Abstract 10788: The Late Na Current INaL Contributes to the Prolongation of the Action Potential in the Aging Canine Myocardium
Aging is associated with alterations in the electrical properties of the heart resulting in an increased incidence of arrhythmic events and defective cardiac performance. The aim of the present study was to determine whether the late sodium current (INaL), which presents slow inactivation kinetics, is upregulated in myocytes from old hearts, contributing to the electrical remodeling of the senescent myocardium. For this purpose, physiological determinations in vivo, in left ventricular (LV) preparations, and in isolated LV myocytes were conducted using young (3 years) and old (11 years) Beagle dogs. Hemodynamic and echocardiographic parameters indicated functional defects in old animals, which were aggravated following treadmill exercise test, pacing, and beta-adrenergic challenge. In the perfused LV myocardium, transmural ECG in old dogs presented prolonged QT interval with respect to young animals; the delayed electrical recovery was associated with a 13% increase in the effective refractory period and a 1.3-fold prolongation of monophasic action potentials (APs). By patch-clamp, isolated LV myocytes from old hearts presented longer AP duration (+31%), in comparison with young. In voltage-clamp mode, the late Na current, which is operative during the repolarization phase of the AP, was 2.3-fold larger in old myocytes with respect to young. Blockade of INaL in old cells with low doses of tetrodotoxin or ranolazine, shortened the AP by 45% and 32%, respectively. Additionally, stimulation frequency protocols revealed that both INaL amplitude and AP duration presented reverse rate dependency. Thus, these findings indicate that INaL represents the ionic basis for the prolonged APs in old cells. To test the possibility that INaL is a critical modulator of the electromechanical coupling in dog myocytes, Ca2+ cycling and contractility were evaluated in isolated cells. Blockade of INaL resulted in a 40% decrease in the amplitude of Ca2+ transients and cell shortening, and promoted faster Ca2+ decay and relaxation. In conclusion, upregulation of INaL prolongs the AP and provides inotropic support to the aging myocardium; re-activation properties of INaL may underlie the impaired rate-dependent cardiac reserve observed in old dogs.
- © 2012 by American Heart Association, Inc.