ArticleCirculation research2013
Genetic inhibition of Na+-Ca2+ exchanger current disables fight or flight sinoatrial node activity without affecting resting heart rate.
Article in Circulation research, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers.
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Who cites it
34 citing papers in PubMed, 54 citations in OpenAlex.
- Emerging Regulatory Mechanisms in Sinoatrial Node Automaticity.Journal of cellular and molecular medicine · 2026Review
- L-Type CaCirculation research · 2026Article
- Genetic determinants of blood pressure and heart rate identified through ENU-induced mutagenesis with automated meiotic mapping.Science advances · 2024Article
- Local tissue mechanics control cardiac pacemaker cell embryonic patterning.Life science alliance · 2023Article
- Sinus node dysfunction: current understanding and future directions.American journal of physiology. Heart and circulatory physiology · 2023Review
- The funny current If is essential for the fight-or-flight response in cardiac pacemaker cells.The Journal of general physiology · 2022Article
- Adenylyl cyclase isoform 1 contributes to sinoatrial node automaticity via functional microdomains.JCI insight · 2022Article
- Intracellular CaBiomolecules · 2022Article
- Acute Genetic Ablation of Cardiac Sodium/Calcium Exchange in Adult Mice: Implications for Cardiomyocyte Calcium Regulation, Cardioprotection, and Arrhythmia.Journal of the American Heart Association · 2021Article
- Bidirectional flow of the funny current (IProceedings of the National Academy of Sciences of the United States of America · 2021Article
- Speeding Up the Heart? Traditional and New Perspectives on HCN4 Function.Frontiers in physiology · 2021Review
- Genetic Complexity of Sinoatrial Node Dysfunction.Frontiers in genetics · 2021Review
- Discovery and characterization of ORM-11372, a novel inhibitor of the sodium-calcium exchanger with positive inotropic activity.British journal of pharmacology · 2020Article
- Article
- The Cardiac Pacemaker Story-Fundamental Role of the NaFrontiers in pharmacology · 2020Review
- Novel NaFrontiers in pharmacology · 2019Article
- Molecular functions and specific roles of circRNAs in the cardiovascular system.Non-coding RNA research · 2018Review
- CaScientific reports · 2017Article
- Two-Pore K+ Channel TREK-1 Regulates Sinoatrial Node Membrane Excitability.Journal of the American Heart Association · 2016Article
- Spontaneous inward currents reflecting oscillatory activation of Na⁺/Ca²⁺ exchangers in human embryonic stem cell-derived cardiomyocytes.Pflugers Archiv : European journal of physiology · 2016Article
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Authors and funding
18 authors at 1 institution in 1 country.
Funding
Abstract
rationaleThe 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.
objectiveTo determine the role of Ncx1 in heart rate. METHODS AND
resultsWe 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 Ca(2+) 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 Ca(2+) 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.
conclusionsPhysiological Ncx1 expression is required for increasing sinus rates in vivo, ex vivo, and in isolated SAN cells, but not for maintaining resting heart rate.
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