[Protection of rat heart myocardium with a selective Na(+)/H(+) exchange inhibitor and ischemic preconditioning].
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.
Pisarenko
O I
OI
Studneva
I M
IM
Serebriakova
L I
LI
Tskitishvili
O V
OV
Timoshin
A A
AA
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D027682:Cation Transport Proteins / Q000037:antagonists & inhibitors*; D004195:Disease Models, Animal; D006146:Guanidines / Q000008:administration & dosage / Q000627:therapeutic use*; D007275:Injections, Intravenous; D019157:Ischemic Preconditioning, Myocardial; D019344:Lactic Acid / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000037:antagonists & inhibitors*; D009203:Myocardial Infarction / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D010725:Phosphocreatine / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D000074082:Sodium-Hydrogen Exchanger 1; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors*; D016896:Treatment Outcome
D027682:Cation Transport Proteins; D006146:Guanidines; D008565:Membrane Proteins; C490997:Slc9a1 protein, mouse; D000074082:Sodium-Hydrogen Exchanger 1; D017923:Sodium-Hydrogen Exchangers; D010725:Phosphocreatine; D019344:Lactic Acid; D000255:Adenosine Triphosphate; C476560:sabiporide