title: Tolterodine reduces veratridine-augmented late INa, reverse-INCXand early afterdepolarizations in isolated rabbit ventricular myocytes.
abstract: OBJECTIVE
  The augmentation of late sodium current (INa.L) not only causes intracellular Na+accumulation, which results in intracellular Ca2+overload via the reverse mode of the Na+/Ca2+exchange current (reverse-INCX), but also prolongs APD and induces early afterdepolarizations (EAD), which can lead to arrhythmia and cardiac dysfunction. Thus, the inhibition of INa.Lis considered to be a potential way for therapeutic intervention in ischemia and heart failure. In this study we investigated the effects of tolterodine (Tol), a competitive muscarinic receptor antagonist, on normal and veratridine (Ver)-augmented INa.L, reverse-INCXand APD in isolated rabbit ventricular myocytes, which might contribute to its cardioprotective activity.
  
  
  METHODS
  Rabbit ventricular myocytes were prepared. The INa.Land reverse-INCXwere recorded in voltage clamp mode, whereas action potentials and Ver-induced early afterdepolarizations (EADs) were recorded in current clamp mode. Drugs were applied via superfusion.
  
  
  RESULTS
  Tol (3-120 nmol/L) concentration-dependently inhibited the normal and Ver-augmented INa.Lwith IC50values of 32.08 nmol/L and 42.47 nmol/L, respectively. Atropine (100 μmol/L) did not affect the inhibitory effects of Tol (30 nmol/L) on Ver-augmented INa.L. In contrast, much high concentrations of Tol was needed to inhibit the transient sodium current (INa.T) with an IC50value of 183.03 μmol/L. In addition, Tol (30 nmol/L) significantly shifted the inactivation curve of INa.Ttoward a more depolarizing membrane potential without affecting its activation characteristics. Moreover, Tol (30 nmol/L) significantly decreased Ver-augmented reverse-INCX. Tol (30 nmol/L) increased the action potential duration (APD) by 16% under the basal conditions. Ver (20 μmol/L) considerably extended the APD and evoked EADs in 18/24 cells (75%). In the presence of Ver, Tol (30 nmol/L) markedly decreased the APD and eliminated EADs (0/24 cells).
  
  
  CONCLUSIONS
  Tol inhibits normal and Ver-augmented INaLand decreases Ver-augmented reverse-INCX. In addition, Tol reverses the prolongation of the APD and eliminates the EADs induced by Ver, thus prevents Ver-induced arrhythmia.
authors: Cardio-Electrophysiological Research Laboratory, Medical College of Wuhan University of Science and Technology, Wuhan 430065, China.|Department of Cardiology, The Third People's Hospital of Chengdu, Chengdu 610031, China.
authors: Chao
authors: C
authors: Wang
authors: Cardio-Electrophysiological Research Laboratory, Medical College of Wuhan University of Science and Technology, Wuhan 430065, China.|Department of Cardiology, Sanming First Hospital, Sanming 365000, China.
authors: Lei-Lei
authors: LL
authors: Wang
authors: Cardio-Electrophysiological Research Laboratory, Medical College of Wuhan University of Science and Technology, Wuhan 430065, China.
authors: Chi
authors: C
authors: Zhang
authors: Cardio-Electrophysiological Research Laboratory, Medical College of Wuhan University of Science and Technology, Wuhan 430065, China.
authors: Zhen-Zhen
authors: ZZ
authors: Cao
authors: Cardio-Electrophysiological Research Laboratory, Medical College of Wuhan University of Science and Technology, Wuhan 430065, China.
authors: An-Tao
authors: AT
authors: Luo
authors: Cardio-Electrophysiological Research Laboratory, Medical College of Wuhan University of Science and Technology, Wuhan 430065, China.
authors: Pei-Hua
authors: PH
authors: Zhang
authors: Cardio-Electrophysiological Research Laboratory, Medical College of Wuhan University of Science and Technology, Wuhan 430065, China.|Department of Cardiology, The Third People's Hospital of Chengdu, Chengdu 610031, China.
authors: Xin-Rong
authors: XR
authors: Fan
authors: Cardio-Electrophysiological Research Laboratory, Medical College of Wuhan University of Science and Technology, Wuhan 430065, China.
authors: Ji-Hua
authors: JH
authors: Ma
mesh_terms: D000200:Action Potentials; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D005260:Female; D006352:Heart Ventricles / Q000166:cytology; D066298:In Vitro Techniques; D008297:Male; D018727:Muscarinic Antagonists / Q000494:pharmacology*; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000502:physiology; D018408:Patch-Clamp Techniques; D011817:Rabbits; D026941:Sodium Channel Blockers / Q000494:pharmacology*; D015222:Sodium Channels / Q000502:physiology*; D019831:Sodium-Calcium Exchanger / Q000378:metabolism*; D000068737:Tolterodine Tartrate / Q000494:pharmacology*; D014701:Veratridine / Q000494:pharmacology*
chemical_list: D000889:Anti-Arrhythmia Agents; D018727:Muscarinic Antagonists; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D019831:Sodium-Calcium Exchanger; D000068737:Tolterodine Tartrate; D014701:Veratridine