Aim of this study was to compare effects of
BIIB-722, a novel Na(+)/H(+) exchanger-1 inhibitor, and ischemic preconditioning (IP) on
infarct size and metabolism of area at risk in rats. Regional
ischemia was induced by 40-min occlusion of a diagonal branch of left anterior descending coronary artery (LAD); it was followed by 60-min reperfusion. Intravenous bolus injection of
BIIB-722 (3 mg/kg) dissolved in 280 mM
xylitol was performed before regional
ischemia or during the first minute of reperfusion. In the control group 280 mM
xylitol was infused before
ischemia or at the beginning of reperfusion at the same mode. IP was initiated by two cycles of 5-min LAD occlusion followed by 5-min reperfusion prior to sustained regional
ischemia. Microdialysis technique was used to monitor pH and
inorganic phosphate (P(i)) in the interstitial fluid of the area at risk. Metabolic state of the area at risk was assessed by
ATP,
phosphocreatine (PCr) and
lactate levels; cellular membrane damage was evaluated by total
creatine (SigmaCr=PCr+Cr) tissue content.
Myocardial infarct size was determined by computer planimetry after staining of left ventricular slices with
2,3,5-triphenyltetrazolium chloride.
BIIB-722 administration before or after
ischemia, as well as IP, had no effect on cardiac hemodynamics and
acid-base indices of arterial blood throughout the experiments. The
infarct size/area at risk ratio was 43.5+/-5.2% in control and was reduced to 11.4+/-3.1% with IP, and to 17.0+/-3.6% and 25.8+/-2.6% with
BIIB-722 infused on early reperfusion and before
ischemia, respectively.
BIIB-722 administration during the first minute of reperfusion as well as IP significantly augmented
ATP and PCr contents, reduced
lactate level and decreased ECr loss at the area at risk by the end of reperfusion as compared with values in control. Additionally significantly higher rates of pH recovery and reduction of P(i) concentration in the interstitial fluid were observed during reperfusion compared with these indices in control.
BIIB-722 administration before
ischemia had much effects on contents of energy and
carbohydrate metabolites at area at risk. The results obtained indicate that ability of
BIIB-722 to limit
infarct size and improve metabolism in the area at risk is comparable to cardioprotective effects of IP. Therefore this study substantiates a possibility of application of a novel Na(+)/H(+) exchange inhibitor for clinical investigations.