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 (IKr) increases APD short-term variability (BVR) beyond what expected by such proportionality. It is unclear whether this may be explained by known IKr 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 IKr blockade can be reversed by injection of current generated by a deterministic numerical IKr model (mIKr); 2) modulation of IKr maximal conductance (gmax) may affect APD and BVR differentially. In guinea-pig myocytes, native IKr was blocked by E4031 and replaced by mIKr by Dynamic-Clamp (DC); 2) the effect on APD and BVR of relatively small changes in mIKr gmax were assessed. The results thus far indicate that: 1) mIKr 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 IKr 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 mIKr.