Abstract 17062: Is Up-Regulation of Beta3-Adrenergic Receptor (AR) in the Failing Myocardium Detrimental or Beneficial?--Effect on Chronic Beta3-AR Blockade in Pacing-Induced Heart Failure
Background: In congestive heart failure (CHF), cardiac θ3-adrenergic receptor (AR)-mediated inhibitory pathway is up-regulated, which suggests a direct contributing role of θ3-AR activation on CHF progression. However, its precise role is still being debated. We hypothesize that up-regulation of θ3-AR is detrimental and chronic θ3-AR blockade may prevent or limit CHF.
Methods: The functional responses of chronic treatment with θ3-AR blockade (θ3-ANT) after CHF were compared in 3 groups of conscious dogs over 6 W: 1) Control (n=5)-no pacing; 2) CHF/θ3-ANT (n=4)-after onset of CHF induced by pacing (220 bpm) for 3 W and then receiving L-748,337, a selective θ3-ANT (10−7 M/kg/day by implanted mini-pump), during 3 additional W of pacing at 190 bpm; and 3) CHF (n=6)-after CHF receiving placebo during the final 3 W of pacing.
Results: Rapid pacing for 6 W without θ3-ANT significantly increased plasma levels of norepinephrine (NE, 1348 vs 246 pg/ml), endothelin-1 (ET-1, 7.4vs17.8 fmol/ml), and angiotensin II (AII, 332 vs 29 pg/ml); whereas, LV contractility (EES, 4.6 vs 7.9 mmHg/ml) and stroke volume (SV) (9.6 vs 15.4ml) decreased, the time constant of LV relaxation increased (?, 48 vs 26 ms). These changes were paralleled with LV myocyte dysfunction as indicated by significant reductions in cell contraction (dL/dtmax, 78 vs 159 μm/s) and relaxation (dR/dtmax, 64 vs 119 μm/s) with a much less increase in dL/dtmax (26 vs 75%) in response to superfusion of isoproterenol (ISO, 10−8 M). These changes were associated with significantly decreased θ1-AR protein levels (0.26 vs 0.52), but increased θ3-AR protein concentration (0.64 vs 0.22). Treatment with θ3-ANT prevented pacing-induced increases in plasma levels of NE, ET-1, and AII and prevented decreases in EES (8.14 mmHg/ml), SV (16.6 ml), and θ (24.8 ms). Myocyte dL/dtmax (150 μm/s) and dR/dtmax (116 μm/s) were improved. The alterations of θ1-AR protein (0.42) and θ3-AR protein (0.24) were reversed to control levels. ISO-induced increase in dL/dtmax (74%) was significantly augmented.
Conclusion: In CHF, up-regulation of θ3-adrenergic signaling is a maladaptive change that directly depresses contractility reserve, exacerbates neurohormonal and sympathetic nervous system activation, and drives CHF progression.
- © 2010 by American Heart Association, Inc.