Genetic Inhibition of Na+-Ca2+ Exchanger Current Disables Fight or Flight Sinoatrial Node Activity Without Affecting Resting Heart Rate

被引：48

作者：

Gao, Zhan ^{[1
,2
]}

Rasmussen, Tyler P. ^{[1
,2
,3
]}

Li, Yue ^{[1
,2
]}

Kutschke, William ^{[1
,2
]}

Koval, Olha M. ^{[1
,2
]}

Wu, Yiming

Wu, Yuejin

Hall, Duane D. ^{[1
,2
]}

Joiner, Mei-ling A. ^{[1
,2
]}

Wu, Xiang-Qiong ^{[5
,6
]}

Swaminathan, Paari D. ^{[1
,2
]}

Purohit, Anil ^{[1
,2
]}

Zimmerman, Kathy ^{[1
,2
]}

Weiss, Robert M. ^{[1
,2
]}

Philipson, Kenneth D. ^{[4
]}

Song, Long-sheng ^{[1
,2
]}

Hund, Thomas J. ^{[5
,6
]}

Anderson, Mark E. ^{[1
,2
,3
]}

机构：

[1] Univ Iowa, Carver Coll Med, Dept Internal Med, Iowa City, IA 52242 USA

[2] Univ Iowa, Carver Coll Med, Cardiovasc Res Ctr, Iowa City, IA 52242 USA

[3] Univ Iowa, Carver Coll Med, Dept Mol Physiol & Biophys, Iowa City, IA 52242 USA

[4] Univ Calif Los Angeles, Dept Physiol, Los Angeles, CA 90024 USA

[5] Ohio State Univ, Dept Biomed Engn, Columbus, OH 43210 USA

[6] Ohio State Univ, Dept Internal Med, Columbus, OH 43210 USA

来源：

CIRCULATION RESEARCH | 2013年 / 112卷 / 02期

基金：

美国国家卫生研究院;

关键词：

ion channel; L-type Ca2+ channels; Na+-Ca2+ exchange; pacemaker current; sinoatrial node; SODIUM-CALCIUM EXCHANGE; CARDIAC-SPECIFIC KNOCKOUT; FUNNY CURRENT; IVABRADINE; CHANNELS; ADULT; DEPOLARIZATION; PACEMAKING; MECHANISM; KB-R7943;

D O I：

10.1161/CIRCRESAHA.111.300193

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Rationale: The sodium-calcium exchanger 1 (NCX1) is predominantly expressed in the heart and is implicated in controlling automaticity in isolated sinoatrial node (SAN) pacemaker cells, but the potential role of NCX1 in determining heart rate in vivo is unknown. Objective: To determine the role of Ncx1 in heart rate. Methods and Results: We used global myocardial and SAN-targeted conditional Ncx1 knockout (Ncx1(-/-)) mice to measure the effect of the NCX current on 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 approximate to 20% of control level NCX current) and control mice were similar, suggesting that physiological NCX1 expression is not required for determining resting heart rate. However, increases in heart rate and SAN cell automaticity 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 and L-type Ca2+ currents were equivalent in control and Ncx1(-/-) SAN cells under resting and isoproterenol-stimulated conditions. Ivabradine, a pacemaker current 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 NCX current in fight or flight rate increases is enhanced after pacemaker current inhibition. Conclusions: 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. (Circ Res. 2013;112:309-317.)

引用

页码：309 / +

页数：27

共 52 条

[1]

Alig J, 2009, P NATL ACAD SCI USA, V106, P12189, DOI 10.1073/pnas.0810332106

[2] The Na+/Ca2+ Exchange Inhibitor 2-(2-(4-(4-Nitrobenzyloxy)phenyl)ethyl)isothiourea Methanesulfonate (KB-R7943) Also Blocks Ryanodine Receptors Type 1 (RyR1) and Type 2 (RyR2) Channels [J].