title: Cardiac beta-adrenoceptor desensitization due to increased beta-adrenoceptor kinase activity in chronic uremia.
abstract: Patients with chronic renal failure develop an autonomic dysfunction with impaired baroreflex control and attenuated cardiovascular beta-adrenoceptor response to noradrenaline. In rats that underwent 5/6-nephrectomy (SNX), cardiac beta-adrenoceptor responsiveness was reduced as well. Therefore, the aim of this study was to further investigate the mechanism underlying cardiac beta-adrenoceptor desensitization in SNX rats. For this purpose, right and left ventricular beta-adrenoceptor density, activity of the G-protein-coupled receptor kinase, and activity and density of the neuronal noradrenaline transporter (uptake1) were assessed in SNX rats. Seven weeks after SNX, rats had developed left heart hypertrophy. Plasma creatinine, urea, and noradrenaline levels were significantly increased; left and right ventricular noradrenaline content was significantly decreased when compared with sham-operated control rats. In these SNX rats, left, but not right, ventricular beta-adrenoceptor density was significantly reduced, and membrane-associated G-protein-coupled receptor kinase activity was significantly increased compared with sham-operated rats. Although right and left ventricular activity of uptake1 was unchanged, the neuronal noradrenaline transporter density was significantly reduced in both ventricles of SNX versus sham-operated rats. An increase in left ventricular G-protein-coupled receptor kinase activity, possibly triggered by enhanced cardiac noradrenaline release, might be responsible for the decrease in left ventricular beta-adrenoceptor responsiveness in SNX rats.
authors.affiliation: *Institute of Pharmacology and Toxicology and Department of Nephrology, Martin-Luther-University of Halle-Wittenberg, Halle, Germany.
authors.forename: Kirsten
authors.initials: K
authors.lastname: Leineweber
authors.affiliation: *Institute of Pharmacology and Toxicology and Department of Nephrology, Martin-Luther-University of Halle-Wittenberg, Halle, Germany.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Heinroth-Hoffmann
authors.affiliation: *Institute of Pharmacology and Toxicology and Department of Nephrology, Martin-Luther-University of Halle-Wittenberg, Halle, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Pönicke
authors.affiliation: *Institute of Pharmacology and Toxicology and Department of Nephrology, Martin-Luther-University of Halle-Wittenberg, Halle, Germany.
authors.forename: Getu
authors.initials: G
authors.lastname: Abraham
authors.affiliation: *Institute of Pharmacology and Toxicology and Department of Nephrology, Martin-Luther-University of Halle-Wittenberg, Halle, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Osten
authors.forename: Otto-Erich
authors.initials: OE
authors.lastname: Brodde
mesh_terms: D000818:Animals; D002462:Cell Membrane / Q000201:enzymology; D002908:Chronic Disease; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D003600:Cytosol / Q000201:enzymology; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D009638:Norepinephrine / Q000097:blood / Q000378:metabolism; D050484:Norepinephrine Plasma Membrane Transport Proteins; D051381:Rats; D017208:Rats, Wistar; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D027981:Symporters / Q000378:metabolism; D014511:Uremia / Q000378:metabolism*; D051552:beta-Adrenergic Receptor Kinases
chemical_list: D050484:Norepinephrine Plasma Membrane Transport Proteins; D011943:Receptors, Adrenergic, beta; C493226:Slc6a2 protein, rat; D027981:Symporters; D017868:Cyclic AMP-Dependent Protein Kinases; D051552:beta-Adrenergic Receptor Kinases; D009638:Norepinephrine