Developmental changes in expression and biophysics of ion channels in the canine ventricle

Abstract

Background Developmental changes in the electrical characteristics of the ventricular myocardium are not well defined. This study examines the contribution of inwardly rectifying K+ current (IK1), transient outward K+ current (Ito), delayed rectifier K+ currents (IKr and IKs) and sodium channel current (INa) to repolarization in the canine neonate myocardium. Methods Single myocytes isolated from the left ventricle of 2-3 week old canine neonate hearts were studied using patch-clamp techniques. Results Neonate cells were ~6-fold smaller than those of adults (28.8±8.8 vs. 176±6.7 pF). IK1 was larger in neonate myocytes and displayed a substantial inward component and an outward component with negative slope conductance, peaking at −60 mV (4.13 pA/pF). IKr tail currents (at −40 mV), were small (<20 pA). IKs could not be detected, even after exposure to isoproterenol (100 nM). Ito was also absent in the neonate, consistent with the absence of a phase 1 in the action potential. Peak INa, late INa and ICa were smaller in the neonate compared with adult. KCND3, KCNIP2 and KCNQ1 mRNA expression was half, while KCNH2 was equal and KCNJ2 was greater in the neonate when compared with adults. Conclusions Two major repolarizing K+ currents (IKs and Ito) present in adult ventricular cells are absent in the 2 week old neonate. Peak and late INa are significantly smaller in the neonate. Our results suggest that the absence of these two currents in the neonate heart may increase the susceptibility to arrhythmias under certain long QT conditions.

Culture in Glucose-Depleted Medium Supplemented with Fatty Acid and 3,3′,5-Triiodo-l-Thyronine Facilitates Purification and Maturation of Human Pluripotent Stem Cell-Derived Cardiomyocytes

“…We measured the expression of major ion channel and cardiac genes in each of the three culture conditions compared to the routine medium condition. We noted significant upregulation of genes encoding for the major cardiac potassium channel subunits associated with the fatty acid and T 3 treatment: KCND3 and KCNQ1 expression, which are known to be more pronounced in canine adult (as compared to neonatal) ventricular tissue ( 25 ), were increased 7.1- and 1.5-fold, respectively. KCNJ2 , which encodes for the pore of the inward rectifier K + channel ( 26 ), a key regulator of phase 3 and known to be upregulated in cardiac development ( 27 ), increased 4.9-fold.…”

Cellular Size, Gap Junctions, and Sodium Channel Properties Govern Developmental Changes in Cardiac Conduction

“…Several key properties governing EpC and conduction overall are known to change during development: Cells in neonatal myocardium do not have fully formed IDs, and Na + channels and GJs are distributed diffusively throughout the sarcolemma (Fromaget et al, 1992;Vreeker et al, 2014). Consistent with reduced Na + channel expression, it has been shown that pediatric cardiomyocytes produce a reduced I Na , compared to adult cardiomyocytes (Cai et al, 2011;Cordeiro et al, 2013). Cx43 is essentially undetectable until 23 weeks in utero and remain randomly distributed on the sarcolemma in neonatal cardiomyocytes (Peters et al, 1994;Hirschy et al, 2006;Vreeker et al, 2014;Swift et al, 2020).…”

“…Na v 1.5channels, however, reside on the lateral membrane in neonatal cardiomyocytes and begin to begin to preferentially localize at the ID around 5 months postnatal, much earlier than Cx43 (Harrell et al, 2007 ; Vreeker et al, 2014 ). Additionally, studies have shown that adult cardiomyocytes are larger than neonatal cardiomyocytes (Cordeiro et al, 2013 ; Vreeker et al, 2014 ; Swift et al, 2020 ). This is especially important given that cell size broadly influences all electrical activity in the cell by altering surface area, cell volume, membrane capacitance, ion channel expression, etc.…”

Regional variation of the inwardly rectifying potassium current in the canine heart and the contributions to differences in action potential repolarization

“…In the canine ventricle, four K + currents play important roles in controlling the cardiac action potential duration 1–5 : (i) a Ca 2+ -independent transient outward K + current ( I to1 ) (in contrast to the Ca 2+ -dependent current, I to2 6 ); (ii) a rapid and slow delayed rectifier K + current ( I Kr and I Ks , respectively) and (iii) an inwardly rectifying K + current ( I K1 ). I K1 has been identified in the myocardium of most mammalian species (for review see 7, 8 ), but the density of I K1 among different species as well as among different cardiac tissue types is highly variable 9–11 .…”