Abstract 9675: Restoration of Normal Cardiomyocyte Basal and Beta-Adrenergic Receptor (AR) Subtype Modulation of L-Type Calcium Current in Heart Failure by Chronic Beta3-AR Deficiency: Insights into the Underlying Electrophysiological Mechanism
Background. We have previously shown that heart failure (HF) is associated with upregulation of the cardiac β3-adrenergic receptor (AR). Isoproterenol (ISO)-induced HF was prevented in β3-AR knockout (β3KO) mice. However, the cellular mechanism is unclear. The L-type calcium current (ICa,L) plays a fundamental role in cardiac function and is impaired in HF. No previous studies have examined the influence of β3KO on ICa,L in normal or diseased states. We assessed the hypothesis that β3KO will prevent HF-induced abnormalities of basal and β-AR subtype-stimulated regulation on ICa,L, thereby preserving normal myocyte function.
Methods. β3KO and wild type (WT) mouse experimental groups received ISO (170 mg/kg sq for 2 days), and β3KO and WTmouse control groups received saline (7/group). After 16 weeks (W) of treatment, we compared the response of myocyte contractile function and ICa,L to β-AR subtype stimulation by random exposure of myocytes to ISO (10-8 M) or a selective β1-, β2-, or β3-agonist, Norepinephrine (NE, 10-7 M), Zinterol (ZIN,10-5 M) and BRL-37,344 (BRL,10-8 M), respectively, during drug superfusion.
Results. ISO-treated WTmice had HF onset at 8W and progressed to severe HF at 16W. Compared with normal myocytes (N), basal ICa,L (HF:4.1 vs N:7.8 pA/pF) and cell contraction (dL/dtmax, 76 vs 144 µm/s) decreased by more than 40% in HF myocytes. ISO-stimulated ICa,L (14% vs 32%) was attenuated accompanied by a diminished NE-mediated increase in ICa,L (16% vs 37%), but enhanced BRL-induced decreases in ICa,L (17% vs 29%).The response of ICa,L (17% vs 29%) to ZIN was relatively unaltered in HF myocytes. Importantly, in ISO/β3KO myocytes, the basal ICa,L (8.1 pA/pF) and dL/dtmax (154 µm/s) remained close to controllevels with preserved β-stimulated positive modulation on ICa,L. The increases in ICa,L in response to ISO (33%), NE (35%) or ZIN (13%) were similar as that in normal WT myocytes, respectively.
Conclusion. Chronic β3-AR deficiency prevents HF-induced abnormalities of basal and β-AR subtype-stimulated modulation on ICa,L and leads to preservation of myocyte contractile function in a mouse model of progressive HF. These findings provide the first electrophysiological evidence that upregulation of β3-AR in HF is detrimental.
- © 2012 by American Heart Association, Inc.