Abstract 10788: The Late Na Current I_NaL Contributes to the Prolongation of the Action Potential in the Aging Canine Myocardium

Abstract

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 (I_NaL), 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 I_NaL 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 I_NaL amplitude and AP duration presented reverse rate dependency. Thus, these findings indicate that I_NaL represents the ionic basis for the prolonged APs in old cells. To test the possibility that I_NaL is a critical modulator of the electromechanical coupling in dog myocytes, Ca²⁺ cycling and contractility were evaluated in isolated cells. Blockade of I_NaL 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 I_NaL prolongs the AP and provides inotropic support to the aging myocardium; re-activation properties of I_NaL may underlie the impaired rate-dependent cardiac reserve observed in old dogs.