Satoh N, Suter T M, Liao R, Colucci W S
Cardiovascular Section, Boston University Medical Center, Myocardial Biology Unit and Cardiac Muscle Research Laboratory, Boston University School of Medicine, Boston, MA 02118, USA.
Circulation. 2000 Oct 31;102(18):2249-54. doi: 10.1161/01.cir.102.18.2249.
Heart failure is characterized by contractile dysfunction of the myocardium and elevated sympathetic activity. We tested the hypothesis that chronic alpha-adrenergic (alpha-ADR) stimulation modifies the molecular and contractile phenotype of cardiac myocytes.
Adult rat ventricular myocytes in culture were exposed to alpha-ADR stimulation (norepinephrine + propranolol) for 48 hours. alpha-ADR stimulation decreased the mRNAs for sarcoplasmic reticulum Ca(2+)-ATPase and Ca(2+) release channel by 56% and 52%, respectively, and increased mRNA and protein for the Na(+)-Ca(2+) exchanger by 70% and 39%, respectively. After washout of the alpha-ADR agonist, simultaneous measurement of Ca(2+) transients with fura 2 and myocyte shortening by video edge-detection showed that Ca(2+) amplitude and myocyte shortening were decreased in alpha-ADR-treated myocytes, and the time to peak and time from peak to 80% decline of both Ca(2+) and myocyte shortening were increased. The concentration-response curve for myocyte shortening by the Na(+) channel activator veratridine was shifted leftward in alpha-ADR-stimulated myocytes (EC(50), 21.6+/-4.6 versus 105.8+/-10.5 nmol/L, P:<0.001).
Chronic alpha-ADR stimulation of cardiac myocytes causes decreases in the expression of sarcoplasmic reticulum Ca(2+)-ATPase and the Ca(2+) release channel that are associated with decreases in Ca(2+) and contractility. alpha-ADR stimulation simultaneously increases Na(+)-Ca(2+) exchanger expression, thereby increasing sensitivity to intracellular Na(+).
心力衰竭的特征是心肌收缩功能障碍和交感神经活动增强。我们检验了慢性α-肾上腺素能（α-ADR）刺激改变心肌细胞分子和收缩表型这一假说。
培养的成年大鼠心室肌细胞暴露于α-ADR刺激（去甲肾上腺素+普萘洛尔）48小时。α-ADR刺激使肌浆网Ca(2+)-ATP酶和Ca(2+)释放通道的mRNA分别减少56%和52%，并使Na(+)-Ca(2+)交换体的mRNA和蛋白分别增加70%和39%。洗脱α-ADR激动剂后，用fura 2同步测量[Ca(2+)]i瞬变并通过视频边缘检测测量心肌细胞缩短，结果显示α-ADR处理的心肌细胞中[Ca(2+)]i幅度和心肌细胞缩短减少，[Ca(2+)]i和心肌细胞缩短从峰值到80%下降的时间均增加。Na(+)通道激活剂藜芦碱引起的心肌细胞缩短浓度-反应曲线在α-ADR刺激的心肌细胞中向左移位（半数有效浓度[EC(50)]，21.6±4.6对105.8±10.5 nmol/L，P<0.001）。
慢性α-ADR刺激心肌细胞导致肌浆网Ca(2+)-ATP酶和Ca(2+)释放通道表达减少，这与[Ca(2+)]i和收缩性降低有关。α-ADR刺激同时增加Na(+)-Ca(+)交换体表达，从而增加对细胞内Na(+)的敏感性。
