Session S83.1

Mechanisms of ß-Adrenergic Modulation of IKs in the Guinea-Pig Ventricle: Insights from Computational Analysis

S Severi, C Corsi, M Rocchetti, A Zaza*

Università di Milano Bicocca
Milano, Italy

The aims of the present study were a) to characterize the ß-adrenergic modulation of the slow delayed rectifier potassium current, IKs, through voltage clamp experiments on guinea-pig ventricular myocytes in presence of isoprenaline (ISO); b) to integrate a coherent set of experimental data into a mathematical description of the IKs kinetic with and without ISO stimulation; and c) to analyse the mechanisms regulating the ß-adrenergic modulation of the current.
The Markov model of Silva and Rudy was used to examine IKs kinetics in control condition (CTRL) and in presence of ISO. Whole-cell current was measured at 36.5 °C in activation, deactivation and S1-S2 reactivation V-clamp protocols. Model parameters were identified to fit experimental data in the two conditions in all protocols.
In myocytes ISO significantly enhanced IKs amplitude so that the maximum current, at 50 mV, was more than doubled (472±64 vs 186±24 pA). ISO slowed down the IKs deactivation with respect to CTRL, so that the was (18% average increase of deactivation time constant). When the two-step protocol was applied, an ISO-induced enhancement of IKs reactivation rate was observed (339±8 vs 410±9 ms estimated steady-state value of treact). Moreover, ISO slowed the restitution process with respect to CTRL. A good fitting of experimental data was obtained by the model for all the examined protocols (e.g.: the estimated time constant of activation restitution was 123 vs 69 ms in ISO vs CTRL, experimental: 132±30 vs 68±19 ms). ISO effects were reproduced by altering the rates of the first slow transition of activation and of the transition from/to the open state.
Both in vitro and in silico quantitative analysis supports the idea of an important role for IKs in cardiac electrophysiology under ß-adrenergic stimulation, e.g. in APD adaptation to increased heart rate, when adrenergic stimulation is present. In particular, model based analysis suggests that ß-adrenergic stimulation regulates the access to a large “available reserve” of IKs channels that don’t normally open, even at high positive potentials.

(Abstract Control Number: 110)