The long-term objective of this work is a comprehensive analysis of the cardioprotective effects of volatile anesthetics. These agents are capable of reducing the contractile deficit (myocardial stunning) following a brief period of ischemia and the extent of myocardial infarction following a prolonged period of coronary artery occlusion. Recently, it was found that a prior, brief exposure to the volatile anesthetic, isoflurane, could reduce myocardial infarct size after its discontinuation. This phenomenon has a strong similarity to ischemic preconditioning, in which a brief period of coronary artery occlusion and reperfusion renders myocardium resistant to infarction after a subsequent prolonged ischemia insult. Anesthetic-induced preconditioning (APC) demonstrates a powerful cardioprotective effect with short and long-term memories. The major hypothesis to be tested in the present investigation is that volatile anesthetics directly produce early and late preconditioning against both myocardial stunning and infarction via enhanced opening of ATP-dependent potassium (KATP) channels. Signal transduction pathways including adenosine receptors and protein kinase C serving as a mechanism(s) for APC will be characterized. APC-induced alterations in the interstitial concentration of adenosine and translocation of PKC isoforms will be measured in ischemic and control myocardium. Cardioprotective effects of the anesthetics will be studied in in vivo canine models of myocardial ventricular pressure-segment length diagrams, and myocardial infarct size will be measured by triphenyl tetrazolium histochemical staining. Alterations in potassium conductance through KATP channels will be studied directly by means of modification of the patch clamp technique in normal and previously ischemic ventricular myocytes. Because of the large number of patients with coronary artery disease undergoing infarction, the proposed research represents an investigation into a clinically relevant problem. Isoflurane has recently been shown to produce APC in patients undergoing coronary artery bypass graft surgery. Thus, this proposal will delineate mechanisms responsible for the novel and unique cardioprotective effects of volatile anesthetics against ischemia and reperfusion injury in vivo and provide direct evidence of the involvement of specific signal transduction pathways modulating the KATP channel in vitro.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Liang, Isabella Y
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Medical College of Wisconsin
Schools of Medicine
United States
Zip Code
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

Showing the most recent 10 out of 89 publications