Class III effects of dofetilide and arrhythmias are modulated by [K+]o in an in vitro model of simulated-ischemia and reperfusion in guinea-pig ventricular myocardium

IKs Protects from Ventricular Arrhythmia during Cardiac Ischemia and Reperfusion in Rabbits by Preserving the Repolarization Reserve

“…The prolongation of MAPD in the early phase of reperfusion, which was reported previously by Bes et al and Ducroq et al in vitro [6], [7], was confirmed in our study in vivo . The careful use of controls in this study also demonstrated that blockade of I Ks by L-768,673 prolonged both the MAPD90 and MAPD60 in the interval between R30and R90, which provided evidence of the increased contribution of the I Ks current in repolarization currents.…”

“…For example, when cardiac ischemia was induced, the contribution of adenosine triphosphate sensitive potassium current (I KATP ) to repolarization was increased, while those of IKr and IK1 were lessened in comparison, which led in turn to a shortening of the APD [5]. The shortening of the APD induced by ischemia is gradually restored by reperfusion, however a temporary prolongation of APD during early reperfusion was observed by Ducroq et al and Bes et al in an in vitro model of simulated ischemia and reperfusion in isolated cardiomyocytes [6], [7]. This phenomenon, which directly involved repolarization ion current function, has not yet been well explained.…”

hERG K+Channels: Structure, Function, and Clinical Significance

“…These results suggest that either reduced I Kr contributes to reperfusion-induced arrhythmias (and therefore reducing it further does not prevent them) or that the magnitude of I Kr during reperfusion is insufficient to modulate the occurrence of reperfusioninduced arrhythmias. In a more recent study, Gerard et al (157) found that when extracellular K ϩ was increased during simulated ischemia (and reperfusion), a low dose of dofetilide caused significant action potential prolongation and, either had a neutral or protective effect against reperfusion-induced arrhythmias. This later study indicates that the effects of hyperkalemia can have a significant impact on I Kr function, although one should probably be cautious in extrapolating the results from the in vitro model used by Gerard et al to the clinical environment where ischemic insults are likely to be much more heterogeneous than in well-controlled in vitro models.…”

IKr vs. IKs blockade and arrhythmogenicity in normoxic rabbit Purkinje fibers: does it really make a difference?

“…However, during simulated ischemia, other currents (i.e. I KATP ) may have come into play [10–13] to modulate and/or add to the effects of I Kr blockers. Nevertheless, it is clear that d‐sotalol and dofetilide may have a double‐edge effect on border‐zone arrhythmias [11–13], and the clinical counterpart was seen in SWORD [1] and DIAMOND [2] trials whereby an increased risk of life‐threatening arrhythmias was observed in the presence of ischemia.…”

“…After comparing several compounds, a quite rarely performed approach, and taking all inherent limitations of experimental investigations into account, it is concluded that in normoxic rabbit Purkinje fibers, I Ks blockade was neutral, whereas I Kr blockade was pro‐arrhythmic, which may make a difference worth exploration in more complex models. As I Kr blockade by the compounds investigated here was also pro‐arrhythmic during simulated ischemia–reperfusion in guinea‐pig ventricular tissue [10–13], there is a need to compare the effects of I Ks blockers in these conditions to put into perspective the roles played by species (rabbit vs. guinea‐pig vs. dog and the inherent I Kr / I Ks ratios [6,17,27,30]) or tissue (endocardium vs. epicardium or M region [28,29]) types and pathophysiology (normoxia [17,18,28–30,35] vs. simulated ischemia–reperfusion [10–13]).…”