Abstract

Investigations to date suggest that 1) oxygen metabolite mediated myocardial ischemia reperfusion injury exists; 2) it causes myocardial dysfunction and arrhythmias; and 3) the perfused-ischemic borderzone is the site of metabolic and functional electrophysiologic instability. Our hypothesis is that: Recover of Cardiac Function in Hearts Subjected to an Ischemia/Reperfusion Insult can be Enhanced by Prior Induction of Myocardial Tolerance to Oxidant Stress. To address this hypothesis, we will employ a standard isolated heart model of global ischemia which affords the advantages of a controlled ischemic insult free from confounding variables of blood born mediators. We have found that sublethal doses of endotoxin (ETX) or its more distal cytokine mediators tumor necrosis factor (TNF) and interleukin-1 (IL-1) given to rats 36 hours prior to isolated heart preparation induce protection from ischemia reperfusion injury. This protection relates to increased endogenous myocardial oxidant defense mechanisms at 36 hours and early (6 hours) neutrophil mediated myocardial oxidant stress.
Our specific aims will investigate: 1) pathophysiology (heart function, hydrogen peroxide levels, and antioxidant enzymes); 2) histopathology (heart neutrophil accumulation); and 3) the mechanism (via xanthine oxidase depletion, neutrophil depletion, and oxygen metabolite scavenger treatment) of ETX, TNF, and IL-1 induced protection. We acknowledge that these are highly focused goals, but believe that progress in this area will have direct application to the million or more Americans each year with ischemia related cardiac dysfunction and dysrhythmias.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL044186-02
Application #
3362969
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Project Start
1990-01-01
Project End
1994-12-31
Budget Start
1991-01-01
Budget End
1991-12-31
Support Year
2
Fiscal Year
1991
Total Cost
Indirect Cost

  Institution

Name
University of Colorado Denver
Department
Type
Schools of Medicine
DUNS #
065391526
City
Aurora
State
CO
Country
United States
Zip Code
80045

  Publications

Meldrum, Daniel R; Partrick, David A; Cleveland Jr, Joseph C et al. (2003) On-pump coronary artery bypass surgery activates human myocardial NF-kappaB and increases TNF-alpha in the heart. J Surg Res 112:175-9
Rowland, R T; Cleveland Jr, J C; Upadhya, P et al. (2000) Transportation or noise is associated with tolerance to myocardial ischemia and reperfusion injury. J Surg Res 89:12-Jul
Cain, B S; Harken, A H; Meldrum, D R (1999) Therapeutic strategies to reduce TNF-alpha mediated cardiac contractile depression following ischemia and reperfusion. J Mol Cell Cardiol 31:931-47
Meldrum, D R; Partrick, D A; Sheridan, B C et al. (1999) Kinetics of interleukin-11 release after cardiopulmonary bypass. J Thorac Cardiovasc Surg 118:193-5
Meldrum, D R; Cain, B S; Meng, X et al. (1999) Calcium preconditioning, but not ischemic preconditioning, bypasses the adenosine triphosphate-dependent potassium (KATP) channel. J Surg Res 85:77-82
Cain, B S; Meldrum, D R; Cleveland Jr, J C et al. (1999) Clinical L-type Ca(2+) channel blockade prevents ischemic preconditioning of human myocardium. J Mol Cell Cardiol 31:2191-7
Cain, B S; Meldrum, D R; Meng, X et al. (1999) p38 MAPK inhibition decreases TNF-alpha production and enhances postischemic human myocardial function. J Surg Res 83:7-12
Cain, B S; Meldrum, D R; Meng, X et al. (1999) Exogenous calcium preconditions myocardium from patients taking oral sulfonylurea agents. J Surg Res 86:171-6
Meldrum, D R; Meng, X; Shames, B D et al. (1999) Liposomal delivery of heat-shock protein 72 into the heart prevents endotoxin-induced myocardial contractile dysfunction. Surgery 126:135-41
Meldrum, D R; Donnahoo, K K (1999) Role of TNF in mediating renal insufficiency following cardiac surgery: evidence of a postbypass cardiorenal syndrome. J Surg Res 85:185-99

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