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首页> 外文期刊>American Journal of 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肌细胞Na +和Ca2 +的负载，并减少再灌注损伤。

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摘要

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 [Ca(2+)](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 degrees C, pacing at 0.5 Hz; i.e., pacing-metabolic inhibition (PMI)]. Na(+)/Ca(2+) 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 microg/ml) reduced [Na(+)](i) and [Ca(2+)](i) during PMI. The NCX inhibitor KB-R7943 (10 microM) or the late Na(+) current (I(Na-L)) inhibitor ranolazine (10 microM) reduced [Ca(2+)](i) during PMI and prevented effects of ODSH on Ca(2+) loading. ODSH also reduced the increase in Na(+) loading in paced myocytes caused by 10 nM sea anemone toxin II, a selective activator of I(Na-L). ODSH directly stimulated NCX and reduced I(Na-L). These results suggest that in the intact heart ODSH reduces Na(+) influx during early reperfusion, when I(Na-L) is activated by a burst of reactive oxygen production. This reduces Na(+) overload and thus Ca(2+) influx via NCX. Stimulation of Ca(2+) extrusion via NCX later after reperfusion may also reduce myocyte Ca(2+) 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由抗炎活性引起的。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。在模拟缺血45分钟后，通过流式细胞术测量了ODSH对[Na（+）]（i）（Na Green）和[Ca（2 +）]（i）（Fluo-3）的作用。用2 mM氰化物，0葡萄糖，37摄氏度，0.5 Hz起搏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未持续减少。 ODSH（100微克/毫升）在PMI期间降低了[Na（+）]（i）和[Ca（2 +）]（i）。 NCX抑制剂KB-R7943（10 microM）或晚期Na（+）电流（I（Na-L））抑制剂雷诺嗪（10 microM）降低PMI期间的[Ca（2 +）]（i）并防止ODSH的作用在Ca（2+）负载上。 ODSH还减少了由10 nM海葵毒素II（I（Na-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I（Na-L）。这些结果表明，在完好的心脏中，ODSH会在早期再灌注过程中减少I（Na-L）被活性氧产生的激增激活而减少Na（+）流入。这样可以减少Na（+）过载，从而减少Ca（2+）通过NCX流入。再灌注后稍后通过NCX刺激Ca（2+）挤出也可能减少心肌细胞Ca（2+）的负载并减小梗塞面积。

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