Reduction of vascular noradrenaline sensitivity by AT1 antagonists depends on functional sympathetic innervation.
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.
Raasch
Walter
W
Institute of Experimental and Clinical Pharmacology and Toxicology, University Clinic of Schleswig-Holstein, Campus Lübeck, Ratzeburger Allee 160, 23538, Lübeck, Germany. raasch@medinf.mu-luebeck.de
Dominiak
Peter
P
Ziegler
Andreas
A
Dendorfer
Andreas
A
D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D001285:Atropine / Q000494:pharmacology; D001562:Benzimidazoles / Q000494:pharmacology*; D001713:Biphenyl Compounds; D001794:Blood Pressure / Q000187:drug effects*; D003891:Desipramine / Q000494:pharmacology; D003971:Diastole / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D019808:Losartan / Q000494:pharmacology*; D008297:Male; D009638:Norepinephrine / Q000037:antagonists & inhibitors*; D050484:Norepinephrine Plasma Membrane Transport Proteins; D011433:Propranolol / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D018341:Receptors, Adrenergic, alpha-2 / Q000187:drug effects / Q000502:physiology; D012110:Reserpine / Q000494:pharmacology / Q000633:toxicity; D013563:Sympathectomy, Chemical; D013564:Sympathetic Nervous System / Q000502:physiology*; D027981:Symporters / Q000037:antagonists & inhibitors / Q000187:drug effects; D013777:Tetrazoles / Q000494:pharmacology*; D014403:Tubocurarine / Q000494:pharmacology; D015016:Yohimbine / Q000494:pharmacology
D000317:Adrenergic alpha-Antagonists; D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D050484:Norepinephrine Plasma Membrane Transport Proteins; D018341:Receptors, Adrenergic, alpha-2; C493226:Slc6a2 protein, rat; D027981:Symporters; D013777:Tetrazoles; D015016:Yohimbine; D001285:Atropine; D012110:Reserpine; D011433:Propranolol; D019808:Losartan; C081643:candesartan; D003891:Desipramine; D014403:Tubocurarine; D009638:Norepinephrine