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首页> 美国卫生研究院文献>American Journal of Physiology - Heart and Circulatory Physiology >Nonanticoagulant heparin reduces myocyte Na+ and Ca2+ loading during simulated ischemia and decreases reperfusion injury
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Nonanticoagulant heparin reduces myocyte Na+ and Ca2+ loading during simulated ischemia and decreases reperfusion injury

机译：非抗凝肝素可减少模拟缺血期间心肌细胞Na +和Ca2 +的负载并减少再灌注损伤

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Heparin desulfated at the 2-O and 3-O positions (ODSH) decreases canine myocardial reperfusion injury. We hypothesized that this occurs from effects on ion channels rather than solely from anti-inflammatory activities, as previously proposed. We studied closed-chest pigs with balloon left anterior descending coronary artery occlusion (75-min) and reperfusion (3-h). ODSH effects on [Na+]i (Na Green) and [Ca2+]i (Fluo-3) were measured by flow cytometry in rabbit ventricular myocytes after 45-min of simulated ischemia [metabolic inhibition with 2 mM cyanide, 0 glucose, 37°C, pacing at 0.5 Hz; i.e., pacing-metabolic inhibition (PMI)]. Na+/Ca2+ exchange (NCX) activity and Na+ channel function were assessed by voltage clamping. ODSH (15 mg/kg) 5 min before reperfusion significantly decreased myocardial necrosis, but neutrophil influx into reperfused myocardium was not consistently reduced. ODSH (100 μg/ml) reduced [Na+]i and [Ca2+]i during PMI. The NCX inhibitor KB-R7943 (10 μM) or the late Na+ current (INa-L) inhibitor ranolazine (10 μM) reduced [Ca2+]i during PMI and prevented effects of ODSH on Ca2+ loading. ODSH also reduced the increase in Na+ loading in paced myocytes caused by 10 nM sea anemone toxin II, a selective activator of INa-L. ODSH directly stimulated NCX and reduced INa-L. These results suggest that in the intact heart ODSH reduces Na+ influx during early reperfusion, when INa-L is activated by a burst of reactive oxygen production. This reduces Na+ overload and thus Ca2+ influx via NCX. Stimulation of Ca2+ extrusion via NCX later after reperfusion may also reduce myocyte Ca2+ loading and decrease infarct size.
机译：肝素在2-O和3-O位置（ODSH）脱硫可减少犬心肌再灌注损伤。我们假设这是由于对离子通道的影响，而不是像先前提出的那样，仅是由于抗炎活性引起的。我们研究了球囊左冠状动脉前降支闭塞（75分钟）和再灌注（3小时）的闭胸猪。流式细胞术检测45-45 d后兔心室肌细胞ODSH对[Na + ] i（Na Green）和[Ca 2 ] i（Fluo-3）的影响。模拟缺血的分钟[用2 mM氰化物，0葡萄糖，37°C，0.5 Hz起搏代谢抑制；即起搏代谢抑制（PMI）]。 Na + / Ca 2 + 交换（NCX）活性和Na + 通道功能通过电压钳制进行评估。再灌注前5分钟的ODSH（15 mg / kg）明显减少了心肌坏死，但中性粒细胞向再灌注心肌的流入并没有持续减少。 ODSH（100μg/ ml）在PMI期间降低了[Na + ] i和[Ca 2 + ] i。 NCX抑制剂KB-R7943（10μM）或晚期Na + 电流（INa-L）抑制剂雷诺嗪（10μM）在PMI期间降低[Ca 2 + ] i并防止了ODSH对Ca 2 + 负载的影响。 ODSH还减少了由10 nM海葵毒素II（一种INa-L的选择性激活剂）引起的起搏心肌细胞中Na + 负荷的增加。 ODSH直接刺激NCX并降低INa-L。这些结果表明，在完整的心脏中，ODa减少了早期再灌注时的Na + 内流，当INa-L被活性氧产生的爆发激活时。这样可以减少Na + 的过载，从而减少Ca 2 + 通过NCX的流入。再灌注后通过NCX刺激Ca 2 + 的挤压也可能减少心肌细胞Ca 2 + 的负荷并减小梗塞面积。

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