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The aim of the present study was to investigate the role of calcineurin in the down-regulation of left ventricular transmural voltage-dependent K(+) currents in heart failure. Transverse aorta was banded by using microsurgical techniques to create mouse heart failure model. Sham-operated (Sham) or aorta banded (Band) mice were randomized to receive calcineurin inhibitor cyclosporine A (CsA) or vehicle. The densities and kinetic properties of voltage-dependent K(+) currents, as well as action potential (AP), of left ventricular subendocardial (Endo) and subepicardial (Epi) myocytes were determined by using whole-cell patch-clamp technique. The results showed that calcineurin activity was significant higher in Endo myocytes than that in Epi ones in all the groups. Compared with Sham group, Band mice showed significantly increased calcineurin activity both in Endo and Epi myocytes. CsA significantly reduced calcineurin activity in Band mice. CsA treatment in Band mice partially reversed the down-regulation of Ito density, completely reversed the down-regulation of IK,slow density both in Endo and Epi myocytes, and Iss density in Endo myocytes. In addition, CsA treatment in Band mice partially antagonized the prolongation of action potential duration (APD), and APD at 50% (APD50) and 90% repolarization (APD90) were significantly reduced. Because of non-parallel shortening of APD in Endo and Epi myocytes, the ratio of Endo/Epi APD90 was reduced from 4.8:1 in Band mice to 2.6:1 in CsA-treated mice, which was close to that in Sham mice. The results suggest that non-parallel activation of calcineurin in Endo and Epi myocytes contributes to the down-regulation of transmural voltage-dependent K(+) currents and the amplification of transmural dispersion of repolarization (TDR) in left ventricular failure hearts. Inhibition of calcineurin may be a potential new therapeutic strategy to prevent and cure arrhythmias and sudden death in heart failure.

Transmural electrical heterogeneity plays an important role in the normal dispersion of repolarizaion and propagation of excitation in the heart. The amplification of transmural electrical heterogeneity contributes to the genesis of arrhythmias in cardiac hypertrophy and failure. We established a mouse model with cardiac failure by aortic banding and investigated the possible contribution of L-type calcium current (I(Ca-L)) to transmural electrical heterogeneity in both normal and failing hearts. Single myocytes were enzymatically isolated from subendocardial and subepicardial myocardium of the free left ventricle wall. The recordings of action potential and I(Ca-L) were performed using the conventional whole-cell patch-clamp technique. The results showed that: (1) The action potential duration at 90% repolarization (APD(90)) of the subendocardial myocytes in normal control mice was (38.2 +/- 6.44) ms, which was significantly longer than that of the subepicardial myocytes [(15.672 +/- 5.31) ms]. The ratio of APD(90) for subendocardial/subepicardial myocytes was about 2.5:1. The peak I(Ca-L) density in subendocardial myocytes was (-2.7 +/- 0.49) pA/pF, which was not different from that in subepicardial myocytes [(-2.54 +/- 0.53) pA/pF]. (2) In failing hearts, both action potential duration at 50% repolarization (APD(50)) and APD(90) were remarkably prolonged either in subendocardial or subepicardial myocytes compared to that in sham hearts. The subendocardial myocytes had much longer APD. The ratio of APD(90) for subendocardial/subepicardial myocytes changed to about 4.2:1. (3) I(Ca-L) density in subendocardial myocytes was significantly decreased in failing hearts compared with that in sham hearts. At four test potentials from +10 mV to +40 mV, the density of I(Ca-L) from subendocardial myocytes in failing hearts was decreased by 20.2%, 21.4%, 21.6% and 25.7%, respectively (P<0.01). However, no significant difference was observed in I(Ca-L) density from subepicardial myocytes in failing hearts. There was no significant difference in the kinetic properties of I(Ca-L) in subendocardial and subepicardial myocytes between the band and sham groups. We conclude that I(Ca-L) may not contribute to the physiological transmural electrical heterogeneity in mouse hearts. The electrical heterogeneity is exaggerated and the density of I(Ca-L) is decreased in the subendocardial myocytes, but not in the subepicardial myocytes in failing hearts. The results obtained suggest that the decreased density of I(Ca-L) in subendocardial myocytes is possibly an adaptive response to the prolongation of action potential due to delayed depolarization and may reduce the transmural dispersion of repolarization in heart failure.