Antecedent ethanol attenuates cerebral ischemia/reperfusion-induced leukocyte-endothelial adhesive interactions and delayed neuronal death: role of large conductance, Ca2+-activated K+ channels.
EtOH-PC reduces postischemic neuronal injury in response to cerebral (I/R). We examined the mechanism underlying this protective effect by determining (i) whether it was associated with a decrease in I/R-induced leukocyte-endothelial adhesive interactions in postcapillary venules, and (ii) whether the protective effects were mediated by activation of large conductance, calcium-activated potassium (BK(Ca)) channels. Mice were administered ethanol by gavage or treated with the BK(Ca) channel opener, NS1619, 24 hours prior to I/R with or without prior treatment with the BK(Ca) channel blocker, PX. Both CCA were occluded for 20 minutes followed by two and three hours of reperfusion, and rolling (LR) and adherent (LA) leukocytes were quantified in pial venules using intravital microscopy. The extent of DND, apoptosis and glial activation in hippocampus were assessed four days after I/R. Compared with sham, I/R elicited increases in LR and LA in pial venules and DND and apoptosis as well as glial activation in the hippocampus. These effects were attenuated by EtOH-PC or antecedent NS1619 administration, and this protection was reversed by prior treatment with PX. Our results support a role for BK(Ca) channel activation in the neuroprotective effects of EtOH-PC in cerebral I/R.
Wang
Qun
Q
Department of Medical Pharmacology and Physiology, University of Missouri School of Medicine, Columbia, Missouri 65212, USA.
Kalogeris
Theodore J
TJ
Wang
Meifang
M
Jones
Allan W
AW
Korthuis
Ronald J
RJ
D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D001812:Blood-Brain Barrier / Q000187:drug effects; D002545:Brain Ischemia / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D002448:Cell Adhesion / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D002560:Cerebrovascular Circulation / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects; D000431:Ethanol / Q000008:administration & dosage*; D007211:Indoles / Q000494:pharmacology; D019194:Ischemic Preconditioning / Q000379:methods; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007962:Leukocytes / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects* / Q000473:pathology; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D016548:Prosencephalon / Q000098:blood supply / Q000187:drug effects / Q000293:injuries; D015427:Reperfusion Injury / Q000097:blood / Q000188:drug therapy* / Q000473:pathology
C530995:BKCa protein, mouse; D001562:Benzimidazoles; D007211:Indoles; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits; D018696:Neuroprotective Agents; C086491:NS 1619; D000431:Ethanol; C048220:paxilline