The long-term objective of this work is a comprehensive analysis of the cardioprotective effects of volatile anesthetics. These agents are capable of reducing reversible and irreversible myocardial injury following coronary artery occlusion and reperfusion. Recently, it was found that a prior, brief exposure to the volatile anesthetic, isoflurane, can reduce myocardial infarct size after its discontinuation. This phenomenon has a strong similarity to ischemic preconditioning (IPC) in which a brief period of coronary artery occlusion and reperfusion renders myocardium resistant to infarction after a subsequent prolonged ischemic insult. Anesthetic preconditioning (APC) demonstrates a powerful cardioprotective effect with early and late memory phases. The major hypothesis to be tested in the present investigation is that volatile anesthetics directly produce late (24 hr after anesthetic exposure) APC against myocardial infarction and apoptosis and preserve mitochondrial function. The intracellular signal transduction pathways for late APC will be characterized in an in vivo rabbit model of myocardial infarction (measured by triphenyltetrazolium histochemical staining) and using bioassays of endogenous mediators.
Specific Aims i nclude:
Aim I : To characterize the efficacy of late APC to reduce infarct size and apoptosis and preserve mitochondrial bioenergetics and to determine its relationship to ROS.
Aim II : To identify the role of the sarc and/or mito KATP channel in late APC.
Aim III : To characterize the role of NOS and COX in late APC. The proposed research represents an investigation into a clinically relevant problem because of the large number of patients wtih coronary artery disease undergoing anesthesia and the morbidity and mortality associated with perioperative myocardial ischemia and infarction. Volatile anesthetics have recently been shown to produce APC in patients undergoing coronary artery bypass graft surgery. Late APC may last longer and occur when ischemic events are most frequent (postoperatively). This proposal will systematically delineate mechanisms and subcellular loci responsible for the novel and unique cardioprotective effects of volatile anesthetics against ischemia and reperfusion injury.
|Baumgardt, Shelley L; Paterson, Mark; Leucker, Thorsten M et al. (2016) Chronic Co-Administration of Sepiapterin and L-Citrulline Ameliorates Diabetic Cardiomyopathy and Myocardial Ischemia/Reperfusion Injury in Obese Type 2 Diabetic Mice. Circ Heart Fail 9:e002424|
|Hirata, Naoyuki; Shim, Yon Hee; Pravdic, Danijel et al. (2011) Isoflurane differentially modulates mitochondrial reactive oxygen species production via forward versus reverse electron transport flow: implications for preconditioning. Anesthesiology 115:531-40|
|Leucker, Thorsten M; Bienengraeber, Martin; Muravyeva, Maria et al. (2011) Endothelial-cardiomyocyte crosstalk enhances pharmacological cardioprotection. J Mol Cell Cardiol 51:803-11|
|Ge, Zhi-Dong; Ionova, Irina A; Vladic, Nikolina et al. (2011) Cardiac-specific overexpression of GTP cyclohydrolase 1 restores ischaemic preconditioning during hyperglycaemia. Cardiovasc Res 91:340-9|
|Pravdic, D; Mio, Y; Sedlic, F et al. (2010) Isoflurane protects cardiomyocytes and mitochondria by immediate and cytosol-independent action at reperfusion. Br J Pharmacol 160:220-32|
|Pagel, Paul S; Krolikowski, John G; Amour, Julien et al. (2009) Morphine reduces the threshold of helium preconditioning against myocardial infarction: the role of opioid receptors in rabbits. J Cardiothorac Vasc Anesth 23:619-24|
|Zhang, Rong; Mio, Yasushi; Pratt, Philip F et al. (2009) Near infrared light protects cardiomyocytes from hypoxia and reoxygenation injury by a nitric oxide dependent mechanism. J Mol Cell Cardiol 46:4-14|
|Pagel, Paul S; Krolikowski, John G; Pratt Jr, Phillip F et al. (2008) The mechanism of helium-induced preconditioning: a direct role for nitric oxide in rabbits. Anesth Analg 107:762-8|
|Pagel, Paul S; Krolikowski, John G; Pratt Jr, Phillip F et al. (2008) Reactive oxygen species and mitochondrial adenosine triphosphate-regulated potassium channels mediate helium-induced preconditioning against myocardial infarction in vivo. J Cardiothorac Vasc Anesth 22:554-9|
|Gu, Weidong; Kehl, Franz; Krolikowski, John G et al. (2008) Simvastatin restores ischemic preconditioning in the presence of hyperglycemia through a nitric oxide-mediated mechanism. Anesthesiology 108:634-42|
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