Abstract 9084: Selective Beta3-Adrenergic Receptor Antagonist Therapy Causes Regression of Cardiac Dysfunction in a Rat Model of Progressive Heart Failure: Insights into Molecular and Cellular Mechanisms

Abstract

Background: Heart failure (CHF) causes cardiac β 3 -adrenergic receptor (AR) upregulation with resultant enhanced β 3 -AR-stimulated-G i -coupled negative modulation on cardiac function. This suggests a direct and contributing role of β 3 -AR activation on CHF progression. However, its precise role is unclear. We hypothesize that up-regulation of cardiac β 3 -AR promotes CHF progression. Chronic β 3 -AR antagonist (ANT) may improve Left ventricular (LV) myocyte function, and β-adrenergic reserve, thus preventing the progression of CHF. Methods: LV and myocyte functional response and β 1 - and β 3 -AR expression were compared in 3 groups of SD male rats (8 each) during 3 months: 1) CHF, 3 months after receiving Isoproterenol (ISO, 170 mg/kg, sq, for 2 days); 2) CHF/β 3 -ANT, 2 months after receiving ISO, L-748,337, a selective β 3 -AR antagonist (β 3 -ANT) (10 -7 M/kg/day, mini pump) was initiated and was given for 1 month; and 3) sham controls. Results: Versus controls, ISO-treated rats had CHF onset at 1 month after ISO and progressed to severe CHF at 3 months. Plasma norepinephrine (NE, 1298 vs 261 pg/ml) increased 4-fold; whereas, stroke volume (SV) and ejection fraction (EF, 34 vs 62%) decreased more than 45%. These changes were parallel with significant reductions in cell contraction (dL/dt max , 95 vs 189 μm/s), relaxation (dR/dt max ,75 vs 158 μm/s) and [Ca 2+ ] i transient ([Ca 2+ ] iT ) (0.17 vs 0.26). Acute superfusion of ISO (10 -8 M) caused much less increases in dL/dt max (34 vs 74%), dR/dt max and [Ca 2+ ] IT (14 vs 28%). These changes were associated with significantly decreased β 1 -AR mRNA (52%, 0.30 vs 0.62), but increased β 3 -AR mRNA (119%, 1.25 vs 0.57) expression. CHF with β 3 -ANT treatment, significantly decreased plasma NE (197 pg/ml). EF (59%) and SV returned to normal control values. The signal ratios of β 1 -AR mRNA (0.59) and β 3 -AR mRNA (0.66) recovered to control levels. ISO-induced increases in dL/dt max (75%), dR/dt max and [Ca 2+ ] iT were also significantly augmented. Conclusion: Chronic β 3 -ANT leads to normalization of LV myocyte β 1 - and β 3 -AR gene expression, restores normal LV myocyte β-AR reserve, and leads to regression of LV and myocyte dysfunction in a rat model of progressive CHF. Thus, β 3 -AR blocker may provide a new therapeutic strategy for the treatment of CHF.