Ventricular hypertrophy plus neurohumoral activation is necessary to alter the cardiac β-adrenoceptor system in experimental heart failure

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 (uptake(1)), and G protein-coupled receptor kinase (GRK) activity. This study aimed to find out factors that determine beta-AR, uptake(1), 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 149 +/- 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 [H-3]-NA/mg tissue slices/15 min) were significantly decreased and RV-membrane GRK activity (100 +/- 15 versus 67 +/- 6 [P-32]-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.