Down-regulation of sodium current in chronic heart failure: effect of long-term therapy with carvedilol
| Autor: | Victor A. Maltsev, Albertas I. Undrovinas, Hani N. Sabbah |
|---|---|
| Rok vydání: | 2002 |
| Předmět: |
Cardiac output
medicine.medical_specialty Patch-Clamp Techniques Adrenergic beta-Antagonists Carbazoles Cardiac Output Low Down-Regulation Sodium Channels Propanolamines Cellular and Molecular Neuroscience Dogs Internal medicine Animals Medicine Patch clamp Molecular Biology Carvedilol Adrenergic alpha-Antagonists Pharmacology Calcium metabolism Ejection fraction business.industry Myocardium Sodium channel Cell Biology medicine.disease medicine.anatomical_structure Ventricle Heart failure Chronic Disease Cardiology Molecular Medicine Calcium business medicine.drug |
| Zdroj: | Cellular and Molecular Life Sciences (CMLS). 59:1561-1568 |
| ISSN: | 1420-9071 1420-682X |
| DOI: | 10.1007/s00018-002-8529-0 |
| Popis: | 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 (INa/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 beta-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 INa was measured by whole-cell patch-clamp. The maximum INa/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, p0.001). The steady-state inactivation and activation of INa remained unchanged in failing compared to normal hearts. Long-term treatment with carvedilol (1 mg/kg, twice daily for 3 months) normalized INa/C in dogs with HF. 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, p0.007). In vitro culture of VCs of failing hearts for 24 h did not restore INa/C. However, INa/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. |
| Databáze: | OpenAIRE |
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