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

Evidence has accumulated recently about the importance of alterations in Ne 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 alpha- and P-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 HE INa/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 longterm therapy with carvedilol. The mechanism of NaCh down-regulation in HF may be linked to poor Ca2+ handling in this stage of disease.