Region-specific mechanisms of corticosteroid-mediated inotropy in rat cardiomyocytes

Caroline Wacker,Michael Wagner,Niklas Dams,Anne Ritzer,Tilmann Volk,Alexander Schauer

doi:10.1038/s41598-020-68308-4

Caroline Wacker, Michael Wagner + Show 4 more

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https://doi.org/10.1038/s41598-020-68308-4

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Abstract

Regional differences in ion channel activity in the heart control the sequence of repolarization and may contribute to differences in contraction. Corticosteroids such as aldosterone or corticosterone increase the L-type Ca2+ current (ICaL) in the heart via the mineralocorticoid receptor (MR). Here, we investigate the differential impact of corticosteroid-mediated increase in ICaL on action potentials (AP), ion currents, intracellular Ca2+ handling and contractility in endo- and epicardial myocytes of the rat left ventricle. Dexamethasone led to a similar increase in ICaL in endocardial and epicardial myocytes, while the K+ currents Ito and IK were unaffected. However, AP duration (APD) and AP-induced Ca2+ influx (QCa) significantly increased exclusively in epicardial myocytes, thus abrogating the normal differences between the groups. Dexamethasone increased Ca2+ transients, contractility and SERCA activity in both regions, the latter possibly due to a decrease in total phospholamban (PLB) and an increase PLBpThr17. These results suggest that corticosteroids are powerful modulators of ICaL, Ca2+ transients and contractility in both endo- and epicardial myocytes, while APD and QCa are increased in epicardial myocytes only. This indicates that increased ICaL and SERCA activity rather than QCa are the primary drivers of contractility by adrenocorticoids.

Highlights

Regional differences in ion channel activity in the heart control the sequence of repolarization and may contribute to differences in contraction
In a previous study[27], insulin was part of the primary culture conditions and we later learned that it is a prerequisite for ICaL regulation by corticosteroids: Fig. 1A displays typical recordings of ICaL obtained from a control myocyte, a myocyte incubated with 1 μM dexamethasone, a myocyte incubated with 100 nM insulin and a myocyte incubated with the combination of both dexamethasone and insulin. 24 h incubation with dexamethasone substantially increased ICaL only in the presence of insulin
Treatment with DI led to a much larger increase in AP duration (APD) and action potentials (AP)-induced C a2+ influx in epicardial myocytes, the increase in intracellular C a2+ transient and, contractility was similar in both regions

Summary

Introduction

Regional differences in ion channel activity in the heart control the sequence of repolarization and may contribute to differences in contraction. Clinical trials provide convincing evidence that MR antagonistic therapy increases survival in patients with heart failure, by, among others, decreasing the rate of fatal a rrhythmias[2,3], which are facilitated by electrical remodeling of the myocardium[4] In line with this observation, a number of studies have demonstrated that MR activation modulates ionic currents and transporters in ventricular cardiomyocytes, including the fast Na+ current[5], the hyperpolarization-activated and cyclic-nucleotide gated c urrent[6], the ryanodine r eceptor[7], and the L-type Ca2+ current ( ICaL)[8]. We show that MR activation substantially increases contractility to a similar extent in both endo- and epicardial myocytes but modulates intracellular Ca2+ handling differently

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