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Myocardial protection with low- molecular dinitrosyl iron complexes Paramagnetic monomeric dinitrosyl iron complexes (DNIC) with thiol-containing ligands ({RS-)2Fe+(NO+)2}+, where RS- are low-molecular compounds or proteins) represent native forms of nitric oxide (NO) carriers in vivo. This study was design to determine whether DNIC confer protection against myocardial ischemia and reperfusion injury. Synthesized low-molecular weight DNIC with reduced glutathione (DNIC-GS) or l-cysteine (DNIC-Cys) were incorporated into the matrix of water-soluble polymers and lyophilized. They were tested in isolated perfused rat hearts subjected to global ischemia and reperfusion and in a model of acute myocardial infarction in rats in vivo. Contractile and pump function indices, infarct size, myocardial energy state and cell membrane damage were assessed (Pisarenko et al., 1999). DNIC contents in blood and myocardial tissue were determined using analysis of EPR signals (Timoshin et al., 2007). Dose-dependent effects of DNIC with both ligands on postischemic functional recovery of isolated rat heat were studied within 25-2500 nM concentration range. Improvement of coronary flow and cardiac function after pre- or postischemic DNIC infusion was accompanied by 2-fold increase in preservation of ATP, total adenine nucleotides and phosphocreatine (PCr) in reperfused hearts compared with that in control (P<0.05-0.02). Additionally, lactate dehydrogenase (LD) leakage into perfusate and loss of myocardial total creatine were reduced during reperfusion (to 138.8+7.2 % of the initial value and by 0.08+0.02 μmol/g dry wt. respect. vs. 233.9+19.4 % and 7.01+1.65 μmol/g dry wt in control, P<0.01). Cardioprotection afforded by DNIC was abolished by the NO scavenger carboxy-PTIO. Administration of DNIC-GS hydrolyzate, containing all bioactive components of the complex separately, did not improve postischemic functional and metabolic recovery of hearts compared to the control. Intravenous bolus injections of DNIC (3.1 μmol/kg body wt.) before LAD occlusion or after regional ischemia reduced the mean arterial pressure in anaesthetized rats by 35+5 and 12+2 % of the initial value respect., P<0.02). These effects were combined with reduction of rhythm disturbance duration during LAD occlusion (170+10 s vs. 445+15 s in control, P<0.01), limitation of infarct size (on the average by 13+1 % vs. the value in control, P<0.01), and a decrease in LD and CK-MB fraction activities in blood plasma (by 22+3% and 37+4% respect. compared with these indices in control, P<0.05) at the end of reperfusion. DNIC-GS administration did not affect significantly metabolism of nonischemic area of the heart. However, DNIC-GS injection appreciably improved energy state of area at risk after reperfusion. It was evidenced by significantly higher values of the energy charge of cardiomyocytes (0.72+0.02 vs. 0.61+0.01 in control, P<0.01), myocardial ATP/ADP ratio (1.71+0.04 vs. 1.32+0.03 in control, P<0.05) and PCr/Cr ratio (0.34+0.02 vs. 0.19+0.01 in control, P<0.02), and a markedly reduced tissue lactate/pyruvate ratio (34.3+4.1 vs. 98.3+6.9 in control, P<0.01). The predominant transfer of DNIC-GS from perfusate or blood into myocardial tissue with formation of protein-bound DNIC was evidenced by EPR signal analysis. The results clearly demonstrate that myocardial protection by low-molecular weight DNIC with thiolate ligands is associated with enhanced energy metabolism and sarcolemma stability in postischemic cardiomyocytes. This finding combined with DNIC vasodilating action substantiates usage of these compounds for creating hypotensive and anti-ischemic drugs.
Pisarenko O.I. et al. (1999) Clin. Exp. Pharmacol. Physiol. 26, 26-31.
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