Abstract 1436: Reversible Blockade of Electron Transport during Ischemia Protects Mitochondrial Function and Decreases Injury in the Aged Heart
The elderly heart is inherently more susceptible to injury during ischemia (ISC) and reperfusion (REP). Aging causes a defect in electron transport complex III of interfibrillar mitochondria (IFM), decreasing activity and enhancing superoxide production in the baseline state. We hypothesized that this defect exacerbates injury in the aged heart under the prooxidant conditions of ISC-REP and proposed that reversible blockade of electron transport into complex III during ISC would attenuate damage to mitochondria and decrease cardiac injury. Amobarbital (AMO) reversibly inhibits complex I, blocking flow into downstream complex III. Langendorff perfused 24 mo. aged Fischer 344 rat hearts received 2.5mM AMO or buffer vehicle over 1 min immediately before 25 min global ISC (37°C) followed by 30 min untreated REP. A third group was perfused as non-ischemic time-matched controls. Subsarcolemmal (SSM) and IFM populations of mitochondria were isolated to measure ADP-stimulated respiration, complex III activity and cytochrome c (CYT c ) content. Contractile function was assessed by the percent recovery of LV developed pressure at end REP. Effluent was collected during the entire REP period for LDH release. AMO treatment preserved maximal state 3 respiration (nAO/min/mg protein) and CYT c content (nmol/mg pr) following ISC-REP in SSM and IFM (table⇓). AMO treatment attenuated ischemic damage to complex III in IFM that contain the aging defect (6461 ± 409 vs. 4833 ± 410* mU/min/mg pr). AMO treatment lessened ISC-REP injury as shown by decreased LDH release (469 ± 94 vs. 835 ± 95* mU/min/gm heart) and improved contractile recovery (79% ± 10 vs. 52% ± 7*). Thus, reversible blockade of electron transport into complex III during ISC preserves mitochondrial function and CYT c retention leading to a reduction in myocardial injury during ISC-REP in the aged heart. Mean ± SEM; * p ≤ 0.05 vs Amobarbital + I-R and time control.