Ebihara Y, Haist J V, Karmazyn M
Department of Pharmacology and Toxicology, University of Western Ontario, London, Canada.
J Mol Cell Cardiol. 1996 Feb;28(2):265-77. doi: 10.1006/jmcc.1996.0025.
Endothelin-1 (ET-1) has been demonstrated to produce numerous cardiac effects and increased production of the peptide has been shown in cardiac disease states. Although the cardiac effects of ET-1 have been examined extensively on its own, few studies have reported potential cross-talk between ET-1 with other endothelium-derived factors. We examined whether nitric oxide (NO) can modulate the effects of ET-1 on isolated rat hearts or ventricular myocytes. At 0.05 nM, ET-1 produced no effects on either systolic or diastolic function although a two-fold increase in left ventricular end-diastolic pressure (LVEDP) was observed in hearts pretreated with 10 microM of the NO synthase inhibitor L-NAME. Higher concentrations of ET-1 (0.5 and 5 nM) produced a direct elevation in LVEDP which was enhanced by L-NAME and totally blocked by the NO donor S-nitrosoacetylpenicillamine (SNAP, 10 microM) although responses to 5 nM ET-1 were highly variable with no significant differences between treatment groups. SNAP totally prevented ventricular fibrillation produced by either 0.05 or 0.5 nM ET-1 whereas the pro-fibrillatory actions of 5 nM ET-1 were unaffected. In cardiac myocytes, SNAP significantly attenuated the elevation in intracellular Ca2+ produced by ET-1 (5 nM). The positive inotropic actions of ET-1 on either hearts or myocytes were unaffected by any treatment. The protective effect of SNAP against ET-1 in both isolated hearts (reduction in LVEDP and incidence of fibrillation) as well as ventricular myocytes (attenuation of the elevation in intracellular Ca2+) was mimicked by 8-bromo-cyclic GMP (50 microM). Our study suggests that NO protects against the cardiotoxic effects of ET-1, possibly via inhibition of intracellular Ca2+ elevations, a property shared by cGMP, the likely mediator of the biological effects of NO.
内皮素 -1（ET-1）已被证明会产生多种心脏效应，并且在心脏疾病状态下该肽的产生会增加。尽管已对ET-1自身的心脏效应进行了广泛研究，但很少有研究报道ET-1与其他内皮衍生因子之间可能存在的相互作用。我们研究了一氧化氮（NO）是否能调节ET-1对离体大鼠心脏或心室肌细胞的作用。在0.05 nM时，ET-1对收缩或舒张功能均无影响，尽管在用10 microM的一氧化氮合酶抑制剂L-NAME预处理的心脏中观察到左心室舒张末期压力（LVEDP）增加了两倍。更高浓度的ET-1（0.5和5 nM）导致LVEDP直接升高，L-NAME可增强这种升高，而NO供体S-亚硝基乙酰青霉胺（SNAP，10 microM）可完全阻断，尽管对5 nM ET-1的反应高度可变，各治疗组之间无显著差异。SNAP完全预防了由0.05或0.5 nM ET-1引起的心室颤动，而5 nM ET-1的促颤动作用不受影响。在心肌细胞中，SNAP显著减弱了ET-1（5 nM）引起的细胞内Ca2+升高。ET-1对心脏或心肌细胞的正性肌力作用不受任何处理的影响。8-溴环鸟苷酸（50 microM）模拟了SNAP对离体心脏（降低LVEDP和颤动发生率）以及心室肌细胞（减弱细胞内Ca2+升高）中ET-1的保护作用。我们的研究表明，NO可能通过抑制细胞内Ca2+升高来保护心脏免受ET-1的心脏毒性作用，这是环鸟苷酸（cGMP）所共有的特性，cGMP可能是NO生物学效应的介质。
