Signal Transduction in the Cardioprotective Effect of Light Alcohol and its clinical application for ischemic preconditioning

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Epidemiologic studies have shown that light to moderate ethanol use is associated with a protective effect against fatal coronary artery disease. We showed that the cardioprotective effect of ethanol requires adenosine A1 receptor activation at the time of ischemia, like experimental ischemic preconditioning(PC). We investigated the potetial downstream mediators of this protection, compared with PC. Furthermore, PC preserves myocardial high-energy phosphate metabolites (HEP) and intracellular pH (pHi) during subsequent sustained ischemia. Reactive oxygen species (ROS) generation may be required to mediate PC, we examined the effects of inhibiting ROS generatio during a PC protocol in vivo using an open-chest porcine model.1. Is phospholipase C (PLC) involved in the cardioprotective effect of light ethanol?Hearts were isolated from guinea pigs after drinkng 2.5% ethanol for 16 weeks and were subjected to global ischemia and reperfusion using Langendorff apparatus. Hearts from animals dr … More inking ethanol showed improved functional recovery and decreased myocyte damage when compared with controls. PLC blockade with U-73122 abolished the protection provided by ethanol consumption. These findings indicate that long-term light alcohol consumption reduces myocardial ischemia-reperfusion injury and that PLC is required for this cardioprotective effect of ethanol. This cardioprotective effect of long-term light alcohol consumption mimics PC and may, in part, account for the beneficial effect of light drinking on cardiac health2. Is PC mediated by reactive oxygen species produced during PC protocol?PC preserves myocardial HEP and intracellular pHi during subsequent sustained ischemia. 31P-NMR data was correlated with myocyte ultrastructural changes using electron microscopy. Open chest pigs underwent 60 minutes of left anterior descending coronary artery occlusion. PC was elicited by a single episode of 5-minute occlusion and 5-minute reperfusion. The cell diffusible free radical scavenger, N-2- mercaptopropionyl glycine (MPG) or placebo saline were infused for 40 minutes starting 30 minutes before PC (PC+MPG group ＆ PC group). Following PC, ATP and pHi were significantly preserved through 25 min of ischemia and phosphocreatine through 20 min of ischemia. This preservation of HEP and pHi was abolished by inhibiting ROS generation with MPG. HEP preservation with PC was associated with reduced ultrastructural damage as demonstrated by electron microscopy, including less myocyte swelling, myofibrillar disruption and nuclear chromatin marginationThese results suggest that the cardioprotective effect of light alcohol can be used for clinical application as a chronic ischemic preconditioning Less