Abstract 16113: Upregulation of Cardiac β3-Adrenergic Signaling Promotes Heart Failure Progression

Abstract

Background. The negative inotrope and upregulation of β 3 -adrenergic receptors (AR) in failing human and animal hearts suggest a direct and contributing role of cardiac β 3 -AR activation on heart failure (HF) progression. However, its precise role is still being debated. We hypothesize that up-regulation of β 3 -AR is detrimental and chronic β 3 -AR blockade may limit or prevent the progression of HF. Methods. We determined Left ventricular (LV) and myocyte functional response and β 1 - and β 3 -AR expressions in 3 groups of rats (6/group) for a period of 4 months: 1) Isoproterenol (ISO)-treated, 4 months after receiving ISO (170 mg/kg, sq, for 2 days); 2) ISO/β 3 -ANT, two months after receiving ISO, L-748,337, a selective β 3 -AR antagonist (β 3 -ANT) (10 -7 M/kg/day by implanted osmotic mini pump) was initiated after established HF and was given for 2 months; and 3) sham controls. Results. Compared with controls, ISO-treated rats had HF onset at one month after ISO and progressed to severe HF at 4 months. Plasma norepinephrine (NE, 1482 vs 247 pg/ml) increased 6 fold. Both stroke volume (SV) and ejection fraction (EF, 32% vs 61%) decreased more than 48%, and LV end-diastolic pressure (P ED , 15.4 vs 6.0 mmHg) doubled, parallel with 48% reductions in cell contraction (dL/dt max, 78 vs 149 μm/s) and relaxation (dR/dt max , 66 vs 128 μm/s) and a much less increase in dL/dt max (30% vs 74%) in response to superfusion of ISO (10 -8 M). These changes were associated with significantly decreased β 1 -AR mRNA (0.30 vs 0.64) and protein levels (0.36 vs 0.62), but increased β 3 -AR mRNA (1.29 vs 0.52) and protein levels (0.35 vs 0.18). Treatment with β 3 -ANT significantly decreased P ED and plasma NE (191 pg/ml). Both SV and EF (59%) increased to more than 76% from ISO-treated values. The signal ratios of β 1 -AR mRNA (0.61) and β 3 -AR mRNA (0.59) remained close to control levels. ISO-induced increase in dL/dt max (75%) was also significantly augmented. Conclusion. Chronic β 3 -ANT prevented plasma norepinephrine elevations and causes normalization of β 1 - and β 3 -AR gene expression, restores normal responsiveness of myocyte to β-AR stimulation, and leads to regression of LV and myocyte dysfunction in a rat model of progressive HF. Thus, β 3 -AR blocker may provide a new therapeutic strategy for the treatment of HF.