BACKGROUND In the present work the effects of ORM-10962 (a follow-up compound of ORM-10103, an earlier NCX inhibitor, [1]) , a novel highly selective NCX inhibitor were studied on the cardiac NCX current and automaticity in experimental arrhythmias. The selectivity of the drug on various transmembrane ionic currents (including measurements of L-type Ca2+ current, the main repolarizing K+ currents, late sodium current, Na+/K+ pump and pacemaker current) was also investigated. METHODS Ion currents and action potential recordings were investigated by applying the whole-cell patch-clamp technique in canine single ventricular cells (CM) and standard microelectrode technique in rabbit cardiac preparations, respectively. Effects of ORM-10962 were studied in ouabain (10 µg/kg/min i.v.) induced arrhythmias in anesthetized guinea-pigs (with pentobarbitone (45 mg/kg intraperitoneally), and ischemia-reperfusion (IR) induced arrhythmias in anesthetized rats (pentobarbitone, 60 mg/kg intraperitoneally). RESULTS ORM-10962 significantly reduced both the inward and outward NCX currents with the estimated EC50 values of 55 nM and 67 nM, respectively. The compound, even at the high concentration of 1 µM, did not change significantly the amplitude of ICaL in CM. ORM-10962 (1 µM) had no influence on the inward rectifier, transient outward, rapid and slow delayed rectifier potassium currents, late sodium current and Na+/K+ pump. ORM-10962 slowed automaticity in Purkinje fibres and sinus node in dogs and rabbits, without altering the ivabradine sensitive pacemaker current. The amplitude of pharmacologically induced delayed afterdepolarizations (by digoxin) was significantly decreased by 1 µM ORM-10962 in canine Purkinje fibres. ORM-10962 (0.3 mg/kg) pre-treatment (i.v. 10 min before starting ouabain infusion) significantly delayed the development of ventricular extrasystoles (by about 50%) or ventricular tachycardia (by about 30 %) in anesthetised guinea pig Fig 1A). On the contrary, ORM-10962 pre-treatment did not result in any change on the development, or the severity of IR induced arrhythmias in anesthetised rat (Fig1B. CONCLUSIONS The present study provides evidence for the strong and highly selective NCX-inhibitory activity of ORM-10962. In addition it is suggested that specific inhibition of the NCX current can influence normal pacemaker function (Ca2+-clock hypothesis) and also contribute to the prevention of DAD based arrhythmias in vivo. However, its effect on ischemia-reperfusion arrhythmias is still uncertain.