[Effects of Na(+)/H(+)-exchanger inhibition on metabolism of area at risk and myocardial infarct size in dogs].

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.