Down-regulation of sodium current in chronic heart failure: effect of long-term therapy with carvedilol
Down-regulation of sodium current in chronic heart failure: effect of long-term therapy with carvedilol
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DOI：
10.1007/s00018-002-8529-0
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发表时间：
2002-09-01
影响因子：
8
通讯作者：
Undrovinas, AI
中科院分区：
文献类型：
--
作者：
Maltsev, VA;Sabbah, HN;Undrovinas, AI
最近有越来越多的证据表明，在梗死和衰竭的心脏中，Ne通道功能改变和心肌传导缓慢对心律失常的重要性。本研究验证了一个假设，即慢性心力衰竭（HF）患者Na+电流I-Na/C密度降低，而长期使用卡维地洛（一种α -和p -肾上腺素能阻断剂）治疗可以恢复Na+通道（NaCh）功能密度。研究使用犬慢性心衰模型进行，该模型是由连续的微球冠状动脉内栓塞引起的。HF在最后一次栓塞后约3个月发生（左心室，左室，射血分数= 28±1%）。酶法分离心室心肌细胞（VCs），用全细胞膜片钳法测定I-Na。与正常心脏（n = 12）相比，衰竭心脏（n = 19）的最大I-NA/C降低（33.1 +/- 1.6 vs 48.5 +/- 5.1 pA/pF，平均+/- SE， p < 0.001）。与正常心脏相比，衰竭时I-Na的稳态失活和激活保持不变。长期服用卡维地洛（1 mg/kg，每日2次，连续3个月）治疗HF犬（n = 6）的HE I-Na/C正常值高于未治疗HF犬（n = 6） （49.4 +/- 0.9 vs 29 +/- 4.8 pA/pF, p < 0.007）。衰竭心脏vc体外培养24 h不能恢复I-Na/C。然而，当vc与细胞内Ca2+缓冲剂BAPTA-AM孵育24小时后，I-Na/C部分恢复。因此，我们得出结论，实验性慢性HF犬导致NaCh功能密度下调，可通过卡维地洛长期治疗恢复。HF中NaCh下调的机制可能与该阶段疾病中Ca2+处理不良有关。
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.