异丙肾上腺素诱导的心肌病大鼠心肌细胞中内皮素-1的变力反应改变。
Altered inotropic response of endothelin-1 in cardiomyocytes from rats with isoproterenol-induced cardiomyopathy.
作者信息
Suzuki M, Ohte N, Wang Z M, Williams D L, Little W C, Cheng C P
机构信息
Cardiology Section, Wake Forest University School of Medicine, Winston-Salem, NC 27157-1045, USA.
出版信息
Cardiovasc Res. 1998 Sep;39(3):589-99. doi: 10.1016/s0008-6363(98)00166-7.
OBJECTIVE
The positive inotropic effect of endothelin-1 (ET-1) on normal myocardial contraction may be altered in pathological states. The purpose of this study was to assess the direct effect of ET-1 on cardiomyocyte performance and its cellular mechanism in congestive heart failure (CHF).
METHODS
We measured the plasma levels of ET-1 and compared the effects of ET-1 (10(-10)-10(-8) M) on contractile performance and the [Ca2+]i transient in the myocytes of left ventricles (LV) from 15 age-matched normal adult rats and 15 rats with isoproterenol (ISO)-induced CHF.
RESULTS
With CHF, the plasma levels of ET-1 (19.7 +/- 6.3 vs. 4.1 +/- 0.5 fmol/ml, p < 0.05) were markedly elevated. In normal myocytes, superfusion of ET-1 caused significant increases in the systolic amplitude (SA, 8-16%) and the peak velocity of shortening (dL/dtmax, 20-35%; p < 0.01) without causing a change in the peak [Ca2+]i transient. In contrast, in myocytes from CHF rats, ET-1 produced significant reductions in SA (9-13%) and in the velocity of relengthening, dR/dtmax (10-14%; p < 0.05). The myocytes' dR/dtmax also decreased by 8-10% (p < 0.05). These changes were associated with a significant decrease in the peak [Ca2+]i transient (20-23%, p < 0.01). These responses to ET-1 were abolished by the incubation of myocytes with an ETA receptor antagonist (BQ123) or a protein kinase C (PKC) inhibitor (H-7 or staurosporine).
CONCLUSION
ISO-induced CHF is associated with elevated plasma ET-1 and an altered cardiomyocyte response to ET-1. After CHF, ET-1 produces a direct depression of cardiomyocyte contractile performance that is associated with a significant decrease in the peak [Ca2+]i transient. These effects are likely to be mediated through ETA receptors and involve the PKC pathway.
目的
内皮素 -1（ET -1）对正常心肌收缩的正性肌力作用在病理状态下可能会改变。本研究的目的是评估ET -1对充血性心力衰竭（CHF）时心肌细胞功能及其细胞机制的直接影响。
方法
我们测量了ET -1的血浆水平，并比较了ET -1（10⁻¹⁰ - 10⁻⁸ M）对15只年龄匹配的正常成年大鼠和15只异丙肾上腺素（ISO）诱导的CHF大鼠左心室（LV）心肌细胞收缩性能和[Ca²⁺]i瞬变的影响。
结果
CHF时，ET -1的血浆水平显著升高（19.7 ± 6.3对4.1 ± 0.5 fmol/ml，p < 0.05）。在正常心肌细胞中，ET -1的灌注导致收缩幅度（SA，8 - 16%）和缩短峰值速度（dL/dtmax，20 - 35%；p < 0.01）显著增加，而[Ca²⁺]i瞬变峰值无变化。相反，在CHF大鼠的心肌细胞中，ET -1使SA显著降低（9 - 13%），再伸长速度dR/dtmax降低（10 - 14%；p < 0.05）。心肌细胞的dR/dtmax也降低了8 - 10%（p < 0.05）。这些变化与[Ca²⁺]i瞬变峰值显著降低（20 - 23%，p < 0.01）有关。用ETA受体拮抗剂（BQ123）或蛋白激酶C（PKC）抑制剂（H - 7或星形孢菌素）孵育心肌细胞可消除对ET -1的这些反应。
结论
ISO诱导的CHF与血浆ET -1升高和心肌细胞对ET -1的反应改变有关。CHF后，ET -1直接抑制心肌细胞收缩性能，这与[Ca²⁺]i瞬变峰值显著降低有关。这些作用可能通过ETA受体介导并涉及PKC途径。
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