Castellá Manuel, Buckberg Gerald D, Tan Zhongtuo, Ignarro Louis J
Department of Surgery, Division of Cardiothoracic Surgery, and the Department of Physiology, University of California, Los Angeles, School of Medicine, Los Angeles, CA 90095-1701, USA.
J Thorac Cardiovasc Surg. 2002 Dec;124(6):1113-21. doi: 10.1067/mtc.2002.125485.
The preconditioning effects of the adjunctive, cardiac-specific sodium-hydrogen ion exchange inhibitor cariporide (cariporide mesilate, HOE 642) were studied in hearts subjected to 30 minutes of normothermic ischemia and reperfusion to assess myocardial and endothelial changes.
Sixteen Yorkshire-Duroc pigs (27-34 kg) receiving cardiopulmonary bypass underwent either cardiopulmonary bypass alone (control, n = 4) or 30 minutes of normothermic ischemia, followed by 30 minutes of blood reperfusion (n = 12). Six hearts were treated with 5 mg/kg cariporide administered intravenously 15 minutes before ischemia.
Cardiopulmonary bypass alone caused no changes. Conversely, 30 minutes of global normothermic ischemia caused 33% mortality and, in survivors, depression of left ventricular function to 22% +/- 6% of baseline preload recruitable stroke work and increased creatine kinase MB by 406% (88 +/- 13 U/L), conjugated dienes by 17% (161 +/- 0.2 AU/mL), and myeloperoxidase activity by 297% (0.036 +/- 0.005 U/g). Myocardial edema developed (3.5% water gain). Coronary sinus endothelin 1 increased by 111% (2.05 +/- 0.38 pg/mL), and nitric oxide production decreased by 10%. These adverse effects were limited by pretreatment with cariporide, which allowed complete survival and restored preload recruitable stroke work to 78% +/- 11%. Measurements of creatine kinase MB, conjugated dienes, myeloperoxidase, water, and endothelin 1 returned to baseline values, and nitric oxide production was accentuated 3-fold.
These observations show that adjunctive pretreatment with cariporide delays myocardial and endothelial injury during ischemia and reperfusion, limits oxygen-derived radical injury, restores function, reduces edema, and preserves endothelin and nitric oxide balance at normal values. The myeloperoxidase changes show that less white blood cell adherence supports reduced reperfusion endothelial damage.
研究辅助性心脏特异性钠氢交换抑制剂卡里波罗（甲磺酸盐卡里波罗，HOE 642）在经历30分钟常温缺血和再灌注的心脏中的预处理作用，以评估心肌和内皮变化。
16只接受体外循环的约克夏-杜洛克猪（27 - 34千克），要么仅接受体外循环（对照组，n = 4），要么经历30分钟常温缺血，随后进行30分钟血液再灌注（n = 12）。6只心脏在缺血前15分钟静脉注射5毫克/千克卡里波罗进行治疗。
仅体外循环未引起变化。相反，30分钟的整体常温缺血导致33%的死亡率，在存活者中，左心室功能降至基线预负荷可募集搏功的22%±6%，肌酸激酶MB增加406%（88±13 U/L），共轭二烯增加17%（161±0.2 AU/mL），髓过氧化物酶活性增加297%（0.036±0.005 U/g）。出现心肌水肿（水分增加3.5%）。冠状窦内皮素1增加111%（2.05±0.38 pg/mL），一氧化氮生成减少10%。卡里波罗预处理限制了这些不良反应，使动物完全存活，并将预负荷可募集搏功恢复至78%±11%。肌酸激酶MB、共轭二烯、髓过氧化物酶、水分和内皮素1的测量值恢复至基线值，一氧化氮生成增强3倍。
这些观察结果表明，卡里波罗辅助预处理可延迟缺血和再灌注期间的心肌和内皮损伤，限制氧自由基损伤，恢复功能，减轻水肿，并使内皮素和一氧化氮平衡维持在正常水平。髓过氧化物酶的变化表明白细胞黏附减少有助于减轻再灌注内皮损伤。
