Recent studies from our laboratory and others indicate that neutrophil adherence to vascular endothelium is required to produce microvascular dysfunction and myocyte necrosis in postischemic skeletal muscle. Recognition of this fact has led to a major research effort directed at evaluating the potential for inhibition of leukocyte adhesion as a novel approach to the treatment of reperfusion injury. Preliminary data from our laboratory indicates that ischemic preconditioning (IPC, a phenomenon n which a tissue is rendered resistant to the deleterious effects of prolonged ischemia and reperfusion by prior exposure to brief, repeated periods of vascular occlusion) prevents muscle necrosis induced by I/R by inhibiting leukocyte adherence and emigration during reperfusion. The overall goal of the projects outlined in this application is to determine the mechanisms by which IPC attenuates leukocyte adhesion to and emigration across postcapillary venules, microvascular barrier disruption, capillary no-reflow, and myocyte necrosis in skeletal muscles subsequently exposed to prolonged ischemia and reperfusion (I/R). Our working hypothesis is that IPC will attenuate microvascular dysfunction and myocyte necrosis in postischemic skeletal muscles via a mechanism that involves adenosine receptor activation during the period of IPC and during reperfusion after prolonged ischemia. To address this issue, we propose to determine: 1) whether IPC will attenuate leukocyte adhesion and emigration, capillary no-flow, venular protein leakage, and myocyte necrosis induced by I/R; 2) the role of adenosine produced during the preconditioning period in the protective effects of IPC that become apparent during reperfusion after prolonged ischemia; 3) whether the beneficial effects of adenosine A/1-receptor activation during the IPC period occur by a mechanism that involves activation of ATP-sensitive potassium channels; 4) the role of IPC-induced increases in 5'- nucleotidase activity during reperfusion after sustained ischemia in the protective actions of IPC; and 5) whether adenosine production is increased during reperfusion of preconditioned skeletal muscles and contributed to the protective actions afforded by IPC by activating adenosine A/2-receptors. To accomplish these aims, we will utilize intravital microscopic approaches to quantitate leukocyte adhesion and emigration, venular protein leakage, and capillary no-reflow in the mouse cremaster muscle. The influence of IPC on I/-induced myocyte necrosis will also be examined. Tissue adenosine levels will be measured by high performance liquid chromatography. The proposed studies should not only substantially improve our understanding of the mechanisms whereby IPC reduces microvascular dysfunction and myocyte necrosis in skeletal muscles subjected to subsequent prolonged periods of ischemia and reperfusion but should also provide a rationale for the pharmacologic treatment of disorders characterized by I/R.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL054797-06
Application #
2735268
Study Section
Cardiovascular and Renal Study Section (CVB)
Project Start
1995-07-01
Project End
2000-04-30
Budget Start
1998-07-01
Budget End
2000-04-30
Support Year
6
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Louisiana State University Hsc Shreveport
Department
Physiology
Type
Schools of Medicine
DUNS #
City
Shreveport
State
LA
Country
United States
Zip Code
71103
Yamaguchi, Taiji; Kamada, Kazuhiro; Dayton, Catherine et al. (2007) Role of eNOS-derived NO in the postischemic anti-inflammatory effects of antecedent ethanol ingestion in murine small intestine. Am J Physiol Heart Circ Physiol 292:H1435-42
Dayton, Catherine; Yamaguchi, Taiji; Kamada, Kazuhiro et al. (2005) Antecedent ethanol ingestion prevents postischemic leukocyte adhesion and P-selectin expression by a protein kinase C-dependent mechanism. Dig Dis Sci 50:684-90
Dayton, Catherine; Yamaguchi, Taiji; Kamada, Kazuhiro et al. (2004) Antecedent ethanol ingestion prevents postischemic P-selectin expression in murine small intestine. Microcirculation 11:709-18
Yamaguchi, Taiji; Dayton, Catherine B; Ross, Chris R et al. (2003) Late preconditioning by ethanol is initiated via an oxidant-dependent signaling pathway. Free Radic Biol Med 34:365-76
Shigematsu, Sakuji; Ishida, Shuji; Hara, Masahide et al. (2003) Resveratrol, a red wine constituent polyphenol, prevents superoxide-dependent inflammatory responses induced by ischemia/reperfusion, platelet-activating factor, or oxidants. Free Radic Biol Med 34:810-7
Shigematsu, Sakuji; Ishida, Shuji; Gute, Dean C et al. (2002) Bradykinin-induced proinflammatory signaling mechanisms. Am J Physiol Heart Circ Physiol 283:H2676-86
Dayton, Catherine; Yamaguchi, Taiji; Warren, April et al. (2002) Ischemic preconditioning prevents postischemic arteriolar, capillary, and postcapillary venular dysfunction: signaling pathways mediating the adaptive metamorphosis to a protected phenotype in preconditioned endothelium. Microcirculation 9:73-89
Korthui, Ronald J; Gute, Dean C (2002) Anti-inflammatory actions of a micronized, purified flavonoid fraction in ischemia/reperfusion. Adv Exp Med Biol 505:181-90
Yamaguchi, Taiji; Dayton, Catherine; Shigematsu, T et al. (2002) Preconditioning with ethanol prevents postischemic leukocyte-endothelial cell adhesive interactions. Am J Physiol Heart Circ Physiol 283:H1019-30
Shigematsu, S; Ishida, S; Gute, D C et al. (2001) Postischemic anti-inflammatory effects of bradykinin preconditioning. Am J Physiol Heart Circ Physiol 280:H441-54

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