity by AT 1 blockade is dependent on the intact functioning of both neuronal noradrenaline uptake via norepinephrine transporter and presynaptic α 2 -mediated autoinhibition, exclusively provided by the sympathetic innervation. These newly identified mechanisms may contribute to the antihypertensive and protective actions of AT 1 blockers.

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