title: Combined Na(+)/Ca(2+) exchanger and L-type calcium channel block as a potential strategy to suppress arrhythmias and maintain ventricular function.
abstract: BACKGROUND
  L-type calcium channel (LTCC) and Na(+)/Ca(2+) exchanger (NCX) have been implicated in repolarization-dependent arrhythmias, but also modulate calcium and contractility. Although LTCC inhibition is negative inotropic, NCX inhibition has the opposite effect. Combined block may, therefore, offer an advantage for hemodynamics and antiarrhythmic efficiency, particularly in diseased hearts. In a model of proarrhythmia, the dog with chronic atrioventricular block, we investigated whether combined inhibition of NCX and LTCC with SEA-0400 is effective against dofetilide-induced torsade de pointes arrhythmias (TdP), while maintaining calcium homeostasis and hemodynamics.
  
  
  RESULTS
  Left ventricular pressure (LVP) and ECG were monitored during infusion of SEA-0400 and verapamil in anesthetized dogs. Different doses were tested against dofetilide-induced TdP in chronic atrioventricular block dogs. In ventricular myocytes, effects of SEA-0400 were tested on action potentials, calcium transients, and early afterdepolarizations. In cardiomyocytes, SEA-0400 (1 μmol/L) blocked 66±3% of outward NCX, 50±2% of inward NCX, and 33±9% of LTCC current. SEA-0400 had no effect on systolic calcium, but slowed relaxation, despite action potential shortening, and increased diastolic calcium. SEA-0400 stabilized dofetilide-induced lability of repolarization and suppressed early afterdepolarizations. In vivo, SEA-0400 (0.4 and 0.8 mg/kg) had no effect on left ventricular pressure and suppressed dofetilide-induced TdPs dose dependently. Verapamil (0.3 mg/kg) also inhibited TdP, but caused a 15±8% drop of left ventricular pressure. A lower dose of verapamil without effects on left ventricular pressure (0.06 mg/kg) was not antiarrhythmic.
  
  
  CONCLUSIONS
  In chronic atrioventricular block dogs, SEA-0400 treatment is effective against TdP. Unlike specific inhibition of LTCC, combined NCX and LTCC inhibition has no negative effects on cardiac hemodynamics.
authors.affiliation: Department of Medical Physiology, Division of Heart and Lungs, University Medical Center Utrecht, University of Utrecht, Utrecht, The Netherlands.
authors.forename: Vincent J A
authors.initials: VJ
authors.lastname: Bourgonje
authors.forename: Marc A
authors.initials: MA
authors.lastname: Vos
authors.forename: Semir
authors.initials: S
authors.lastname: Ozdemir
authors.forename: Nicolas
authors.initials: N
authors.lastname: Doisne
authors.forename: Karoly
authors.initials: K
authors.lastname: Acsai
authors.forename: Andras
authors.initials: A
authors.lastname: Varro
authors.forename: Anita
authors.initials: A
authors.lastname: Sztojkov-Ivanov
authors.forename: Istvan
authors.initials: I
authors.lastname: Zupko
authors.forename: Erik
authors.initials: E
authors.lastname: Rauch
authors.forename: Lars
authors.initials: L
authors.lastname: Kattner
authors.forename: Virginie
authors.initials: V
authors.lastname: Bito
authors.forename: Marien
authors.initials: M
authors.lastname: Houtman
authors.forename: Roel
authors.initials: R
authors.lastname: van der Nagel
authors.forename: Jet D
authors.initials: JD
authors.lastname: Beekman
authors.forename: Toon A B
authors.initials: TA
authors.lastname: van Veen
authors.forename: Karin R
authors.initials: KR
authors.lastname: Sipido
authors.forename: Gudrun
authors.initials: G
authors.lastname: Antoons
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000814:Aniline Compounds / Q000494:pharmacology*; D000818:Animals; D000889:Anti-Arrhythmia Agents; D001145:Arrhythmias, Cardiac / Q000188:drug therapy* / Q000503:physiopathology; D020746:Calcium Channels, L-Type / Q000187:drug effects* / Q000378:metabolism; D004195:Disease Models, Animal; D004285:Dogs; D004562:Electrocardiography; D006352:Heart Ventricles / Q000187:drug effects* / Q000503:physiopathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010647:Phenyl Ethers / Q000494:pharmacology*; D019831:Sodium-Calcium Exchanger / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016276:Ventricular Function / Q000187:drug effects*; D017725:Ventricular Pressure / Q000187:drug effects*
chemical_list: D000814:Aniline Compounds; D000889:Anti-Arrhythmia Agents; D020746:Calcium Channels, L-Type; D010647:Phenyl Ethers; C430918:SEA 0400; D019831:Sodium-Calcium Exchanger