Down-regulation of sodium current in chronic heart failure: effect of long-term therapy with carvedilol

Abstract.

Evidence has accumulated recently about the importance of alterations in Na⁺ channel function and slow myocardial conduction for arrhythmias in the infarcted and failing heart. The present study tested a hypothesis that Na⁺ current (I_Na/C) density decreases in chronic heart failure (HF) and that Na⁺ channel (NaCh) functional density can be restored by long-term therapy with carvedilol, a mixed α- and β-adrenergic blocker. Studies were performed using a canine model of chronic HF produced in dogs by sequential intracoronary embolizations with microspheres. HF developed approximately 3 months after the last embolization (left ventricle, LV, ejection fraction = 28 ± 1 %). Ventricular cardiomyocytes (VCs) were isolated enzymatically from LV mid-myocardium, and I_Na was measured by whole-cell patch-clamp. The maximum I_NA/C was decreased in failing (n = 19) compared to normal (n = 12) hearts (33.1 ± 1.6 vs 48.5 ± 5.1 pA/pF, mean ± SE, p < 0.001). The steady-state inactivation and activation of I_Na remained unchanged in failing compared to normal hearts. Long-term treatment with carvedilol (1 mg/kg, twice daily for 3 months) normalized I_Na/C in dogs with HF. I_Na/C in HF dogs (n = 6) treated with carvedilol was higher compared to that of non-treated HF dogs (n = 6) (49.4 ± 0.9 vs 29 ± 4.8 pA/pF, p < 0.007). In vitro culture of VCs of failing hearts for 24 h did not restore I_Na/C. However, I_Na/C was partially restored when VCs were incubated for 24 h with BAPTA-AM, an intracellular Ca²⁺ buffer. Thus, we conclude that experimental chronic HF in dogs results in down-regulation of the functional density of NaCh that can be restored by long-term therapy with carvedilol. The mechanism of NaCh down-regulation in HF may be linked to poor Ca²⁺ handling in this stage of disease.