Journal article
Genetic Inhibition of Na+-Ca2+ Exchanger Current Disables Fight or Flight Sinoatrial Node Activity Without Affecting Resting Heart Rate
Circulation research, Vol.112(2), pp.309-317
01/18/2013
DOI: 10.1161/CIRCRESAHA.111.300193
PMCID: PMC3562595
PMID: 23192947
Abstract
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 ≈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.
Details
- Title: Subtitle
- Genetic Inhibition of Na+-Ca2+ Exchanger Current Disables Fight or Flight Sinoatrial Node Activity Without Affecting Resting Heart Rate
- Creators
- Zhan Gao - Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IATyler P Rasmussen - Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IAYue Li - Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IAWilliam Kutschke - Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IAOlha M Koval - Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IAYiming Wu - Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IAYuejin Wu - Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IADuane D Hall - Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IAMei-ling A Joiner - Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IAXiang-Qiong Wu - Departments of Biomedical Engineering and Internal Medicine, The Ohio State University, Columbus, OHPaari D Swaminathan - Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IAAnil Purohit - Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IAKathy Zimmerman - Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IARobert M Weiss - Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IAKenneth D Philipson - Department of Physiology, University of California, Los Angeles, CALong-sheng Song - Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IAThomas J Hund - Departments of Biomedical Engineering and Internal Medicine, The Ohio State University, Columbus, OHMark E Anderson - Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA
- Resource Type
- Journal article
- Publication Details
- Circulation research, Vol.112(2), pp.309-317
- DOI
- 10.1161/CIRCRESAHA.111.300193
- PMID
- 23192947
- PMCID
- PMC3562595
- ISSN
- 0009-7330
- eISSN
- 1524-4571
- Grant note
- R01 HL070250 || HL / National Heart, Lung, and Blood Institute : NHLBI R01 HL096652 || HL / National Heart, Lung, and Blood Institute : NHLBI R01 HL079031 || HL / National Heart, Lung, and Blood Institute : NHLBI R01 HL113001 || HL / National Heart, Lung, and Blood Institute : NHLBI
- Language
- English
- Date published
- 01/18/2013
- Academic Unit
- Cardiovascular Medicine; Biology; Fraternal Order of Eagles Diabetes Research Center; Biochemistry and Molecular Biology; Internal Medicine
- Record Identifier
- 9984094750102771
Metrics
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