AICAR preconditioning prevents postischemic leukocyte rolling and adhesion: role of K(ATP) channels and heme oxygenase.
OBJECTIVE
We previously demonstrated that pharmacologic activation of AMP-activated protein kinase (AMPK) with 5-aminoimidazole-4-carboxamide 1-beta-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 (K(ATP)) 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 K(ATP) 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 K(ATP) channel or heme oxygenase inhibition during I/R.


CONCLUSIONS
Our results indicate that the antiadhesive effects of AICAR-PC are mediated by K(ATP) channel- and heme oxygenase-dependent mechanisms during I/R.
Gaskin
F Spencer
FS
Department of Medical Pharmacology and Physiology, University of Missouri-Columbia, One Hospital Drive, Columbia, MO 65212, USA.
Kamada
Kazuhiro
K
Yusof
Mozow
M
Durante
William
W
Gross
Garrett
G
Korthuis
Ronald J
RJ
D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism*; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007421:Intestine, Small / Q000378:metabolism; D036904:Leukocyte Rolling / Q000187:drug effects*; D007962:Leukocytes / Q000378:metabolism*; D008297:Male; D051379:Mice; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D015221:Potassium Channels / Q000378:metabolism*; D015427:Reperfusion Injury / Q000378:metabolism*; D012265:Ribonucleotides / Q000494:pharmacology*; D013997:Time Factors
D007004:Hypoglycemic Agents; D015221:Potassium Channels; D012265:Ribonucleotides; D000620:Aminoimidazole Carboxamide; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D006419:Heme Oxygenase (Decyclizing); D055372:AMP-Activated Protein Kinases; C031143:AICA ribonucleotide