After brief episode(s) of ischemia which cause no necrosis (non-lethal myocyte injury), the myocardium exhibits persistent metabolic and contractile changes and has increased tolerance to a later sustained episode of ischemia, a rapid adaptive change termed ischemic preconditioning. Preconditioned myocardium which again becomes ischemic has a much slower rate of energy utilization and a delayed onset of lethal cell injury manifest as a marked limitation of infarct size after 60 minutes of ischemia, followed by reperfusion. The cause(s) of infarct limitation and the reduced rate of energy metabolism are unknown but could be a direct effect of known changes in the intracellular milieu, e.g. excess sarcoplasmic Pi, Mg2+, glucose, and creatine phosphate (the CP overshoot), or less adenine nucleotide and glycogen. Alternatively, preconditioning could result from activation of one or more signaling pathways. One candidate pathway involves protein kinase C (PKC). Activated PKC phosphorylates many proteins, one or more of which may modulate key energy utilizing pathways in ischemic myocytes. The applicant hypothesizes that the major effector mechanism of the reduced energy demand and consequent infarct limitation involves enhanced opening of K+ATP channels. The applicant hypothesizes that PKC facilitates the opening of these channels, that increased K+ is released into the extracellular fluid (ECF), and that this increased K+ reduces energy demand by reducing ion traffic and contractile effort. The applicant will assess changes in the intracellular milieu in relation to the presence or absence of protection after different durations of reperfusion. The applicant also will study the role of the K+ATP channel in the cardioprotective and metabolic effects of preconditioning, using channel openers and inhibitors. The applicant will study the time-course of PKC activation in ischemia by biochemical and immunofluorescent assays and the role of PKC in ischemic preconditioning will be assessed using direct PKC activators and inhibitors. Cardioprotection will be assessed by measuring myocardial infarct size and the rate of ischemic metabolism (rate of change of adenine nucleotides and intermediates of anaerobic glycolysis during ischemia).

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL027416-15
Application #
2609212
Study Section
Cardiovascular and Renal Study Section (CVB)
Project Start
1990-04-01
Project End
2000-11-30
Budget Start
1997-12-01
Budget End
1998-11-30
Support Year
15
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Duke University
Department
Pathology
Type
Schools of Medicine
DUNS #
071723621
City
Durham
State
NC
Country
United States
Zip Code
27705
Meijs, Loek P B; Galeotti, Loriano; Pueyo, Esther P et al. (2014) An electrocardiographic sign of ischemic preconditioning. Am J Physiol Heart Circ Physiol 307:H80-7
Jennings, Robert B (2013) Historical perspective on the pathology of myocardial ischemia/reperfusion injury. Circ Res 113:428-38
Jennings, Robert B (2011) Commentary on selected aspects of cardioprotection. J Cardiovasc Pharmacol Ther 16:340-8
Schwartz, L M; Sebbag, L; Jennings, R B et al. (2001) Duration and reinstatement of myocardial protection against infarction by ischemic preconditioning in open chest dogs. J Mol Cell Cardiol 33:1561-70
Jennings, R B; Sebbag, L; Schwartz, L M et al. (2001) Metabolism of preconditioned myocardium: effect of loss and reinstatement of cardioprotection. J Mol Cell Cardiol 33:1571-88
Schwartz, L M; Verbinski, S G; Vander Heide, R S et al. (1997) Epicardial temperature is a major predictor of myocardial infarct size in dogs. J Mol Cell Cardiol 29:1577-83
Schwartz, L M; Jennings, R B; Reimer, K A (1997) Premedication with the opioid analgesic butorphanol raises the threshold for ischemic preconditioning in dogs. Basic Res Cardiol 92:106-14
Sebbag, L; Katsuragawa, M; Verbinski, S et al. (1996) Intracoronary administration of the alpha 1-receptor agonist, methoxamine, does not reproduce the infarct-limiting effect of ischemic preconditioning in dogs. Cardiovasc Res 32:830-8
Reimer, K A (1996) The slowing of ischemic energy demand in preconditioned myocardium. Ann N Y Acad Sci 793:13-26
Vander Heide, R S; Hill, M L; Reimer, K A et al. (1996) Effect of reversible ischemia on the activity of the mitochondrial ATPase: relationship to ischemic preconditioning. J Mol Cell Cardiol 28:103-12

Showing the most recent 10 out of 49 publications