5. Attenuation of myocardial ischemia and reperfusion injury by novel analogues of apelin-12

The C-terminal residue of adipokine apelin (RPRLSHKGPMP, A12) is able to reduce myocardial ischemia/reperfusion (I/R) injury. To enhance A12 resistance to enzymatic degradation in vivo we synthesized its structural analogues [MeR1,NLe10]-A12 (I) and [MeR1,NLe10]-A12amide (II). The aim of the study was to evaluate cardioprotective effects of these peptides in comparison with [d-Ala12]-A12 (III), a putative antagonist of APJ receptor. Isolated working rat hearts, perfused with Krebs-Henseleit buffer (KHB), were subjected to 35 min global ischemia followed by 30 min reperfusion. A 5 min infusion of KHB containing A12, I, II or III was applied prior to ischemia (400 nmol/g/min); infusion of KHB was performed in control. Treatment with A12, I or II significantly increased recovery of cardiac function and coronary flow during reperfusion compared with control. These effects were accompanied by enhanced restoration of myocardial ATP, adenine nucleotide pool, phosphocreatine and reduced accumulation of myocardial lactate. Infusion of III reduced metabolic and functional recovery of postischemic hearts compared with infusion of A12, I or II. The overall protective effect of the peptides increased in the following rank III Keywords Apelin --- Cardioprotection --- Ischemic heart --- Myocardial metabolism