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(Hypertension. 2004;44:346.)
© 2004 American Heart Association, Inc.

Scientific Contributions

Reduction of Vascular Noradrenaline Sensitivity by AT₁ Antagonists Depends on Functional Sympathetic Innervation

Walter Raasch; Peter Dominiak; Andreas Ziegler; Andreas Dendorfer

From the Institutes of Experimental and Clinical Pharmacology and Toxicology (W.R., P.D., A.D.) and Medical Biometry and Statistics (A.Z.), University Clinic of Schleswig-Holstein, Campus Lübeck, Germany.

Correspondence to Walter Raasch, PhD, Institute of Experimental and Clinical Pharmacology and Toxicology, University Clinic of Schleswig-Holstein, Campus Lübeck, Ratzeburger Allee 160, 23538, Lübeck, Germany. E-mail raasch{at}medinf.mu-luebeck.de

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.

Key Words: angiotensin antagonist • receptors, angiotensin • catecholamines • vasopressins