title: A model study of changes in excitability of ventricular muscle cells: inhibition, facilitation, and hysteresis.
abstract: 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 responsible for various phenomena, including electrotonic inhibition, active facilitation, and hysteresis of excitability in ventricular muscle at slow frequencies of stimulation. Experimental studies suggested that with repetitive activity the inward rectifier potassium current (IK1) is not a passive component of membrane response and that the dynamics of IK1 are responsible for the changes in excitability at long cycle lengths. In the present study, we have used new experimental data as the basis to modify the equations for IK1 in the ionic model for ventricular muscle of the Luo and Rudy (LR) model. The modified equations for IK1 incorporate an additional slow gate (s-gate), which governs the transition from a high steady-state conductance at rest to a lower conductance with repetitive stimulation. In simulation studies, electronic inhibition was seen in the original and the modified LR model and was shown to depend on changes in the delayed rectifier current (IK). However, addition of the s-gate to IK1 of the LR model extended 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 involved in the dynamic control of membrane excitability. The overall results provide mechanistic explanations for heart rate-dependent excitation abnormalities that may be involved in the genesis of cardiac arrhythmias.
authors.affiliation: Department of Pharmacology, State University of New York Health Science Center at Syracuse 13210.
authors.forename: J
authors.initials: J
authors.lastname: Beaumont
authors.forename: D C
authors.initials: DC
authors.lastname: Michaels
authors.forename: M
authors.initials: M
authors.lastname: Delmar
authors.forename: J
authors.initials: J
authors.lastname: Davidenko
authors.forename: J
authors.initials: J
authors.lastname: Jalife
mesh_terms: D000465:Algorithms; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000209:etiology / Q000503:physiopathology; D004558:Electric Stimulation; D004594:Electrophysiology; D006321:Heart / Q000502:physiology*; D006339:Heart Rate / Q000502:physiology; D006352:Heart Ventricles / Q000166:cytology; D066298:In Vitro Techniques; D015640:Ion Channel Gating / Q000502:physiology; D007473:Ion Channels / Q000378:metabolism; D008564:Membrane Potentials / Q000502:physiology; D008955:Models, Cardiovascular; D016276:Ventricular Function
chemical_list: D007473:Ion Channels