IKr impact on repolarization and its variability assessed by Dynamic-Clamp

In previous work we have shown that action potential duration (APD) and its response to modulation are “intrinsically” proportional. Nevertheless, loss of the rapid delayed rectifier K⁺ current (I_Kr) increases APD short-term variability (BVR) beyond what expected by such proportionality. It is unclear whether this may be explained by known I_Kr gating properties and which among them prevails in limiting BVR. As a preliminary approach to the problem, we investigated whether: 1) BVR changes caused by I_Kr blockade can be reversed by injection of current generated by a deterministic numerical I_Kr model (mI_Kr); 2) modulation of I_Kr maximal conductance (g_max) may affect APD and BVR differentially. In guinea-pig myocytes, native I_Kr was blocked by E4031 and replaced by mI_Kr by Dynamic-Clamp (DC); 2) the effect on APD and BVR of relatively small changes in mI_Kr g_max were assessed. The results thus far indicate that: 1) mI_Kr effectively reversed E4031 effects on both APD and BVR; 2) a 30% decrease in g_max, inadequate to prolong APD, increased BVR significantly. We conclude that 1) the effect of I_Kr changes on BVR may exceed that expected from modulation of APD only; 2) this can be accounted for by the known channel gating features implemented in mI_Kr.