About half of the late sodium current in cardiac myocytes from dog ventricle is due to non-cardiac-type Na(+) channels

Abstract

Voltage gated sodium channels (Na(V)s) are essential to propagate neuronal and cardiac electrical impulses. While the cardiac Na(+) current (I(Na)) is often all attributed to the cardiac isoform, Na(V)1.5, some evidence suggests that other Na(+) channel isoforms are also expressed in the heart ventricle. One way to distinguish Na(+) channels is by their sensitivity to tetrodotoxin (TTX); various "non-cardiac-type" Na(+) channels are relatively sensitive to TTX (denoted tNa(V) channels) compared to Na(V)1.5 channels. tNa(V) channels have been detected in hearts with various pathological conditions such as hypertrophy, infarction and ischemia, where they might enhance the late Na(+) current (I(NaL)) thereby prolonging the action potential under such conditions (resulting in a prolonged QT interval on the EKG). The principal aim of this article is to evaluate the extent to which non-cardiac isotypes contribute to I(NaL) under normal physiological conditions. I(NaL) was measured in acutely dissociated dog cardiomyocytes using the patch-clamp technique. Our results indicate that 44% on average of the late I(Na) current is due to non-cardiac Na(V)s. Previous studies indicated that the overexpression of non-cardiac Na(V) channels is responsible for the prolonged duration of the cardiac action potential (and, thereby, a prolonged QT interval) under pathophysiological conditions associated with various heart diseases. Our finding indicates that non-cardiac Na(V) channels are strong contributors to I(NaL) under physiological conditions thereby suggesting that these channels are also major determinants of the duration of the cardiac action potential even in healthy hearts. Interestingly, these results may explain the observations of cardiac arrhythmias associated with prolonged QT intervals in people with inherited neuronal and musculoskeletal diseases involving mutations that enhance the current from non-cardiac-type Na(V)s, a connection which apparently was never made before.