title: Selective Na(+) /Ca(2+) exchanger inhibition prevents Ca(2+) overload-induced triggered arrhythmias.
abstract: OBJECTIVE
  Augmented Na(+) /Ca(2+) exchanger (NCX) activity may play a crucial role in cardiac arrhythmogenesis; however, data regarding the anti-arrhythmic efficacy of NCX inhibition are debatable. Feasible explanations could be the unsatisfactory selectivity of NCX inhibitors and/or the dependence of the experimental model on the degree of Ca(2+) i overload. Hence, we used NCX inhibitors SEA0400 and the more selective ORM10103 to evaluate the efficacy of NCX inhibition against arrhythmogenic Ca(2+) i rise in conditions when [Ca(2+) ]i was augmented via activation of the late sodium current (INaL ) or inhibition of the Na(+) /K(+) pump.
  
  
  METHODS
  Action potentials (APs) were recorded from canine papillary muscles and Purkinje fibres by microelectrodes. NCX current (INCX ) was determined in ventricular cardiomyocytes utilizing the whole-cell patch clamp technique. Ca(2+) i transients (CaTs) were monitored with a Ca(2+) -sensitive fluorescent dye, Fluo-4.
  
  
  RESULTS
  Enhanced INaL increased the Ca(2+) load and AP duration (APD). SEA0400 and ORM10103 suppressed INCX and prevented/reversed the anemone toxin II (ATX-II)-induced [Ca(2+) ]i rise without influencing APD, CaT or cell shortening, or affecting the ATX-II-induced increased APD. ORM10103 significantly decreased the number of strophanthidin-induced spontaneous diastolic Ca(2+) release events; however, SEA0400 failed to restrict the veratridine-induced augmentation in Purkinje-ventricle APD dispersion.
  
  
  CONCLUSIONS
  Selective NCX inhibition - presumably by blocking rev INCX (reverse mode NCX current) - is effective against arrhythmogenesis caused by [Na(+) ]i -induced [Ca(2+) ]i elevation, without influencing the AP waveform. Therefore, selective INCX inhibition, by significantly reducing the arrhythmogenic trigger activity caused by the perturbed Ca(2+) i handling, should be considered as a promising anti-arrhythmic therapeutic strategy.
authors: MTA-SZTE Research Group of Cardiovascular Pharmacology, Hungarian Academy of Sciences, Szeged, Hungary.
authors: Norbert
authors: N
authors: Nagy
authors: Anita
authors: A
authors: Kormos
authors: Zsófia
authors: Z
authors: Kohajda
authors: Áron
authors: Á
authors: Szebeni
authors: Judit
authors: J
authors: Szepesi
authors: Piero
authors: P
authors: Pollesello
authors: Jouko
authors: J
authors: Levijoki
authors: Károly
authors: K
authors: Acsai
authors: László
authors: L
authors: Virág
authors: Péter P
authors: PP
authors: Nánási
authors: Julius Gy
authors: JG
authors: Papp
authors: András
authors: A
authors: Varró
authors: András
authors: A
authors: Tóth
mesh_terms: D000200:Action Potentials / Q000187:drug effects*; D000814:Aniline Compounds / Q000494:pharmacology*; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000209:etiology; D001578:Benzopyrans / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism*; D003064:Cnidarian Venoms / Q000494:pharmacology; D004285:Dogs; D006934:Hypercalcemia / Q000150:complications; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D010210:Papillary Muscles / Q000187:drug effects* / Q000378:metabolism; D018408:Patch-Clamp Techniques; D010647:Phenyl Ethers / Q000494:pharmacology*; D011690:Purkinje Fibers / Q000187:drug effects* / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology*; D019831:Sodium-Calcium Exchanger / Q000037:antagonists & inhibitors*
chemical_list: C000590774:5-nitro-2-(2-phenylchroman-6-yloxy)pyridine; D000814:Aniline Compounds; D001578:Benzopyrans; D003064:Cnidarian Venoms; D010647:Phenyl Ethers; D011725:Pyridines; C430918:SEA 0400; D019831:Sodium-Calcium Exchanger; C028800:toxin II (Anemonia sulcata); D002118:Calcium