New Trends in therapeutic strategies against ischemia/reperfusion injury; Postconditioning and pharmacological intervention in acute myocardial infarction

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Despite better outcomes with early coronary artery reperfusion for the treatment of acute myocardial infarction (AMI), morbidity and mortality from AMI remain significant, and myocardial reperfusion injury is a critical contributor to the final infarct size. In the past decade, several pharmacological treatments applied at early reperfusion have been tested in experimental models and in the clinical setting. Unfortunately, efforts at reducing reperfusion injury by several studies have largely been unsuccessful. There is a need to provide better cardioprotective therapy that reduces the amount of necrosis that may be coupled with better clinical outcomes.Postconditioning: Ischemic postconditioning, defined as brief periods of ischemia immediately after the onset of reperfusion, has been recently shown to be one of the novel strategies of cardioprotection against reperfusion injury. However, recent clinical trials have not elucidated the protective effects of postconditioning. The protective effect of postconditioning is thought to result from delayed recovery from intracellular acidosis during the reperfusion period. It is generally accepted that lactate accumulation is responsible for intracellular acidosis during ischemia. As a higher extracellular lactate concentration impedes lactate transport from inside the cells, reperfusion with lactate-enriched blood should protect myocardial cell against reperfusion injury through prolonged intracellular acidification. We therefore modified the original postconditioning protocol by using lactated Ringer's solution to achieve controlled reperfusion with tissue oxygenation and minimal lactate washout from the cells. Ischemic postconditioning with lactate-enriched blood consistently suppressed the various detrimental effects of reperfusion and preserved myocardial viability well. Given the excellent microcirculation recovery consistently observed in this series, the modified ischemic postconditioning protocol might be a promising approach to effectively suppress myocardial reperfusion injury.Pharmacological intervention: Recent clinical trials of cardiovascular disease have demonstrated that carperitide, a synthetic alpha-human atrial natriuretic peptide (ANP), improve survival in patients with acute myocardial infarction due to their cardioprotective effects. On the other hand, Rho kinase (ROCK) activation plays a major role as a mediator of irreversible injury in reperfused myocardium. We hypothesized that ROCK is activated specifically after ischemia-reperfusion (I-R) and that suppression of ROCK activity during I-R by ANP limits infarct size. A rat model of myocardial I-R injury was investigated by ligating the left descending coronary artery for 30 min and then reperfusing for 180 min. Continuous infusion of ANP (0.1 ug/kg/min) was started 5 min after the ligation and lasting for 175 min. Phosphorylation of the ROCK substrate protein myosin phosphatase targeting subunit (MYPT)-1 assessed by western blotting was used as a marker of ROCK activation. The myocardial infarct size and the area at risk of ischemia were measured by staining with triphenyltetrazolium chloride (TTC). The results showed that I-R injury induced ROCK activation significantly, and ANP reduced infarct size compared to control (9.4 ± 4.3 vs. 35.9 ± 3.5%, ANP vs. control, mean±SD, p < 0.05). Interestingly, the cardioprotective effect of ANP was abolished by 5-Hydroxydecanoate (5-HD), a putative mitochondrial KATP (mKATP) channel inhibitor (32.6±2.9% infarction). In Western blot analysis, attenuation of ROCK activation by ANP was reversed by 5HD, L-NAME, but not wortmannin, an inhibitor of phosphatidylinositol-3-kinase/Akt signaling. In conclusion, inhibition of ROCK activation by ANP limits infarct size via an opening of mKATP/NO-dependent mechanism.

New Trends in therapeutic strategies against ischemia/reperfusion injury; Postconditioning and pharmacological intervention in acute myocardial infarction

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