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This Article Full Text Full Text (PDF) All Versions of this Article: 294/4/H1597    most recent 00484.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Maltsev, V. A. Articles by Undrovinas, A. PubMed PubMed Citation Articles by Maltsev, V. A. Articles by Undrovinas, A.

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

Department of Internal Medicine, Henry Ford Hospital, Detroit, Michigan

Submitted 23 April 2007 ; accepted in final form 11 January 2008

Augmented and slowed late Na⁺ current (I_NaL) is implicated in action potential duration variability, early afterdepolarizations, and abnormal Ca²⁺ handling in human and canine failing myocardium. Our objective was to study I_NaL 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. I_NaL 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. I_NaL 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 I_NaL modulation in failing vs. normal myocytes. Similarities include the following: 1) CaMKII slows I_NaL decay and decreases the amplitude of fast exponentials, and 2) Ca²⁺ shifts SSI rightward. Differences include the following: 1) slowing of I_NaL 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 I_NaL 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.

heart failure; arrhythmia