用HOE642抑制Na(+)/H(+)交换可改善缺血后恢复，这是由于其减轻了再灌注时的Ca(2+)超载并延长了酸中毒时间。

Na(+)/H(+) exchange inhibition with HOE642 improves postischemic recovery due to attenuation of Ca(2+) overload and prolonged acidosis on reperfusion.

作者信息

Strömer H, de Groot M C, Horn M, Faul C, Leupold A, Morgan J P, Scholz W, Neubauer S

机构信息

Medizinische Universitätsklinik, Würzburg, Germany.

出版信息

Circulation. 2000 Jun 13;101(23):2749-55. doi: 10.1161/01.cir.101.23.2749.

DOI:10.1161/01.cir.101.23.2749

PMID:10851214

Abstract

BACKGROUND

Na(+)/H(+) exchange inhibition with HOE642 (cariporide) improves postischemic recovery of cardiac function, but the mechanisms of action remain speculative. Because Na(+)/H(+) exchange is activated on reperfusion, it was hypothesized that its inhibition delays realkalinization and decreases intracellular Na(+) and, via Na(+)/Ca(2+) exchange, Ca(2+) overload. Attenuated Ca(2+) overload and prolonged acidosis are known to be cardioprotective.

METHODS AND RESULTS

Left ventricular developed and end-diastolic pressures were measured in isolated buffer-perfused rat hearts subjected to 30 minutes of no-flow ischemia and 30 minutes of reperfusion (37 degrees C) with or without 1 micromol/L HOE642 added to the perfusate 15 minutes before ischemia. Intracellular Ca(2+) concentration (Ca(2+)) and pH(i) were measured with aequorin (n=10 per group) and (31)P NMR spectroscopy (n=6 per group), respectively. HOE642 did not affect preischemic mechanical function, Ca(2+), or pH(i). Mechanical recovery after 30 minutes of reperfusion was substantially improved with HOE642: left ventricular developed pressure (in percent of preischemic values) was 92+/-3 versus 49+/-7 and left ventricular end-diastolic pressure was 16+/-3 versus 46+/-5 mm Hg (P<0.05 for HOE642-treated versus untreated hearts). End-ischemic Ca(2+) was significantly lower in HOE642-treated than in untreated hearts (1.04+/-0.06 versus 1.84+/-0. 02 micromol/L, P<0.05). Maximal intracellular Ca(2+) overload during the first 60 seconds of reperfusion was attenuated with HOE642 compared with untreated hearts: 2.0+/-0.3 versus 3.2+/-0.3 micromol/L (P<0.05). pH(i) was not different at end ischemia ( approximately 5.9+/-0.05). Realkalinization was similar in the first 90 seconds of reperfusion and significantly delayed in the next 3 minutes (eg, 6.8+/-0.07 in HOE642-treated hearts compared with 7. 2+/-0.07 in untreated hearts; P<0.05).

CONCLUSIONS

HOE642 improves postischemic recovery by reducing Ca(2+) overload during ischemia and early reperfusion and by prolonging postischemic acidosis.

摘要

背景

HOE642（卡里波罗德）抑制钠氢交换可改善心脏功能的缺血后恢复，但作用机制仍属推测。由于钠氢交换在再灌注时被激活，因此推测其抑制作用会延迟再碱化并降低细胞内钠浓度，进而通过钠钙交换减少钙超载。已知减轻钙超载和延长酸中毒具有心脏保护作用。

方法与结果

在离体缓冲液灌注的大鼠心脏中测量左心室舒张末压和左心室发展压，这些心脏经历30分钟无血流缺血和30分钟再灌注（37℃），在缺血前15分钟向灌注液中添加或不添加1微摩尔/升HOE642。分别用发光蛋白（每组n = 10）和磷-31核磁共振波谱法（每组n = 6）测量细胞内钙浓度（[Ca²⁺]i）和pH值（pH(i)）。HOE642不影响缺血前的机械功能、[Ca²⁺]i或pH(i)。HOE642可显著改善再灌注30分钟后的机械恢复：左心室发展压（占缺血前值的百分比）为92±3，而未处理组为49±7；左心室舒张末压为16±3，而未处理组为46±5毫米汞柱（HOE642处理组与未处理组心脏相比，P<0.05）。HOE642处理组心脏缺血末期的[Ca²⁺]i显著低于未处理组（1.04±0.06对1.84±0.02微摩尔/升，P<0.05）。与未处理组心脏相比，HOE642可减轻再灌注最初60秒内的最大细胞内钙超载：2.0±0.3对3.2±0.3微摩尔/升（P<0.05）。缺血末期pH(i)无差异（约5.9±0.05）。再灌注最初90秒内的再碱化情况相似，而在接下来的3分钟内显著延迟（例如，HOE642处理组心脏为6.8±0.07，未处理组心脏为7.2±0.07；P<0.05）。