Modulation of late sodium current by Ca2+, calmodulin, and CaMKII in normal and failing dog cardiomyocytes: similarities and differences

Abstract

Augmented and slowed late Na+ current ( INaL) is implicated in action potential duration variability, early afterdepolarizations, and abnormal Ca2+ handling in human and canine failing myocardium. Our objective was to study INaL modulation by cytosolic Ca2+ concentration ([Ca2+]i) in normal and failing ventricular myocytes. Chronic heart failure was produced in 10 dogs by multiple sequential coronary artery microembolizations; 6 normal dogs served as a control. INaL fine structure was measured by whole cell patch clamp in ventricular myocytes and approximated by a sum of fast and slow exponentials produced by burst and late scattered modes of Na+ channel gating, respectively. INaL greatly enhanced as [Ca2+]i increased from “Ca2+ free” to 1 μM: its maximum density increased, decay of both exponentials slowed, and the steady-state inactivation (SSI) curve shifted toward more positive potentials. Testing the inhibition of CaMKII and CaM revealed similarities and differences of INaL modulation in failing vs. normal myocytes. Similarities include the following: 1) CaMKII slows INaL decay and decreases the amplitude of fast exponentials, and 2) Ca2+ shifts SSI rightward. Differences include the following: 1) slowing of INaL by CaMKII is greater, 2) CaM shifts SSI leftward, and 3) Ca2+ increases the amplitude of slow exponentials. We conclude that Ca2+/CaM/CaMKII signaling increases INaL and Na+ influx in both normal and failing myocytes by slowing inactivation kinetics and shifting SSI. This Na+ influx provides a novel Ca2+ positive feedback mechanism (via Na+/Ca2+ exchanger), enhancing contractions at higher beating rates but worsening cardiomyocyte contractile and electrical performance in conditions of poor Ca2+ handling in heart failure.