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  • Title: Reduction of vascular noradrenaline sensitivity by AT1 antagonists depends on functional sympathetic innervation.
    Author: Raasch W, Dominiak P, Ziegler A, Dendorfer A.
    Journal: Hypertension; 2004 Sep; 44(3):346-51. PubMed ID: 15262904.
    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 alpha2-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 alpha2-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 alpha2-mediated autoinhibition, exclusively provided by the sympathetic innervation. These newly identified mechanisms may contribute to the antihypertensive and protective actions of AT1 blockers.
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