title: Ventricular hypertrophy plus neurohumoral activation is necessary to alter the cardiac beta-adrenoceptor system in experimental heart failure.
abstract: Treatment of rats with monocrotaline (MCT) leads to pulmonary hypertension, right ventricular (RV) hypertrophy, and finally to RV heart failure. This is associated with characteristic changes in right ventricular beta-adrenoceptors (beta-AR), neuronal noradrenaline transporter (NAT) density and activity (uptake1), and G protein-coupled receptor kinase (GRK) activity. This study aimed to find out factors that determine beta-AR, uptake1, and GRK changes. Thus, 6-week-old rats were treated with 50 mg/kg MCT subcutaneous or 0.9% saline. Within 13 to 19 days after MCT application (group A), RV weight (222+/-6 versus 147+/-5 mg) and RV/left ventricular (LV) weight ratio (0.42+/-0.01 versus 0.29+/-0.01) were significantly increased, whereas plasma noradrenaline, RV beta-AR density, RV NAT density and activity, and RV GRK activity were not significantly altered. Twenty-one to twenty-eight days after MCT (group B), however, not only RV weight (316+/-4 versus 148+/-2 mg) and RV/LV weight ratio (0.61+/-0.01 versus 0.3+/-0.01) were markedly increased but also plasma noradrenaline (645+/-63 versus 278+/-18 pg/mL); now, RV beta-AR density (13.4+/-1.3 versus 26.5+/-1.1 fmol/mg protein), RV NAT density (50.9+/-11.3 versus 79.6+/-2.9 fmol/mg protein), and RV NAT activity (65.4+/-7.4 versus 111.8+/-15.9 pmol [3H]-NA/mg tissue slices/15 min) were significantly decreased and RV-membrane GRK activity (100+/-15 versus 67+/-6 [32P]-rhodopsin in cpm) significantly increased. LV parameters of MCT-treated rats were only marginally different from control LV. We conclude that in MCT-treated rats ventricular hypertrophy per se is not sufficient to cause characteristic alterations in the myocardial beta-AR system often seen in heart failure; only if ventricular hypertrophy is associated with neurohumoral activation beta-ARs are downregulated and GRK activity is increased.
authors.affiliation: Institute of Pharmacology, Martin-Luther-University of Halle-Wittenberg, Halle, Germany.
authors.forename: Kirsten
authors.initials: K
authors.lastname: Leineweber
authors.forename: Katja
authors.initials: K
authors.lastname: Brandt
authors.forename: Beate
authors.initials: B
authors.lastname: Wludyka
authors.forename: Anja
authors.initials: A
authors.lastname: Beilfuss
authors.forename: Klaus
authors.initials: K
authors.lastname: Pönicke
authors.forename: Ingrid
authors.initials: I
authors.lastname: Heinroth-Hoffmann
authors.forename: Otto-Erich
authors.initials: OE
authors.lastname: Brodde
mesh_terms: D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects / Q000502:physiology; D002462:Cell Membrane / Q000737:chemistry / Q000378:metabolism; D004195:Disease Models, Animal; D005136:Eye Proteins; D005473:Fluoxetine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D051606:G-Protein-Coupled Receptor Kinase 1; D006333:Heart Failure / Q000139:chemically induced / Q000150:complications / Q000503:physiopathology*; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000150:complications; D017380:Hypertrophy, Right Ventricular / Q000139:chemically induced / Q000150:complications / Q000503:physiopathology*; D008297:Male; D016686:Monocrotaline; D009206:Myocardium / Q000378:metabolism*; D009638:Norepinephrine / Q000097:blood / Q000493:pharmacokinetics; D050484:Norepinephrine Plasma Membrane Transport Proteins; D009929:Organ Size / Q000187:drug effects; D011494:Protein Kinases / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D017981:Receptors, Neurotransmitter / Q000378:metabolism*; D012243:Rhodopsin / Q000493:pharmacokinetics; D027981:Symporters / Q000032:analysis / Q000378:metabolism
chemical_list: D005136:Eye Proteins; D050484:Norepinephrine Plasma Membrane Transport Proteins; D011943:Receptors, Adrenergic, beta; D017981:Receptors, Neurotransmitter; C493226:Slc6a2 protein, rat; D027981:Symporters; D005473:Fluoxetine; C011386:nisoxetine; D016686:Monocrotaline; D012243:Rhodopsin; D011494:Protein Kinases; D051606:G-Protein-Coupled Receptor Kinase 1; C496765:Grk1 protein, rat; D009638:Norepinephrine