Abstract
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.
Highlights
The aged heart sustains increased injury during ischemiareperfusion in both experimental models [1,2,3,4] and in elderly patients [5]
We evaluated if protection by direct modulation of mitochondrial function during early reperfusion is mediated by the protection of mitochondrial inner membrane integrity
The novel findings of the present study are (1) reversible blockade of electron transport at the onset of reperfusion decreases myocardial injury in aged hearts; (2) the protection by amobarbital treatment during reperfusion was mediated by protection of the inner mitochondrial membrane
Summary
The aged heart sustains increased injury during ischemiareperfusion in both experimental models [1,2,3,4] and in elderly patients [5]. Aging hearts are resistant to the powerful endogenous protections provided by ischemic preconditioning and postconditioning [6,7,8,9,10,11,12]. Pharmacological conditioning such as anesthetic preconditioning does not protect the aging heart during ischemia-reperfusion [13]. Improvement of ageinduced mitochondrial dysfunction with supplementation of acetylcarnitine decreases myocardial injury during ischemiareperfusion [17], supporting that the electron transport chain defects present in the aged heart contribute to the increased myocardial injury
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