Department of Cardiology, Renmin Hospital of Wuhan Universityand Cardiovascular Research Institute, Wuhan University, Wuhan, PR China.
Tohoku J Exp Med. 2010 Nov;222(3):167-74. doi: 10.1620/tjem.222.167.
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 (INCX), 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 INCX, 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.
慢性心力衰竭（CHF）中的室性心律失常被认为与β肾上腺素能受体（β-ARs）的刺激有关。已经鉴定出三种β-AR 类；重要的是，与β1和β2亚型不同，β3-AR 可以抑制心律失常。细胞内 Ca2+ 被认为是心力衰竭期间心律失常的主要效应物。然而，β3-AR 在心律失常和 CHF 中 Ca2+ 调节中的确切作用尚不清楚。因此，我们研究了 BRL37344（一种特定的β3-AR 激活剂）对 CHF 相关室性心律失常和细胞内 Ca2+ 转运的影响。通过主动脉瓣关闭不全和主动脉缩窄联合诱导 CHF 的兔子在存在或不存在β1-AR 和β2-AR 刺激的情况下用 BRL37344 治疗。然后，我们评估了钠钙交换电流（INCX）产生的电流，INCX 是通过离子转运蛋白钠钙交换（NCX）异常去除 Ca2+的电标记物，钙瞬变，是 Ca2+进入细胞的标志，肌浆网（SR）中 Ca2+浓度（SR Ca2+负荷）及其异常释放（SR Ca2+渗漏）。用 BRL37344 处理后，β1-AR 或β2-AR 激活剂输注引起的室性心律失常的发生率显著降低。同样，β3-AR 刺激显著抑制了β1-AR 或β2-AR 激活引起的 INCX、钙瞬变、SR Ca2+负荷和渗漏的增加。特异性β3-AR 阻断剂 SR59230A 消除了 BRL37344 的抑制作用。这些结果表明，β3-AR 激活可通过调节细胞内 Ca2+抑制室性心律失常。因此，β3-AR 是治疗 CHF 中室性心律失常的可行治疗靶点。
