Objective:To examine cardioprotective effects of Ρ-terminal fragment of adipokine apelin-12 (A12), its novel structural analogue [MeArg1, NLe10]-A12 (I), and [d-Ala12]-A12 (II), a putative antagonist of APJ receptor, employing in vivo model of ischemia/reperfusion (I/R) injury.Materials and Methods:Peptides were synthesized by the automatic solid phase method using Fmoc technology. Anesthetized open-chest male Wistar rats were subjected to left anterior descending (LAD) coronary artery occlusion and coronary reperfusion. Hemodynamic variables and electrocardiogram (ECG) were monitored throughout the experiment. Myocardial injury was assessed by infarct size (IS), activity of necrosis markers in plasma, and metabolic state of the area at risk (AAR).Results:Intravenous injection of A12, I, or II at the onset of reperfusion led to a transient reduction of the mean arterial pressure. A12 or I administration decreased the percent ratio of IS/AAR by 40% and 30%, respectively, compared with control animals which received saline. Both peptides improved preservation of high-energy phosphates, reduced lactate accumulation in the AAR, and lowered CK-MB and LDH activities in plasma at the end of reperfusion compared with these indices in control. Treatment with II did not significantly affect either the IS/AAR, % ratio, or activities of both markers of necrosis compared with control. The overall metabolic protection of the AAR in the treated groups increased in the following rank: II < A12 < I.Conclusions:The structural analogue of apelin-12 [MeArg1, NLe10]-A12 may be a promising basis to create a new drug for the treatment of acute coronary syndrome.

Apelin-12 (A-12) peptide was synthesized by automated solid phase method and purified by reverse phase HPLC. Its homogeneity and structure were confirmed by HPLC, (1)H-NMR spectroscopy, and mass spectroscopy. Acute myocardial infarction was induced by 40-min occlusion of the left coronary artery with subsequent 60-min reperfusion in narcotized Wistar rats. Peptide A-12 was injected (intravenous bolus, 0.07 or 0.35 μmol/kg) to experimental animals simultaneously with the beginning of reperfusion. Injections of A-12 in these doses led to reduction of systolic BP to 67 and 85% of the initial level, respectively, which was virtually restored completely by the end of reperfusion, and to a significant reduction of the infarction focus in the myocardium (by 21 and 34% in comparison with the control, respectively). Injection of A-12 in a dose of 0.35 μmol/kg led to reduction of plasma concentrations of necrosis markers in comparison with the control by the end of reperfusion: MB-creatine kinase by 56%, lactate dehydrogenase by 30%. The results attest to vasodilatory effects of A-12 under conditions of heart reperfusion in vivo; the peptide injected after local ischemia limits the myocardial infarction size and reduces damage to cardiomyocyte membrane.

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This work was designed to explore efficacy of apelin-12 (A-12) as a cardioprotective agent when given before ischemia or at reperfusion using the isolated working heart model. Hearts of male Wistar rats were subjected to 30-min stabilization period followed by 35-min global ischemia and 30-min reperfusion. A short-term infusion of Krebs-Henseleit buffer (KHB) con-taining A-12 (35, 70, 140, 280 or 560 ?M) was ap-plied prior to ischemia (A-12-I) or at onset of reperfusion (A-12-R). KHB infusion was used as control. A-12 infusions induced a dose-dependent increase in recovery of coronary flow, contractile and pump function during reperfu-sion, with the largest augmentation of these indices in the A-12-I group. Both A-12 groups exhibited a significant reduction of LV diastolic pressure rise during reperfusion compared with control. Enhanced functional recovery in the A-12-I group was combined with a decrease in LDH leakage in perfusate on early reperfusion (by 36% vs. control, p < 0.05). Preischemic infusion of 140 ?M A-12 markedly increased myocardial ATP content, enhanced preservation of the total adenine nucleotide pool and improved recovery of the energy charge in reperfused hearts. There was a trend towards increase in myocardial phosphocreatine by the end of re- perfusion in the A-12-I group; however this benefit did not reach statistical significance. At the end of reperfusion, myocardial lactate and lactate/pyruvate ratio were on average 5-fold lower in A-12-I treated hearts compared with control ones and did not differ significantly from the initial values. Therefore, improved cardiac dysfunction after I/R injury and less cell mem-brane damage induced by A-12 are associated with maintaining high energy phosphates, particularly ATP, in reperfused myocardium. Changes in energy metabolism may play a role in mechanisms of cardioprotection afforded by A-12 during I/R stress

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