An J, Varadarajan S G, Camara A, Chen Q, Novalija E, Gross G J, Stowe D F
Anesthesiology Research Laboratory, Department of Anesthesiology, The Medical College of Wisconsin, Milwaukee, 53226, USA.
Am J Physiol Heart Circ Physiol. 2001 Dec;281(6):H2398-409. doi: 10.1152/ajpheart.2001.281.6.H2398.
We determined in intact hearts whether inhibition of Na(+)/H(+) exchange (NHE) decreases intracellular Na(+) and Ca(2+) during ischemia and reperfusion, improves function during reperfusion, and reduces infarct size. Guinea pig isolated hearts were perfused with Krebs-Ringer solution at 37 degrees C. Left ventricular (LV) free wall intracellular Na(+) concentration (Na(+)) and intracellular Ca(2+) concentration (Ca(2+)) were measured using fluorescence dyes. Hearts were exposed to 30 min of ischemia with or without 10 microM of benzamide (BIIB-513), a selective NHE-1 inhibitor, infused for 10 min just before ischemia or for 10 min immediately on reperfusion. At 2 min of reperfusion, BIIB-513 given before ischemia decreased peak increases in Na(+) and Ca(2+), respectively, from 2.5 and 2.3 times (controls) to 1.6 and 1.3 times pre-ischemia values. At 30 min of reperfusion, BIIB-513 increased systolic-diastolic LV pressure (LVP) from 49 +/- 2% (controls) to 80 +/- 2% of pre-ischemia values. BIIB-513 reduced ventricular fibrillation by 54% and reduced infarct size from 64 +/- 1% to 20 +/- 3%. First derivative of the LVP, O(2) consumption, and cardiac efficiency were also improved by BIIB-513. Similar results were obtained with BIIB-513 given on reperfusion. These data show that Na(+) loading is a marker of reperfusion injury in intact hearts in that inhibiting NHE reduces Na(+) and Ca(2+) loading during reperfusion while improving function. These results clearly implicate the ionic basis by which inhibiting NHE protects the guinea pig intact heart from ischemia-reperfusion injury.
我们在完整心脏中确定，抑制钠/氢交换（NHE）是否会在缺血和再灌注期间降低细胞内钠和钙水平，改善再灌注期间的功能，并减小梗死面积。将豚鼠离体心脏在37℃下用 Krebs-Ringer 溶液灌注。使用荧光染料测量左心室（LV）游离壁细胞内钠浓度（[Na⁺]i）和细胞内钙浓度（[Ca²⁺]i）。心脏经历30分钟的缺血，在缺血前10分钟或再灌注即刻输注10分钟的10微摩尔苯甲酰胺（BIIB-513，一种选择性NHE-1抑制剂），或不进行该处理。在再灌注2分钟时，缺血前给予BIIB-513分别使[Na⁺]i和[Ca²⁺]i的峰值增加从2.5倍和2.3倍（对照组）降至缺血前值的1.6倍和1.3倍。在再灌注30分钟时，BIIB-513使左心室收缩-舒张压力（LVP）从49±2%（对照组）增加至缺血前值的80±2%。BIIB-513使心室颤动减少54%，并使梗死面积从64±1%减小至20±3%。LVP的一阶导数、耗氧量和心脏效率也因BIIB-513而得到改善。再灌注时给予BIIB-513也得到了类似结果。这些数据表明，钠负荷是完整心脏再灌注损伤的一个标志物，因为抑制NHE可在再灌注期间减少钠和钙负荷，同时改善功能。这些结果清楚地表明了抑制NHE保护豚鼠完整心脏免受缺血-再灌注损伤的离子基础。
