Abstract 10793: Alterations of the Ionic Current Profile Underlie the Defective Electromechanical Coupling of Old Myocytes
Cardiac pathologies are characterized by prolongation of the action potential (AP) in myocytes, but whether a similar adaptation is present in the aging myocardium and impact on electromechanical coupling is poorly understood. The aim of this study was to establish whether the ionic current profile of myocytes is modified by age, altering electrical and mechanical properties of the senescent myocardium. For this purpose, LV myocytes were obtained from young (3 months) and old (30 months) mice and Ca2+ imaging, contractility and patch-clamp experiments were performed and integrated with assays using isometrically twitching papillary muscles. Under field stimulation, Ca2+ transient and sarcomere shortening in myocytes from old mice were characterized by smaller amplitudes and prolonged timing parameters, with respect to young cells. In current-clamp mode, old myocytes showed prolonged early, intermediate and late repolarization phases of the action potential, in comparison to cells from young animals. In voltage-clamp, the transient outward K current (Ito) was reduced by 40% in old myocytes, whereas the slow inactivating late Na current (INaL) was 1.7-fold larger with respect to young cells. Activation, steady state inactivation and time constants for INaL were comparable in the two groups of cells, indicating that the enhanced late current in old was mediated by an increased maximal conductance. Thus, in the attempt to restore the AP profile of old myocytes, INaL was inhibited with low doses of tetrodotoxin or mexiletine. This intervention shortened by 24% and 48% the intermediate and late phases of the AP, respectively. Similarly, INaL blockade shortened the time to peak and decay of Ca2+ transients and sarcomere shortening and further reduced their amplitudes. SR Ca2+ load was not affected when INaL was blocked, pointing to the AP shape as the major determinant of the altered Ca2+ release. Using papillary muscle preparations from old animals, inhibition of INaL reduced active developed and diastolic tensions, whereas increasing INaL in muscles from young mice with anemonetoxin had opposite effects. In conclusion, the late sodium current INaL is upregulated with aging, provides inotropic support and exacerbate relaxation of the senescent myocardium.
- © 2012 by American Heart Association, Inc.