A MODEL STUDY OF CHANGES IN EXCITABILITY OF VENTRICULAR MUSCLE-CELLS - INHIBITION, FACILITATION, AND HYSTERESIS

A model study was carried out to investigate the mechanism of changes in excitability at long cycle lengths (i.e., > 1,000 ms), which are re sponsible for various phenomena, including electrotonic inhibition, ac tive facilitation, and hysteresis of excitability in ventricular muscl e at slow frequencies of stimulation. Experimental studies suggested t hat with repetitive activity the inward rectifier potassium current (I -K1) is not a passive component of membrane response and that the dyna mics of I-K1 are responsible for the changes in excitability at long c ycle lengths. In the present study, we have used new experimental data as the basis to modify the equations for I-K1 in the ionic model for ventricular muscle of the Luo and Rudy (LR) model. The modified equati ons for I-K1 incorporate an additional slow gate (s-gate), which gover ns the transition from a high steady-state conductance at rest to a lo wer conductance with repetitive stimulation. In simulation studies, el ectrotonic inhibition was seen in the original and the modified LR mod el and was shown to depend on changes in the delayed rectifier current (I-K) However, addition of the s-gate to I-K1 Of the LR model extende d the frequency dependence of excitability to longer cycle lengths and allowed for the demonstration of active facilitation and hysteresis. These results support the hypothesis that the inward rectifier is invo lved in the dynamic control of membrane excitability. The overall resu lts provide mechanistic explanations for heart rate-dependent excitati on abnormalities that may be involved in the genesis of cardiac arrhyt hmias.