Mechanisms of L-type Ca2+ current downregulation in rat atrial myocytes during heart failure
Mechanisms of L-type Ca2+ current downregulation in rat atrial myocytes during heart failure
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DOI：
10.1161/hh1901.096702
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发表时间：
2001-09-28
影响因子：
20.1
通讯作者：
Hatem, SN
中科院分区：
文献类型：
--
作者：
Boixel, C;Gonzalez, W;Hatem, SN
L型钙电流(IC1)下调是病变心房电重构的重要决定因素。采用大鼠缺血性心脏病心力衰竭(HF)模型，采用全细胞膜片钳技术和生化分析方法，研究了大鼠左心房肌细胞内ICa的变化。ICa密度(1.7+/-0.1pA/pF)明显低于假手术组(S)(4.1+/-0.2pA/pF)，但其门控特性无明显变化。钙通道α(1C)亚单位的数量在S组和心力衰竭组无显著差异。β-肾上腺素能激动剂异丙肾上腺素(1mU/L)对心力衰竭细胞内钙的刺激作用远大于S(2.5倍对1倍)，从而抑制电流密度的差异。用100Mol/L cAMP透析细胞或用磷酸酶抑制剂冈田酸预处理细胞，也能增加细胞内钙离子浓度，抑制S与HF的密度差异。磷酸二酯酶抑制剂3-异丁基-1-甲基黄嘌呤对IC的影响在HF组比S组大(76.0+/-11.2%比15.8+/-21.2%)，而心钠素对IC的抑制作用在S组比HF组更明显(54.1+/-4.8%比24.3+/-8.8%)。心衰心肌细胞分泌的cGMP高于S(55.8+/-8.0和6.2+/-4.0pmol)。Ml(-1))。因此，心力衰竭大鼠心房肌细胞Ica的下调是由基础cAMP依赖的电流调节改变引起的，并与对儿茶酚胺的反应增加有关。
Downregulation of the L-type Ca2+ current (Ic,) is an important determinant of the electrical remodeling of diseased atria. Using a rat model of heart failure (HF) due to ischemic cardiopathy, we studied Ic, in isolated left atrial myocytes with the whole-cell patch-clamp technique and biochemical assays. Ica density was markedly reduced (1.7 +/- 0.1 pA/pF) compared with sham-operated rats (S) (4.1 +/- 0.2 pA/pF), but its gating properties were unchanged. Calcium channel alpha (1C)-subunit quantities were not significantly different between S and HF. The beta -adrenergic agonist isoproterenol (1 mu mol/L) had far greater stimulatory effects on I-Ca in HF than in S (2.5- versus I-fold), thereby suppressing the difference in current density. Dialyzing cells with 100 mu mol/L cAMP or pretreating them with the phosphatase inhibitor okadaic acid also increased I-Ca and suppressed the difference in density between S and HF. Intracellular cAMP content was reduced more in HF than in S. The phosphodiesterase inhibitor 3-isobutyl-1-methyl-xanthine had a greater effect on Ic, in HF than in S (76.0 +/- 11.2% versus 15.8 +/- 21.2%), whereas the inhibitory effect of atrial natriuretic peptide on Ic, was more important in S than in HF (54.1 +/- 4.8% versus 24.3 +/- 8.8%). Cyclic GMP extruded from HF myocytes was enhanced compared with S (55.8 +/- 8.0 versus 6.2 +/- 4.0 pmol . mL(-1)). Thus, Ica downregulation in atrial myocytes from rats with heart failure is caused by changes in basal cAMP-dependent regulation of the current and is associated with increased response to catecholamines.