title: Genetic inhibition of Na+-Ca2+ exchanger current disables fight or flight sinoatrial node activity without affecting resting heart rate.
abstract: BACKGROUND
  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.
  
  
  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 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.
  
  
  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.
authors.affiliation: Department of Internal Medicine and Cardiovascular Research Center, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Zhan
authors.initials: Z
authors.lastname: Gao
authors.forename: Tyler P
authors.initials: TP
authors.lastname: Rasmussen
authors.forename: Yue
authors.initials: Y
authors.lastname: Li
authors.forename: William
authors.initials: W
authors.lastname: Kutschke
authors.forename: Olha M
authors.initials: OM
authors.lastname: Koval
authors.forename: Yiming
authors.initials: Y
authors.lastname: Wu
authors.forename: Yuejin
authors.initials: Y
authors.lastname: Wu
authors.forename: Duane D
authors.initials: DD
authors.lastname: Hall
authors.forename: Mei-ling A
authors.initials: ML
authors.lastname: Joiner
authors.forename: Xiang-Qiong
authors.initials: XQ
authors.lastname: Wu
authors.forename: Paari D
authors.initials: PD
authors.lastname: Swaminathan
authors.forename: Anil
authors.initials: A
authors.lastname: Purohit
authors.forename: Kathy
authors.initials: K
authors.lastname: Zimmerman
authors.forename: Robert M
authors.initials: RM
authors.lastname: Weiss
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Philipson
authors.forename: Long-sheng
authors.initials: LS
authors.lastname: Song
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Hund
authors.forename: Mark E
authors.initials: ME
authors.lastname: Anderson
mesh_terms: D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009924:Organ Culture Techniques; D012146:Rest / Q000502:physiology*; D012849:Sinoatrial Node / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D019831:Sodium-Calcium Exchanger / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism / Q000502:physiology
chemical_list: D000318:Adrenergic beta-Agonists; C499849:NCX1 protein, mouse; D019831:Sodium-Calcium Exchanger