Myocardial injury is increased in the aged heart following ischemia-reperfusion (ISC-REP) compared to adult hearts. Intervention at REP with ischemic postconditioning decreases injury in the adult heart by attenuating mitochondrial driven cell injury. Unfortunately, postconditioning is ineffective in aged hearts. Blockade of electron transport at the onset of REP with the reversible inhibitor amobarbital (AMO) decreases injury in adult hearts. We tested if AMO treatment at REP protects the aged heart via preservation of mitochondrial integrity. Buffer-perfused elderly Fischer 344？24？mo. rat hearts underwent 25？min global ISC and 30？min REP. AMO (2.5？mM) or vehicle was given for 3？min at the onset of REP. Subsarcolemmal (SSM) and interfibrillar (IFM) mitochondria were isolated after REP. Oxidative phosphorylation (OXPHOS) and mitochondrial inner membrane potential were measured. AMO treatment at REP decreased cardiac injury. Compared to untreated ISC-REP, AMO improved inner membrane potential in SSM and IFM during REP, indicating preserved inner membrane integrity. Thus, direct pharmacologic modulation of electron transport at REP protects mitochondria and decreases cardiac injury in the aged heart, even when signaling-induced pathways of postconditioning that are upstream of mitochondria are ineffective. 1. Introduction The aged heart sustains increased injury during ischemia-reperfusion in both experimental models [1–4] and in elderly patients [5]. Aging hearts are also resistant to the powerful endogenous protections provided by ischemic preconditioning and postconditioning [6–12]. Pharmacological conditioning such as anesthetic preconditioning also does not protect the aging heart during ischemia-reperfusion [13]. Aging causes dysfunction in interfibrillar mitochondria [14]. The aging defect in complex III and cytochrome oxidase decreases oxidative phosphorylation and increases the generation of reactive oxygen species [14–16]. Improvement of age-induced mitochondrial dysfunction with supplementation of acetylcarnitine decreases myocardial injury during ischemia-reperfusion [17], supporting that the electron transport chain defects present in the aged heart contribute to the increased myocardial injury. Cardiac ischemia damages the electron transport chain and leads to the increased generation of reactive oxygen species (ROS) and mitochondrial calcium over load [18–22]. Opening of the mitochondrial permeability transition pore (MPTP) is a critical step in the onset of cardiomyocyte death [23, 24]. The increased generation of ROS and calcium overload
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