Orphan targets for reperfusion injury.
Cardiomyocyte death secondary to transient ischaemia occurs mainly during the first minutes of reperfusion in the form of contraction band necrosis. Research on the mechanisms leading to sarcolemmal rupture and necrosis during initial reperfusion identified several promising pharmacological targets directed either to correct the alterations in Ca(2+) handling occurring during this period (Na(+)/H(+)-exchanger, reverse mode of Na(+)/Ca(2+)-exchanger, sarcoplasmic reticulum) or to interfere with its consequences [hypercontracture, calpain activation, and mitochondrial permeability transition pore (mPTP) opening]. However, despite the fact that pharmacological tools against some of these targets have consistently demonstrated that it is possible to reduce infarct size in experimental studies by interventions applied at the time of reperfusion, the translation of these approaches to clinical practice has failed due in part to the lack of drugs able to be tested in humans. Recently, the benefits of both post-conditioning and inhibition of mPTP have been supported by proof-of-concept trials demonstrating the clinical applicability of strategies aimed at preventing lethal reperfusion injury. These promising results should stimulate efforts to develop drugs testable in humans against known, unexploited targets involved in reperfusion injury and to identify and validate additional ones.
Laboratorio de Cardiología Experimental, Servicio de Cardiología, Hospital Universitari Vall d'Hebron, Passeig Vall d'Hebron, 119-129, 08035 Barcelona, Spain.
Javier
J
Inserte
José A
JA
Barrabés
Víctor
V
Hernando
David
D
Garcia-Dorado
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects; D002317:Cardiovascular Agents / Q000627:therapeutic use*; D019610:Cytoprotection; D017629:Gap Junctions / Q000187:drug effects / Q000473:pathology; D006801:Humans; D009203:Myocardial Infarction / Q000473:pathology / Q000628:therapy*; D015425:Myocardial Reperfusion / Q000009:adverse effects*; D015428:Myocardial Reperfusion Injury / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D009336:Necrosis; D013997:Time Factors; D016896:Treatment Outcome
D002317:Cardiovascular Agents; D002118:Calcium