Genetic inhibition of Na+-Ca2+ exchanger current disables fight or flight sinoatrial node activity without affecting resting heart rate.
Genetic inhibition of Na+-Ca2+ exchanger current disables fight or flight sinoatrial node activity without affecting resting heart rate.
复制标题
DOI：
10.1161/circresaha.111.300193
复制
发表时间：
2013-01-18
影响因子：
20.1
通讯作者：
Anderson ME
中科院分区：
文献类型：
--
作者：
Gao Z;Rasmussen TP;Li Y;Kutschke W;Koval OM;Wu Y;Wu Y;Hall DD;Joiner ML;Wu XQ;Swaminathan PD;Purohit A;Zimmerman K;Weiss RM;Philipson KD;Song LS;Hund TJ;Anderson ME
钠钙交换器1（NCX 1）主要在心脏中表达，并参与控制孤立的窦房结（SAN）起搏细胞的自律性，但NCX 1在体内确定心率的潜在作用尚不清楚。确定Ncx 1在心率中的作用我们采用了全局心肌和SAN靶向条件性Ncx 1敲除（Ncx 1 −/−）小鼠来测量NCX电流（INCX）在体内、离体和分离的SAN细胞中起搏活性的影响。我们使用Cre/loxP系统诱导了条件Ncx 1 −/−。出乎意料的是，体内和离体心脏和分离的SAN细胞显示，Ncx 1 −/−（保留约20%的对照水平INCX）和对照小鼠的基础心率相似，表明生理性NCX 1表达不是确定静息心率所必需的。然而，在Ncx 1 −/−小鼠中，异丙肾上腺素或二氢吡啶钙通道激动剂BayK 8644引起的心率和SAN细胞自律性增加显著减弱或消除，表明NCX 1对战斗或逃跑心率反应很重要。相反，在静息和异丙肾上腺素刺激条件下，对照和Ncx 1 −/− SAN细胞中的“起搏器”电流（If）和L型Ca 2+电流是相等的。伊伐布雷定是一种具有临床疗效的If拮抗剂，在对照组和Ncx 1 −/−小鼠中降低基础SAN细胞自律性的作用相似。然而，与异丙肾上腺素给药后的对照SAN细胞相比，伊伐布雷定更有效地降低了从Ncx 1 −/−小鼠中分离的SAN细胞的自律性，表明If抑制后INCX在战斗或逃跑率增加中的重要性增强。生理Ncx 1的表达是增加窦性心率在体内，离体和分离的SAN细胞所需的，但不是为了维持静息心率。
The sodium-calcium exchanger 1 (NCX1) is predominantly expressed in the heart and is implicated in controlling automaticity in isolated sinoatrial nodal (SAN) pacemaker cells, but the potential role of NCX1 in determining heart rate in vivo is unknown. Determine the role of Ncx1 in heart rate. We employed global myocardial and SAN-targeted conditional Ncx1 knockout (Ncx1−/−) mice to measure the effect of the NCX current (INCX) in pacemaking activity in vivo, ex vivo and in isolated SAN cells. We induced conditional Ncx1−/− using a Cre/loxP system. Unexpectedly, in vivo and ex vivo hearts and isolated SAN cells showed that basal rates in Ncx1−/− (retaining ~20% of control level INCX) and control mice were similar, suggesting that physiological NCX1 expression is not required for determining resting heart rate. However, heart rate and SAN cell automaticity increases in response to isoproterenol or the dihydropyridine Ca2+ channel agonist BayK8644 were significantly blunted or eliminated in Ncx1−/− mice, indicating that NCX1 is important for fight or flight heart rate responses. In contrast the ‘pacemaker’ current (If) and L-type Ca2+ currents were equivalent in control and Ncx1−/− SAN cells under resting and isoproterenol-stimulated conditions. Ivabradine, an If antagonist with clinical efficacy, reduced basal SAN cell automaticity similarly in control and Ncx1−/− mice. However, ivabradine decreased automaticity in SAN cells isolated from Ncx1−/− mice more effectively than in control SAN cells after isoproterenol, suggesting that the importance of INCX in fight or flight rate increases is enhanced after If inhibition. Physiological Ncx1 expression is required for increasing sinus rates in vivo, ex vivo and in isolated SAN cells but not for maintaining resting heart rate.