No abstract

Pathological conditions linked to imbalances in oxygen supply and demand (for example, ischaemia, hypoxia and heart failure) are associated with disruptions in intracellular sodium ( ] i leads to electrical instability (arrhythmias), mechanical dysfunction (reduced contractility and increased diastolic tension) and mitochondrial dysfunction. These events increase ATP hydrolysis and decrease ATP formation and, if left uncorrected, they cause cell injury and death. The relative contributions of various pathways (sodium channels, exchangers and transporters) to the rise in [Na + ] i remain a matter of debate. Nevertheless, both the sodium-hydrogen exchanger and abnormal sodium channel conductance (that is, increased late sodium current (I Na )) are likely to contribute to the rise in [Na + ] i . The focus of this review is on the role of the late (sustained/persistent) I Na in the ionic disturbances associated with ischaemia/hypoxia and heart failure, the consequences of these ionic disturbances, and the cardioprotective effects of the antianginal and anti-ischaemic drug ranolazine. Ranolazine selectively inhibits late I Na , reduces [Na + ] i -dependent calcium overload and attenuates the abnormalities of ventricular repolarisation and contractility that are associated with ischaemia/reperfusion and heart failure. Thus, inhibition of late I Na can reduce [Na + ] i -dependent calcium overload and its detrimental effects on myocardial function.

Reactive oxygen species (ROS), including H 2 O 2 , cause intracellular calcium overload and ischemia-reperfusion damage. The objective of this study was to examine the hypothesis that H 2 O 2 -induced arrhythmic activity and contractile dysfunction are the results of an effect of H 2 O 2 to increase the magnitude of the late sodium current (late I Na ). Guinea pig and rabbit isolated ventricular myocytes were exposed to 200 M H 2 O 2 . Transmembrane voltages and currents and twitch shortening were measured using the whole-cell patch-clamp technique and video edge detection, respectively.

Inhibition of cardiac late sodium current (late I Na ) is a strategy to suppress arrhythmias and sodium-dependent calcium overload associated with myocardial ischemia and heart failure. Current inhibitors of late I Na are unselective and can be proarrhythmic. This study introduces GS967 (6-[4-(trifluoromethoxy), a potent and selective inhibitor of late I Na , and demonstrates its effectiveness to suppress ventricular arrhythmias. The effects of GS967 on rabbit ventricular myocyte ion channel currents and action potentials were determined. Anti-arrhythmic actions of GS967 were characterized in ex vivo and in vivo rabbit models of reduced repolarization reserve and ischemia. GS967 inhibited Anemonia sulcata toxin II (ATX-II)-induced late I Na in ventricular myocytes and isolated hearts with IC 50 values of 0.13 and 0.21 mM, respectively. Reduction of peak I Na by GS967 was minimal at a holding potential of 2120 mV but increased at 280 mV. GS967 did not prolong action potential duration or the QRS interval. GS967 prevented and reversed proarrhythmic effects (afterdepolarizations and torsades de pointes) of the late I Na enhancer ATX-II and the I Kr inhibitor E-4031 in isolated ventricular myocytes and hearts. GS967 significantly attenuated the proarrhythmic effects of methoxamine1clofilium and suppressed ischemiainduced arrhythmias. GS967 was more potent and effective to reduce late I Na and arrhythmias than either flecainide or ranolazine. Results of all studies and assays of binding and activity of GS967 at numerous receptors, transporters, and enzymes indicated that GS967 selectively inhibited late I Na . In summary, GS967 selectively suppressed late I Na and prevented and/or reduced the incidence of experimentally induced arrhythmias in rabbit myocytes and hearts.

The purpose of this review is to examine the role of the extracellular A1-adenosine (Ado) receptor in modulating membrane potential and currents in cardiac cells. The cellular electrophysiological effects of adenosine are both cell type- and species-dependent. In supraventricular tissues (SA, AV node, and atrium) of all species studied, the "direct" cAMP-independent activation of the inwardly rectifying K+ current IKAdo seems to be the most important action of adenosine. This current is activated by both adenosine and acetylcholine and flows through K+ channels with unitary slope conductance of about 45 pS and an open time constant of 1.4 ms. The density of K(+)-ACh,Ado channels is much less in ventricular than in atrial myocytes, and thus adenosine has little or no effect on the ventricular action potential. In atrial myocytes adenosine has a small inhibitory effect on basal L-type calcium current (ICa,L), but no effect on T-type calcium current (ICa,T). In ventricular myocytes, adenosine does not inhibit ICa,L (except ferret), ICa,T, or the sodium inward current INa. Adenosine has recently been shown to activate IKATP in ventricular membrane patches, but the relevance of this finding remains to be defined. Irrespective of cell type and species, adenosine inhibits membrane currents that are stimulated by beta-adrenergic agonists and other agents known to stimulate the activity of the enzyme adenylyl cyclase. This indirect cAMP-dependent mechanism of action has been shown to be responsible for the inhibition by adenosine of isoproterenol-stimulated ICa,L, delayed rectifier K+ current (IK), chloride current (ICl), the transient inward current ITi, and the pacemaker current IF. The importance of the actions of adenosine on membrane currents in modulation of atrial, ventricular, sinoatrial, and atrioventricular nodal function are discussed. Likewise, the antiarrhythmic and proarrhythmic actions of adenosine are discussed and the clinical implications of these actions are noted.