Joyeux-Faure M, Ramond A, Béguin P C, Belaïdi E, Godin-Ribuot D, Ribuot C
Laboratoire HP2, Hypoxie Physio-Pathologie Respiratoire et Cardiovasculaire, Faculté de Médecine-Pharmacie, Université Grenoble I, France, INSERM ERI 0017, EA 3745, France.
Fundam Clin Pharmacol. 2006 Feb;20(1):51-6. doi: 10.1111/j.1472-8206.2005.00392.x.
Administration of recombinant human erythropoietin (rhEPO) is known to induce protection against cardiac ischaemia injury improving functional recovery and reducing apoptosis. But the underlying mechanisms are not elucidated. We determined the role of nitric oxide synthases (NOS) as well as ATP-dependent (K(ATP)) and calcium-activated (K(Ca)) potassium channels in the early cardioprotection induced by rhEPO. Wistar male rats were divided into two experimental groups treated by rhEPO (5,000 IU/kg, i.p.) or saline (control group). One hour later, rats were anaesthetized, hearts isolated, retrogradely perfused and submitted to a 30-min no-flow global ischaemia followed by 120 min of reperfusion sequence. Cardiac functional recovery (left ventricular developed pressure, LVDP) was significantly higher in the group treated by rhEPO (LVDP at 30 min reperfusion: 71.7 +/- 2.3 mmHg) compared with the control group (57.4 +/- 5.8 mmHg). We observed the same significant effect on its derivative (dP/dt). The rhEPO-induced improvement in ventricular function was abolished by perfusion prior to ischaemia with either N-nitro-l-arginine methyl ester (l-NAME, a nonspecific NOS inhibitor) or N-(3-(aminomethyl)benzyl)acetamidine (1,400W, a specific inducible NOS inhibitor) or 5-hydroxydecanoic acid (5HD, a mitochondrial K(ATP) channel blocker) but not with paxilline (a K(Ca) channel inhibitor). Thus, in vivo rhEPO administration provides early preconditioning against ischaemic injury in the isolated perfused rat heart that is dependent on iNOS and mitochondrial K(ATP) channels.
已知给予重组人促红细胞生成素（rhEPO）可诱导对心脏缺血损伤的保护作用，改善功能恢复并减少细胞凋亡。但其潜在机制尚未阐明。我们确定了一氧化氮合酶（NOS）以及ATP依赖性（K(ATP)）和钙激活（K(Ca)）钾通道在rhEPO诱导的早期心脏保护中的作用。将雄性Wistar大鼠分为两组，分别用rhEPO（5000 IU/kg，腹腔注射）或生理盐水（对照组）处理。1小时后，将大鼠麻醉，分离心脏，逆行灌注，并进行30分钟无血流的全心缺血，随后进行120分钟的再灌注程序。与对照组（57.4±5.8 mmHg）相比，rhEPO处理组的心脏功能恢复（左心室舒张末压，LVDP）明显更高（再灌注30分钟时的LVDP：71.7±2.3 mmHg）。我们在其导数（dP/dt）上观察到了相同的显著效果。在缺血前灌注N-硝基-L-精氨酸甲酯（L-NAME，一种非特异性NOS抑制剂）或N-（3-（氨基甲基）苄基）乙脒（1400W，一种特异性诱导型NOS抑制剂）或5-羟基癸酸（5HD，一种线粒体K(ATP)通道阻滞剂）可消除rhEPO诱导的心室功能改善，但用帕吉林（一种K(Ca)通道抑制剂）则不能。因此，体内给予rhEPO可在离体灌注大鼠心脏中提供针对缺血损伤的早期预处理，这依赖于诱导型NOS和线粒体K(ATP)通道。
