Tohoku J. Exp. Med., 2010, 222(3)

Activation of β3-Adrenergic Receptor Inhibits Ventricular Arrhythmia in Heart Failure through Calcium Handling

HAITAO LI,^1,2 YU LIU,^1,2 HE HUANG,^1,2 YANHONG TANG,^1,2 BO YANG^1,2 and CONGXIN HUANG^1,2

¹Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, P.R. China
²Cardiovascular Research Institute, Wuhan University, Wuhan, P.R. China

Ventricular arrhythmia in chronic heart failure (CHF) is considered to be associated with stimulation of β-adrenergic receptors (β-ARs). Three classes of β-ARs have been identified; importantly, distinct from β1 and β2 subtypes, β3-AR could inhibit arrhythmia. Intracellular Ca²⁺ is considered as a predominant effecter of arrhythmia during heart failure. However, the exact role of β3-AR in arrhythmia and Ca²⁺ regulation in CHF is not clear yet. Therefore, we studied the effect of BRL37344, a specific β3-AR activator, on CHF-related ventricular arrhythmia and cellular Ca²⁺ transport. Rabbits with CHF induced by combined aortic insufficiency and aortic constriction were treated with BRL37344 in the presence or absence of β1-AR and β2-AR stimulation. We then evaluated the current produced by sodium calcium exchanger (I_NCX), an electrical marker of abnormal Ca²⁺ removal through ion transporter protein sodium calcium exchanger (NCX), Ca²⁺ transient, a sign of Ca²⁺ entering the cell, concentration of Ca²⁺ in sarcoplasmic reticulum (SR) (SR Ca²⁺ load) and its abnormal release (SR Ca²⁺ leak). After treatment with BRL37344, the incidence of ventricular arrhythmias induced by infusion of a β1-AR or β2-AR activator decreased significantly. Similarly, β3-AR stimulation remarkably inhibited increase of I_NCX, Ca²⁺ transient, SR Ca²⁺ load and leak induced by activation of β1-AR or β2-AR. SR59230A, a specific β3-AR blocker, abolished the inhibitory effects of BRL37344. These results suggest that β3-AR activation could inhibit ventricular arrhythmia through regulating intracellular Ca²⁺. Thus, β3-AR is a feasible therapeutic target that holds promise in the treatment of ventricular arrhythmias in CHF.

keywords —— beta3-adrenergic receptor; ventricular arrhythmia; chronic heart failure; calcium handling; rabbit

© 2010 Tohoku University Medical Press

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Tohoku J. Exp. Med., 2010, 222, 167-174

Correspondence: Congxin Huang, Cardiovascular Research Institute, Wuhan University, Division of Cardiology, Renmin Hospital of Wuhan University, 238 Jiefang Road, Wuchang, Wuhan, 430060, P.R. China.

e-mail: mdlht@hotmail.com