Inhibitor of nuclear factor-Kappa B activation attenuates venular constriction, leukocyte rolling-adhesion and microvessel rupture induced by ethanol in intact rat brain microcirculation: relation to ethanol-induced brain injury.
The present study was designed to test the hypothesis that acute, local administration of a specific inhibitor of nuclear factor-Kappa B activation (which prevents rapid proteolysis of IKB-alpha) will attenuate cerebral (cortical) venular constrictions, leukocyte-endothelial wall interactions and postcapillary damage induced by medium to high concentrations of ethanol in the intact rat brain. Perivascular or i.p. administration of ethanol (100, 250 mg/dl) to the intact rat brain resulted in concentration-dependent venular vasospasm, rolling and adherence of leukocytes to venular walls and rupture of postcapillary venules with focal hemorrhages. Superfusion of the in-situ brain with N(alpha)-L-tosyl-L-phenylalanine chloromethyl ketone (TPCK), a specific inhibitor of IKB-alpha proteolysis, attenuated greatly the spasmogenic, leukocyte rolling-endothelial cell adhesion and postcapillary hemorrhages induced by ethanol. These new data suggest that inhibition of alcohol-inducible degradation of IKB-alpha by TPKC can prevent much of the adverse microvascular actions of ethanol in the intact rat brain. Moreover, these new in-situ results suggest that activation of nuclear factor-Kappa B seems to play a major modulatory role in the adverse cerebral vascular actions of concentrations of alcohol found in the blood of alcohol-intoxicated subjects and human stroke victims.
Altura
Burton M
BM
Department of Physiology and Pharmacology, State University of New York, Downstate Medical Center, Brooklyn, NY 11203, USA. baltura@netmail.hscbklyn.edu
Gebrewold
Asefa
A
D000818:Animals; D002540:Cerebral Cortex / Q000098:blood supply / Q000187:drug effects; D002560:Cerebrovascular Circulation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000008:administration & dosage / Q000633:toxicity; D020300:Intracranial Hemorrhages / Q000209:etiology; D036904:Leukocyte Rolling / Q000187:drug effects*; D008297:Male; D008833:Microcirculation / Q000187:drug effects*; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D014108:Tosylphenylalanyl Chloromethyl Ketone / Q000494:pharmacology*; D014661:Vasoconstriction / Q000187:drug effects*; D014699:Venules / Q000187:drug effects
D016328:NF-kappa B; D011500:Protein Synthesis Inhibitors; D000431:Ethanol; D014108:Tosylphenylalanyl Chloromethyl Ketone