Abstract
Objective: We previously demonstrated that pharmacologic activation of AMP-activated protein kinase (AMPK) with 5-aminoimidazole-4-carboxamide 1-β-D-ribofuranoside (AICAR) 24 hours prior to (AICAR preconditioning; AICAR-PC) ischemia/reperfusion (I/R) prevents postischemic leukocyte-endothelial cell adhesive interactions (LEI) by a mechanism initiated by endothelial nitric oxide synthase (eNOS)-dependent NO production during the period of AICAR-PC. The major aim of this study was to examine the role of ATP-sensitive potassium (KATP) channels and heme oxygenase as mediators of the antiadhesive effects of AICAR-PC during I/R 24 hours later.
Methods: Intravital fluorescence microscopy was used to quantify LEI in the small intestine of AICAR-preconditioned C57BL/6J mice treated with KATP channel or heme oxygenase inhibitors during I/R 24 hours after AICAR-PC in separate experiments.
Results: I/R induced marked increases in LEI relative to sham control mice, proadhesive responses that were prevented by AICAR-PC 24 hours prior to I/R. The effects of AICAR-PC to prevent postischemic LEI were abolished by KATP channel or heme oxygenase inhibition during I/R.
Discussion/Conclusion: Our results indicate that the antiadhesive effects of AICAR-PC are mediated by KATP channel- and heme oxygenase-dependent mechanisms during I/R.
Acknowledgements
Kazuhiro Kamada has returned to Japan and is currently with the Department of Inflammation and Immunology, Kyoto Prefectural University of Medicine, Graduate School of Medical Science (Kyoto, Japan). This work was supported by grants from the National Institutes of Health (AA-14945, HL-82816, HL-59976, and HL-73414).