%0 Journal Article
%T Calpain Inhibition Reduces Amplitude and Accelerates Decay of the Late Sodium Current in Ventricular Myocytes from Dogs with Chronic Heart Failure
%A Albertas Undrovinas
%A Victor A. Maltsev
%A Hani N. Sabbah
%J PLOS ONE
%D 2013
%I Public Library of Science (PLoS)
%R 10.1371/journal.pone.0054436
%X Calpain is an intracellular Ca2+ -activated protease that is involved in numerous Ca2+ dependent regulation of protein function in many cell types. This paper tests a hypothesis that calpains are involved in Ca2+ -dependent increase of the late sodium current (INaL) in failing heart. Chronic heart failure (HF) was induced in 2 dogs by multiple coronary artery embolization. Using a conventional patch-clamp technique, the whole-cell INaL was recorded in enzymatically isolated ventricular cardiomyocytes (VCMs) in which INaL was activated by the presence of a higher (1米M) intracellular [Ca2+] in the patch pipette. Cell suspensions were exposed to a cell- permeant calpain inhibitor MDL-28170 for 1每2 h before INaL recordings. The numerical excitation-contraction coupling (ECC) model was used to evaluate electrophysiological effects of calpain inhibition in silico. MDL caused acceleration of INaL decay evaluated by the two-exponential fit (而1 = 42㊣3.0 ms 而2 = 435㊣27 ms, n = 6, in MDL vs. 而1 = 52㊣2.1 ms 而2 = 605㊣26 control no vehicle, n = 11, and vs. 而1 = 52㊣2.8 ms 而2 = 583㊣37 ms n = 7, control with vehicle, P<0.05 ANOVA). MDL significantly reduced INaL density recorded at 每30 mV (0.488㊣0.03, n = 12, in control no vehicle, 0.4502㊣0.0210, n = 9 in vehicle vs. 0.166㊣0.05pA/pF, n = 5, in MDL). Our measurements of current-voltage relationships demonstrated that the INaL density was decreased by MDL in a wide range of potentials, including that for the action potential plateau. At the same time the membrane potential dependency of the steady-state activation and inactivation remained unchanged in the MDL-treated VCMs. Our ECC model predicted that calpain inhibition greatly improves myocyte function by reducing the action potential duration and intracellular diastolic Ca2+ accumulation in the pulse train. Conclusions Calpain inhibition reverses INaL changes in failing dog ventricular cardiomyocytes in the presence of high intracellular Ca2+. Specifically it decreases INaL density and accelerates INaL kinetics resulting in improvement of myocyte electrical response and Ca2+ handling as predicted by our in silico simulations.
%U http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0054436