Mechanisms of ß-adrenergic modulation of IKs in the guinea-pig ventricle: insights from experimental and model-based analysis

Detailed understanding of IKs gating complexity may provide clues regarding the mechanisms of repolarization instability and the resulting arrhythmias. We developed and tested a kinetic model to interpret physiologically relevant IKs properties, including pause-dependence and modulation by b-adrenergic receptors (b-AR). IKs gating was evaluated in guinea-pig ventricular myocytes at 36C in control and during b-AR stimulation (0.1 mmol/L isoprenaline (ISO)). We tested voltage dependence of steady-state conductance (Gss), voltage dependence of activation and deactivation time constants (tact, tdeact), and pause-dependence of tact during repetitive activations (treact). The IKs model was developed from the Silva and Rudy formulation. Parameters were optimized on control and ISO experimental data, respectively. ISO strongly increased Gss and its voltage dependence, changed the voltage dependence of tact and tdeact, and modified the pause-dependence of treact. A single set of model parameters reproduced all experimental data in control. Modification of only three transition rates led to a second set of parameters suitable to fit all ISO data. Channel unitary conductance and density were unchanged in the model, thus implying increased open probability as the mechanism of ISO-induced Gss enhancement. The new IKs model was applied to analyze ISO effect on repolarization rate-dependence. IKs kinetics and its b-AR modulation were entirely reproduced by a single Markov chain of transitions (for each channel monomer). Model-based analysis suggests that complete opening of IKs channels within a physiological range of potentials requires concomitant b-AR stimulation. Transient redistribution of state occupancy, in addition to direct modulation of transition rates, may underlie b-AR modulation of IKs time dependence.