Abstract 13438: The Role and Mechanism of Chronic Beta3-Adrenergic Receptor Blockade on the Progression of Heart Failure in a Rat Model

• Published in: Circulation (New York, N.Y.) Vol. 142; no. Suppl_3 Suppl 3; p. A13438
• Main Authors: Sun, Xiaoqiang, Cheng, Che, Cao, Jing, Zhang, Zhi, Li, Tiankai, Zhang, Xiaowei, Cheng, Heng Jie
• Format: Journal Article
• Language: English
• Published: by the American College of Cardiology Foundation and the American Heart Association, Inc 17.11.2020
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/circ.142.suppl_3.13438

BackgroundThe negative inotrope and up-regulation of β3-adrenergic receptors (AR) in human and animal failing hearts suggest a direct and contributing role of cardiac β3-AR activation on the progression of congestive heart failure (CHF). However, its precise role is still being debated. We hypothesize that up-regulation of cardiac β3-AR is detrimental and chronic β3-AR blockade may prevent CHF-caused intrinsic defects of left ventricular (LV) myocyte force-generating capacity and relaxation and improve β-AR regulation, thereby limiting the progression of CHF.MethodsWe compared the alterations of LV and myocyte functional responses and [Ca]i transient ([Ca]iT) in SD rats divided into 3 groups (8/group)1) CHF 3 months after isoproterenol (ISO) (170 mg/kg, sq, for 2 days); 2) ISO/β3-ANT, 2 months after receiving ISO, a selective β3-AR antagonist (ANT), L-748,337, was initiated (10 M/kg/day, sq. by mini-pump) and was given for 1 month; and 3) Sham controls.ResultsCompared with controls, the animals that received ISO treatment had CHF onset at 1 month and progressed to severe HF at 3 months after ISO. Plasma norepinephrine (NE) (1295 vs 259 pg/ml) increased 5-fold; whereas, stroke volume (SV) (39 vs 91 μl) and ejection fraction (EF) (39 vs 62%) significantly decreased, and LV end-diastolic pressure (PED) (13.9 vs 6.0 mmHg) was doubled. These changes were paralleled with about 50% reductions in cell contraction (dL/dtmax, 93 vs 186 μm/s) and relaxation (dR/dtmax, 96 vs 159 μm/s) associated with a significant decrease in the peak systolic [Ca]iT, (0.17 vs 0.26). In addition, superfusion of ISO (10 M) caused much less increases in dL/dtmax (39 vs 68%), dR/dtmax (23 vs 54%), and [Ca]IT (14 vs 28%). Treatment with β3-ANT increased SV (89 μl) and EF (60%), decreased PED more than 90% from ISO-treated values, and corrected the elevation of plasma NE (301 pg/ml), dL/dtmax (184 μm/s), dR/dtmax (152 μm/s), and [Ca]iT (0.24). ISO-induced increase in dL/dtmax and [Ca]iT also returned close to control levels.ConclusionChronic β3-ANT treatment after CHF significantly improves LV and myocyte contractile function and [Ca]i regulation and limits the development of CHF. Thus, β3-AR blocker may provide a new therapeutic strategy for the treatment of CHF.