Pisarenko O I, Serebriakova L I, Tskitishvili O V, Studneva I M, Timoshin A A
Cardiology Research Complex, ul. Tretiya Cherepkovskaya 15a, 121552 Moscow, Russia.
Kardiologiia. 2003;43(12):65-70.
The aim of this work was to study cardioprotective effects of BIIB 722, a novel Na(+)/H(+) exchanger-1 inhibitor, during regional ischemia and reperfusion in canine myocardium. The experiments were carried out on anaesthetized dogs intubated and artificially ventilated with room air enriched with oxygen. Regional ischemia was induced by 30-min occlusion of a diagonal branch of left anterior descending coronary artery (LAD), which was followed by 60-min reperfusion. BIIB 722, dissolved in 280 mM xylitol, was infused intracoronary for 10 min prior to LAD occlusion and at the beginning of reperfusion at the rate of 1 ml/min (30 microg/g myocardial tissue). In the control group, 280 mM xylitol was used for intracoronary administration with the same regimen. Microdialysis probes were implanted in the region of LAD occlusion to monitor interstitial pH, inorganic phosphate (Pi) and hydroxyl radical adduct. Energy state of the area at risk was evaluated by ATP and phosphocreatine (PCr) contents, cell membrane damage was assessed by total creatine (SigmaCr=PCr+Cr) tissue content. Myocardial infarct size was determined by staining with Evans Blue dye and further incubation of left ventricular slices in 2,3,5-triphenyltetrazolium chloride. The percentage ratio of infarct size to area at risk was calculated by computer planimetry. BIIB 722 administration had no effect on cardiac hemodynamics and acid-base indices of arterial blood throughout the experiments but induced 1.8-fold reduction of myocardial infarct size comparing with control. Treatment with BIIB 722 decreased acidification of the interstitial fluid following ischemia and facilitated recovery of pH to initial value on reperfusion. This effect was combined with significantly less Pi formation in the area at risk during LAD occlusion and reduction of this index to the initial value during reperfusion. At the end of reperfusion, the treated group showed augmented recovery of ATP and PCr tissue levels and higher content of SigmaCr comparing with the control. Additionally, BIIB 722 treatment markedly decreased generation of free oxygen radicals following LAD occlusion and completely avoided their formation on early reperfusion. The results indicate that BIIB 722 ability to limit myocardial infarct size in dogs is tightly connected with its influence on energy metabolism and oxygen radical generation.
本研究旨在探讨新型钠氢交换体-1抑制剂BIIB 722在犬心肌局部缺血及再灌注过程中的心脏保护作用。实验在麻醉、气管插管并使用富氧空气进行人工通气的犬身上进行。通过闭塞左前降支冠状动脉（LAD）的一条对角支30分钟诱导局部缺血，随后进行60分钟再灌注。在LAD闭塞前10分钟以及再灌注开始时，以1 ml/分钟（30微克/克心肌组织）的速率将溶解于280 mM木糖醇中的BIIB 722冠状动脉内输注。在对照组中，采用相同方案冠状动脉内给予280 mM木糖醇。在LAD闭塞区域植入微透析探针以监测细胞间pH值、无机磷酸盐（Pi）和羟自由基加合物。通过ATP和磷酸肌酸（PCr）含量评估危险区域的能量状态，通过总肌酸（SigmaCr = PCr + Cr）组织含量评估细胞膜损伤。用伊文思蓝染料染色并将左心室切片进一步在2,3,5-三苯基氯化四氮唑中孵育来测定心肌梗死面积。通过计算机图像分析计算梗死面积与危险区域面积的百分比。在整个实验过程中，给予BIIB 722对心脏血流动力学和动脉血酸碱指标无影响，但与对照组相比，可使心肌梗死面积减少1.8倍。BIIB 722治疗可减少缺血后细胞间液酸化，并促进再灌注时pH值恢复至初始值。该作用与LAD闭塞期间危险区域Pi生成显著减少以及再灌注期间该指标降至初始值相关。再灌注结束时，与对照组相比，治疗组显示ATP和PCr组织水平恢复增强，SigmaCr含量更高。此外，BIIB 722治疗显著减少LAD闭塞后游离氧自由基的生成，并完全避免早期再灌注时自由基的形成。结果表明，BIIB 722限制犬心肌梗死面积的能力与其对能量代谢和氧自由基生成的影响密切相关。
