title: ORM-10103, a novel specific inhibitor of the Na+/Ca2+ exchanger, decreases early and delayed afterdepolarizations in the canine heart.
abstract: OBJECTIVE
  At present there are no small molecule inhibitors that show strong selectivity for the Na(+) /Ca(2+) exchanger (NCX). Hence, we studied the electrophysiological effects of acute administration of ORM-10103, a new NCX inhibitor, on the NCX and L-type Ca(2+) currents and on the formation of early and delayed afterdepolarizations.
  
  
  METHODS
  Ion currents were recorded by using a voltage clamp technique in canine single ventricular cells, and action potentials were obtained from canine and guinea pig ventricular preparations with the use of microelectrodes.
  
  
  RESULTS
  ORM-10103 significantly reduced both the inward and outward NCX currents. Even at a high concentration (10 μM), ORM-10103 did not significantly change the L-type Ca(2+) current or the maximum rate of depolarization (dV/dtmax ), indicative of the fast inward Na(+) current. At 10 μM ORM-10103 did not affect the amplitude or the dV/dtmax of the slow response action potentials recorded from guinea pig papillary muscles, which suggests it had no effect on the L-type Ca(2+) current. ORM-10103 did not influence the Na(+) /K(+) pump or the main K(+) currents of canine ventricular myocytes, except the rapid delayed rectifier K(+) current, which was slightly diminished by the drug at 3 μM. The amplitudes of pharmacologically- induced early and delayed afterdepolarizations were significantly decreased by ORM-10103 (3 and 10 μM) in a concentration-dependent manner.
  
  
  CONCLUSIONS
  ORM-10103 is a selective inhibitor of the NCX current and can abolish triggered arrhythmias. Hence, it has the potential to be used to prevent arrhythmogenic events.
authors: Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Szeged, Szeged, Hungary; Division of Cardiovascular Pharmacology, Hungarian Academy of Sciences, Szeged, Hungary.
authors: N
authors: N
authors: Jost
authors: N
authors: N
authors: Nagy
authors: C
authors: C
authors: Corici
authors: Z
authors: Z
authors: Kohajda
authors: A
authors: A
authors: Horváth
authors: K
authors: K
authors: Acsai
authors: P
authors: P
authors: Biliczki
authors: J
authors: J
authors: Levijoki
authors: P
authors: P
authors: Pollesello
authors: T
authors: T
authors: Koskelainen
authors: L
authors: L
authors: Otsomaa
authors: A
authors: A
authors: Tóth
authors: J Gy
authors: JG
authors: Papp
authors: A
authors: A
authors: Varró
authors: L
authors: L
authors: Virág
mesh_terms: D000200:Action Potentials; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D001578:Benzopyrans / Q000494:pharmacology*; D020746:Calcium Channels, L-Type / Q000187:drug effects / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D006168:Guinea Pigs; D006352:Heart Ventricles / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D010210:Papillary Muscles / Q000187:drug effects / Q000378:metabolism; D011188:Potassium / Q000378:metabolism; D011690:Purkinje Fibers / Q000187:drug effects / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology*; D012964:Sodium / Q000378:metabolism; D019831:Sodium-Calcium Exchanger / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013997:Time Factors
chemical_list: C000590774:5-nitro-2-(2-phenylchroman-6-yloxy)pyridine; D000889:Anti-Arrhythmia Agents; D001578:Benzopyrans; D020746:Calcium Channels, L-Type; D011725:Pyridines; D019831:Sodium-Calcium Exchanger; D012964:Sodium; D011188:Potassium
keywords: DAD; EAD; NCX; ORM-10103; sodium/calcium exchanger
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