Organ dysfunction following regional and global ischemia/reperfusion. Intervention with postconditioning and adenocaine

Abstract

Cardiac arrest and acute myocardial infarction are leading causes of death in the middle-aged and elderly, whereas trauma primarily affects the younger segment of the population. The three conditions are all characterized by a period of reduced blood flow either regionally in the heart or globally, and treatment strategies target the restoration of normal blood flow. Paradoxically, reperfusion of ischemic tissue contributes to cellular injury in all three settings. Ischemic postconditioning initiated immediately at reperfusion was in 2003 introduced as a new potential treatment to limit injury following acute myocardial infarction. The aim of this dissertation was explore the mechanism of ischemic postconditioning during regional ischemia and test the effects of early pharmacological postconditioning using adenocaine in models of global I/R injury. In the first study, the mechanisms of postconditioning were explored. In a rat model of regional ischemia, it was demonstrated that postconditioning reduced infarct size. However when postconditioning was applied in already PMN-depleted rats, no further reduction in infarct size was observed. Furthermore, in a canine model of regional ischemia, postconditioning attenuated PMN superoxide production, implying that cardioprotection by postconditioning involves inhibition of PMNs. In the second study, treatment with adenocaine as pharmacological postconditioning during the immediate phase of cardiopulmonary resuscitation, attenuated early post-resuscitation myocardial dysfunction, augmented pulmonary and cardiac blood flow and reduced PMN superoxide production in a porcine model of cardiac arrest. In the third study, treatment with ALM/AL during the early phase of resuscitation was tested in a porcine model of hemorrhagic shock. Resuscitation with ALM/AL reduced fluid requirements during fluid resuscitation, transiently reduced whole body O2 consumption and improved cardiac and renal function. In conclusion, early intervention with either postconditioning or adenocaine attenuates I/R injury and organ dysfunction in animal models of acute myocardial infarction, cardiac arrest or hemorrhagic shock. Postconditioning and adenocaine may be promising new therapies for protection against I/R after acute myocardial infarction, cardiac arrest and hemorrhagic shock.