Abstract 13100: Rescue Myocardial Aging Caused a Progressive Decline in Cardiac Function and β-Adrenergic Reserve With a Selective Beta3-Adrenergic Receptor Antagonist, but Not Beta1-Adrenergic Receptor Blocker in a Murine Model

Abstract

Background: Cardiac aging (CA) leads to the progressive decline in cardiac function- increasing risk for heart failure (HF) and cardiac mortality. Both down-regulation of β 1 -adrenergic receptors (AR) and up-regulation of a newly-described inhibitory pathway mediated by β 3 -AR may play a crucial role in the development of CA. β-AR blockers are a mainstay in the therapy of several cardiovascular diseases, including HF. However the therapeutic effects of different β blockers in CA are unknown. We tested the hypothesis that up-regulation of cardiac β 3 -AR with enhanced negative inotropic actions, rather than the desensitization of β 1 -AR, is the critical determinant of the dysfunctional β-AR regulation that occurs in CA. Thus, β 3 -AR antagonists (β 3 ANT), but not β 1 Blockade, may reverse the progression of age-associated deficits in LV myocyte functional performance. Methods: LV myocyte basal and isoproterenol (ISO)-stimulated functional and [Ca 2+ ] i transient ([Ca 2+ ] iT ) responses were compared in 4 groups (7/group) of wild-type (WT) mice: 1) YWT , young (Y, 6 mo); 2) Aβ 3 ANT , aged (A, 26 mo) treated with β 3 ANT (L-748,337, 10 -7 M/kg/day, mini-pump) for 12 weeks (W);3) Aβ 1 Blockade , metoprolol XL (1.5 mg/kg/day, po), a selective β 1 blocker was given for 12 W and 4) AWT , aged sham control. Results: Compared with YWT, AWT myocytes had about 30% decreases in basal cell contraction (dL/dt max , 85.9 vs 122.3 μm/s) and relaxation (dR/dt max , 69.4 vs 99.2 μm/s) with reduced the peak [Ca 2+ ] iT (0.17 vs 0.21). ISO (10 -8 M)-stimulated increases in dL/dt max (33% vs 69%), dR/dt max (31% vs 62%) and [Ca 2+ ] iT (15% vs 34%) also significantly reduced. In Aβ 1 Blockade group, metoprolol therapy failed to improve basal dL/dt max (86.3 μm/s), dR/dt max (68.9 μm/s) and [Ca 2+ ] iT (0.18). ISO-stimulated increases in dL/dt max (34%), dR/dt max (35%) and [Ca 2+ ] iT (17%) remained attenuated. By contrary, Aβ 3 ANT myocytes showed normal basal cell contraction (131.0 μm/s), relaxation (101.9 μm/s) and [Ca 2+ ] iT (0.21) with preserved ISO-stimulated increases in dL/dt max (68%), dR/dt max (59%) and [Ca 2+ ] iT (32%). Conclusions: Chronic β 3 -AR antagonist, but not β 1 -AR blocker leads to the preservation of myocyte function, [Ca 2+ ] iT , and β-adrenergic responsiveness in a murine model of cardiac aging.