title: Na+-induced Ca2+ influx through reverse mode of Na+-Ca2+ exchanger in mouse ventricular cardiomyocyte.
abstract: BACKGROUND
  Dobutamine is commonly used for clinical management of heart failure and its pharmacological effects have long been investigated as inotropics via β-receptor activation. However, there is no electrophysiological evidence if dobutamine contributes inotropic action due at least partially to the reverse mode of Na+-Ca2+ exchanger (NCX) activation.
  
  
  METHODS
  Action potential (AP), voltage-gated Na+ (INa), Ca2+ (ICa), and K+ (Ito and IK1) currents were observed using whole-cell patch technique before and after dobutamine in ventricular cardiomyocytes isolated from adult mouse hearts. Another sets of observation were also performed with Kb-r7943 or in the solution without [Ca2+]o.
  
  
  RESULTS
  Dobutamine (0.1-1.0 μM) significantly enhanced the AP depolarization with prolongation of AP duration (APD) in a concentration-dependent fashion. The density of INa was also increased concentration-dependently without alternation of voltage-dependent steady-status of activation and inactivation, reactivation as well. Whereas, the activities for ICa, Ito, and IK1 were not changed by dobutamine. Intriguingly, the dobutamine-mediated changes in AP repolarization were abolished by 3 μM Kb-r7943 pretreatment or by simply removing [Ca2+]o without affecting accelerated depolarization. Additionally, the ratio of APD50/APD90 was not significantly altered in the presence of dobutamine, implying that effective refractory period was remain unchanged.
  
  
  CONCLUSIONS
  This novel finding provides evidence that dobutamine upregulates of voltage-gated Na+ channel function and Na+ influx-induced activation of the reverse mode of NCX, suggesting that dobutamine may not only accelerate ventricular contraction via fast depolarization but also cause Ca2+ influx, which contributes its positive inotropic effect synergistically with β-receptor activation without increasing the arrhythmogenetic risk.
authors: Department of Pharmacology, Harbin Medical University, Harbin, China.|Riley Heart Research Center, Division of Pediatric Cardiology, Herman B. Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, USA.
authors: Zhen-Yu
authors: ZY
authors: Yan
authors: Department of Pharmacology, Harbin Medical University, Harbin, China.|Key Laboratory of Cardiovascular Medicine Research, Harbin Medical University, Harbin, China.
authors: Tao
authors: T
authors: Ban
authors: Department of Pharmacology, Harbin Medical University, Harbin, China.
authors: Yao
authors: Y
authors: Fan
authors: Department of Pharmacology, Harbin Medical University, Harbin, China.
authors: Wei-Ran
authors: WR
authors: Chen
authors: Department of Pharmacology, Da-Qing Campus of Harbin Medical University, Da-Qing, China.
authors: Hong-Li
authors: HL
authors: Sun
authors: Department of Pharmacology, Da-Qing Campus of Harbin Medical University, Da-Qing, China.
authors: Hanying
authors: H
authors: Chen
authors: Department of Pharmacology, Harbin Medical University, Harbin, China.|Key Laboratory of Cardiovascular Medicine Research, Harbin Medical University, Harbin, China.
authors: Quo-Fen
authors: QF
authors: Qiao
authors: Department of Pharmacology, Harbin Medical University, Harbin, China.
authors: Bai-Yan
authors: BY
authors: Li
mesh_terms: D000200:Action Potentials; D000818:Animals; D002118:Calcium / Q000737:chemistry; D004280:Dobutamine / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D006321:Heart / Q000502:physiology; D006333:Heart Failure / Q000473:pathology; D006352:Heart Ventricles / Q000473:pathology; D008297:Male; D051379:Mice; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D011943:Receptors, Adrenergic, beta / Q000378:metabolism; D019831:Sodium-Calcium Exchanger / Q000378:metabolism*; D013890:Thiourea / Q000031:analogs & derivatives / Q000737:chemistry
chemical_list: C101670:2-(2-(4-(4-nitrobenzyloxy)phenyl)ethyl)isothiourea methanesulfonate; D011943:Receptors, Adrenergic, beta; D019831:Sodium-Calcium Exchanger; C110374:sodium-calcium exchanger 1; D004280:Dobutamine; D013890:Thiourea; D002118:Calcium
keywords: Pathology Section; action potential; dobutamine; reverse mode of Na+-Ca2+ exchanger; ventricular cardiomyocyte; voltage-gated ion channel