Role of Cardiac IKs Current in Repolarization Reserve Process During Late Sodium Current (INaL) Activation
Richard Printemps1, Céline Salvetat1, Jean-François Faivre2, Marie Le Grand1, Patrick Bois 2, Hamid Moha ou Maati1, 3 — 1 PhysioStim, Zone Industrielle de Brénas, 81440 Lautrec, France | 2 CNRS, ERL 7003, Laboratoire STIM, Université de Poitiers, F-86073 Poitiers, France | 3 Institut de Génomique Fonctionnel IGF CNRS INSERM UMR5203, 141 rue de la Cardonille, F-34090 Montpellier France
ABSTRACT
The slow delayed rectifier K+ current (IKs) mediated by KCNQ1/KCNE1 channels contributes to the cardiac action potential in human and other species. Several studies have shown that IKs protects the heart from excessive action potential prolongation induced by the rapid delayed rectifier K+ current (IKr) inhibition. Moreover, several studies have shown that combined pharmacological inhibition of IKs and IKr currents increases cardiac parameters such as instability and dispersion of repolarization, and short term QT interval variability. It is known these effects promote a high risk of occurrence of « torsade de pointes ». However, the consequences of combined IKs current inhibition with an increase of the late sodium current (INaL) on cardiac repolarization has not been studied and reported in the literature.
The aim of this work is to study the effects of pharmacological inhibition of IKs with chromanol 293B, a reference inhibitor of IKs current, during action potential prolongation promoted by INaL pharmacological activation by veratridine. These effects were also evaluated in the presence of doxorubicin, an anti cancer drug increasing cardiac ventricular repolarisation and QT interval duration.