The B-vitamin folic acid (FA) is important to mitochondrial protein and nucleic acid synthesis, is an anti-oxidant, and enhances nitric oxide synthase activity. Here, we tested whether FA reduces myocardial ischemic dysfunction and post-reperfusion injury.
Wistar rats were pretreated with either FA (10mg/d) or placebo for 1-wk, and then underwent in vivo transient left coronary artery occlusion for 30min with or without 90min reperfusion (total:n=131; sub-groups used for various analyses). FA (4.5•10-6M i.c) pretreatment and global ischemia/reperfusion (30 min/30min), was also performed in vitro (n=28).
After 30min ischemia, global function declined more in controls than FA-pretreated rats (ΔdP/dtmax -878±586 mmHg/s vs. placebo -1956±351 mmHg/s, p=0.03), and regional thickening was better preserved (37.3±5.3% vs. 5.1±0.6%-placebo, p=0.004). Anterior-wall perfusion fell similarly (-78.4±9.3% vs. -71.2±13.8%-placebo at 30 min); yet myocardial high energy phosphates ATP and ADP reduced by ischemia in controls were better preserved by FA-pretreatment (e.g. ATP: control: 2740±58; ischemia: 947±55; ischemia+FA: 1332±101 nmol/g, p=0.02). Basal oxypurines (xanthine, hypoxanthine, and urate) rose with FA-pretreatment, but increased less during ischemia than in controls. Ischemic superoxide generation declined (3124±280 FA vs. 5898±474 placebo, cpm/mg, p=0.001). After reperfusion, FA-treated hearts had smaller infarcts (3.8±1.2% vs 60.3±4.1%-placebo area at risk, p<0.002), less contraction band necrosis, TUNEL-positivity, superoxide, and nitric oxide synthase uncoupling. Infarct size declined similarly with 1 mg/d FA as well.
FA-pretreatment blunts myocardial dysfunction during ischemia, and ameliorates post-reperfusion injury. This is coupled to preservation of high energy phosphates, reducing subsequent ROS-generation, eNOS-uncoupling and post-reperfusion cell death.