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Reduced Na? current density underlies impaired propagation in the diabetic rabbit ventricle.

ABSTRACT: Diabetes is associated with an increased risk of sudden cardiac death, but the underlying mechanisms remain unclear. Our goal was to investigate changes occurring in the action potential duration (APD) and conduction velocity (CV) in the diabetic rabbit ventricle, and delineate the principal ionic determinants. A rabbit model of alloxan-induced diabetes was utilized. Optical imaging was used to record electrical activity in isolated Langendorff-perfused hearts in normo-, hypo- and hyper-kalemia ([K(+)]o=4, 2, 12 mM respectively). Patch clamp experiments were conducted to record Na(+) current (I(Na)) in isolated ventricular myocytes. The mRNA/protein expression levels for Nav1.5 (the ?-subunit of I(Na)) and connexin-43 (Cx43), as well as fibrosis levels were examined. Computer simulations were performed to interpret experimental data. We found that the APD was not different, but the CV was significantly reduced in diabetic hearts in normo-, hypo-, and, hyper-kalemic conditions (13%, 17% and 33% reduction in diabetic vs. control, respectively). The cell capacitance (Cm) was increased (by ~14%), and the density of INa was reduced by ~32% in diabetic compared to control hearts, but the other biophysical properties of I(Na) were unaltered. The mRNA/protein expression levels for Cx43 were unaltered. For Nav1.5, the mRNA expression was not changed, and though the protein level tended to be less in diabetic hearts, this reduction was not statistically significant. Staining showed no difference in fibrosis levels between the control and diabetic ventricles. Computer simulations showed that the reduced magnitude of I(Na) was a key determinant of impaired propagation in the diabetic ventricle, which may have important implications for arrhythmogenesis.

SUBMITTER: Stables CL

PROVIDER: S-EPMC4066653 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

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Reduced Na⁺ current density underlies impaired propagation in the diabetic rabbit ventricle.

Stables Catherine L CL Musa Hassan H Mitra Aditi A Bhushal Sandesh S Deo Makarand M Guerrero-Serna Guadalupe G Mironov Sergey S Zarzoso Manuel M Vikstrom Karen L KL Cawthorn William W Pandit Sandeep V SV

Journal of molecular and cellular cardiology 20140109

Diabetes is associated with an increased risk of sudden cardiac death, but the underlying mechanisms remain unclear. Our goal was to investigate changes occurring in the action potential duration (APD) and conduction velocity (CV) in the diabetic rabbit ventricle, and delineate the principal ionic determinants. A rabbit model of alloxan-induced diabetes was utilized. Optical imaging was used to record electrical activity in isolated Langendorff-perfused hearts in normo-, hypo- and hyper-kalemia ...[more]

PMID: 24412579

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Project description:BackgroundEarly afterdepolarizations (EADs) are triggers of cardiac arrhythmia driven by L-type Ca(2+) current (ICaL) reactivation or sarcoplasmic reticulum Ca(2+) release and Na(+)/Ca(2+) exchange. In large mammals the positive action potential plateau promotes ICaL reactivation, and the current paradigm holds that cardiac EAD dynamics are dominated by interaction between ICaL and the repolarizing K(+) currents. However, EADs are also frequent in the rapidly repolarizing mouse action potential, which should not readily permit ICaL reactivation. This suggests that murine EADs exhibit unique dynamics, which are key for interpreting arrhythmia mechanisms in this ubiquitous model organism. We investigated these dynamics in myocytes from arrhythmia-susceptible calcium calmodulin-dependent protein kinase II delta C (CaMKIIδC)-overexpressing mice (Tg), and via computational simulations.Methods and resultsIn Tg myocytes, β-adrenergic challenge slowed late repolarization, potentiated sarcoplasmic reticulum Ca(2+) release, and initiated EADs below the ICaL activation range (-47 ± 0.7 mV). These EADs were abolished by caffeine and tetrodotoxin (but not ranolazine), suggesting that sarcoplasmic reticulum Ca(2+) release and Na(+) current (INa), but not late INa, are required for EAD initiation. Simulations suggest that potentiated sarcoplasmic reticulum Ca(2+) release and Na(+)/Ca(2+) exchange shape late action potential repolarization to favor nonequilibrium reactivation of INa and thereby drive the EAD upstroke. Action potential clamp experiments suggest that lidocaine eliminates virtually all inward current elicited by EADs, and that this effect occurs at concentrations (40-60 μmol/L) for which lidocaine remains specific for inactivated Na(+) channels. This strongly suggests that previously inactive channels are recruited during the EAD upstroke, and that nonequilibrium INa dynamics underlie murine EADs.ConclusionsNonequilibrium reactivation of INa drives murine EADs.

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Reduced Na? current density underlies impaired propagation in the diabetic rabbit ventricle.

Publications

Reduced Na⁺ current density underlies impaired propagation in the diabetic rabbit ventricle.

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