The goal of this research proposal is to examine mechanisms by which opioid receptor agonists provide protection from ischemia/reperfusion injury when administered at the time of reperfusion and when administered as chronic therapy. We hypothesize that delta and kappa opioid receptor agonists confer cardioprotection when administered prior to reperfusion by activating pro-survival signaling pathways including the PI3K/akt/GSKbeta/ERK 1/2 axis (reperfusion injury salvage kinases or the RISK pathway). With chronic therapy, we hypothesize that sustained cardioprotection is mediated by two complementary mechanisms: 1) up-regulation of cardioprotective proteins including 12-LO, iNOS, and COX-2 (delayed inducible salvage pathway or the DISP pathway), and 2) induction of beta-2 adrenergic receptors resulting in inhibition of adenylyl cyclase. Overall, we predict that the sarcolemmal isoform of the ATP-sensitive potassium (KATP) channel is the trigger and the mitochondrial KATP channel is the end-effector of opioid receptor-induced cardioprotection. Our studies involve the use of an in vivo rat/mouse model of infarction and an isolated mouse heart model of global ischemia and reperfusion in which infarct size and recovery of left ventricular contractile function are used as indices of ischemic injury, respectively. The involvement of specific signaling pathways, cardioprotective proteins, and receptor subtypes will be assessed by using selective pharmacological probes, gene """"""""knock-out"""""""" mice, Western immunoblotting, radioligand binding analysis, and recording of sarcolemmal (patch clamp recordings of isolated cardiac myocytes) and mitochondrial (recordings of KATP channel currents in mitochondrial lipid bi-layers) KATP channel currents. Collectively, these studies combine state-of-the-art techniques to provide new information regarding mechanisms by which opioid receptor agonists provide protection from ischemia/reperfusion injury. Information gained from these studies will hopefully lead to new therapies to treat patients with ischemic heart disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL008311-43
Application #
7545881
Study Section
Special Emphasis Panel (ZRG1-MIM (01))
Program Officer
Schwartz, Lisa
Project Start
1979-06-01
Project End
2010-12-31
Budget Start
2009-01-01
Budget End
2010-12-31
Support Year
43
Fiscal Year
2009
Total Cost
$287,299
Indirect Cost
Name
Medical College of Wisconsin
Department
Pharmacology
Type
Schools of Medicine
DUNS #
937639060
City
Milwaukee
State
WI
Country
United States
Zip Code
53226
Auchampach, John A; Maas, Jason E; Wan, Tina C et al. (2011) Are we putting too much stock in mice? J Mol Cell Cardiol 50:584-5
Gumina, Richard J; Newman, Peter J; Gross, Garrett J (2011) Effect on ex vivo platelet aggregation and in vivo cyclic flow with Na+/H+ exchange inhibition: Gumina, NHE-1 inhibition and platelet aggregation. J Thromb Thrombolysis 31:431-5
Peart, Jason N; Hoe, Louise E See; Gross, Garrett J et al. (2011) Sustained ligand-activated preconditioning via ýý-opioid receptors. J Pharmacol Exp Ther 336:274-81
Maas, Jason E; Wan, Tina C; Figler, Robert A et al. (2010) Evidence that the acute phase of ischemic preconditioning does not require signaling by the A 2B adenosine receptor. J Mol Cell Cardiol 49:886-93
Gross, Garrett J; Baker, John E; Hsu, Anna et al. (2010) Evidence for a role of opioids in epoxyeicosatrienoic acid-induced cardioprotection in rat hearts. Am J Physiol Heart Circ Physiol 298:H2201-7
Gross, Eric R; Hsu, Anna K; Gross, Garrett J (2009) Acute methadone treatment reduces myocardial infarct size via the delta-opioid receptor in rats during reperfusion. Anesth Analg 109:1395-402
Gross, Eric R; Gross, Garrett J (2007) Ischemic Preconditioning And Myocardial Infarction: An Update and Perspective. Drug Discov Today Dis Mech 4:165-174
Gross, Garrett J; Auchampach, John A (2007) Reperfusion injury: does it exist? J Mol Cell Cardiol 42:12-8
Bolte, Craig S; Liao, Siyun; Gross, Garrett J et al. (2007) Remote preconditioning-endocrine factors in organ protection against ischemic injury. Endocr Metab Immune Disord Drug Targets 7:167-75
Auchampach, John A; Jin, Xiaowei; Moore, Jeannine et al. (2004) Comparison of three different A1 adenosine receptor antagonists on infarct size and multiple cycle ischemic preconditioning in anesthetized dogs. J Pharmacol Exp Ther 308:846-56

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