title: Acute and chronic effects of endotoxin on cerebral circulation in lambs.
abstract: The impact of endotoxemia on cerebral endothelium and cerebral blood flow (CBF) regulation was studied in conscious newborn lambs. Bacterial endotoxin [LPS, 2 microg/kg iv] was infused on 3 consecutive days. Cerebrovascular function was assessed by monitoring CBF and cerebral vascular resistance (CVR) over 12 h each day and by the endothelium-dependent vasodilator bradykinin (BK) (n = 10). Inflammatory responses were assessed by plasma tumor necrosis factor-alpha (TNF-alpha, n = 5). Acutely, LPS disrupted the cerebral circulation within 1 h, with peak cerebral vasoconstriction at 3 h (CBF -28 and CVR +118%, P < 0.05) followed by recovery to baseline by 12 h. TNF-alpha and body temperature peaked approximately 1 h post-LPS. BK-induced vasodilatation (CVR -20%, P < 0.05) declined with each LPS infusion, was abolished after 3 days, and remained absent for at least the subsequent 5 days. Histological evidence of brain injury was found in four of five LPS-treated newborns. We conclude that endotoxin impairs cerebral perfusion in newborn lambs via two mechanisms: 1) acute vasoconstriction (over several hours); and 2) persistent endothelial dysfunction (over several days). Endotoxin-induced circulatory impairments may place the newborn brain at prolonged risk of CBF dysregulation and injury as a legacy of endotoxin exposure.
authors.affiliation: Ritchie Centre for Baby Health Research, Monash Institute of Medical Research, Monash University, Victoria, Australia.
authors.forename: Susan Y S
authors.initials: SY
authors.lastname: Feng
authors.forename: Thilini
authors.initials: T
authors.lastname: Samarasinghe
authors.forename: David J
authors.initials: DJ
authors.lastname: Phillips
authors.forename: Theodora
authors.initials: T
authors.lastname: Alexiou
authors.forename: Jacob H
authors.initials: JH
authors.lastname: Hollis
authors.forename: Victor Y H
authors.initials: VY
authors.lastname: Yu
authors.forename: Adrian M
authors.initials: AM
authors.lastname: Walker
mesh_terms: D000208:Acute Disease; D000818:Animals; D000831:Animals, Newborn; D001831:Body Temperature / Q000187:drug effects / Q000502:physiology; D001920:Bradykinin / Q000097:blood / Q000494:pharmacology; D001921:Brain / Q000098:blood supply / Q000473:pathology; D002560:Cerebrovascular Circulation / Q000187:drug effects / Q000502:physiology*; D002561:Cerebrovascular Disorders / Q000139:chemically induced* / Q000503:physiopathology*; D002908:Chronic Disease; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology; D019446:Endotoxemia / Q000473:pathology / Q000503:physiopathology*; D008070:Lipopolysaccharides / Q000633:toxicity*; D008264:Macrophages / Q000473:pathology; D009566:Nitrates / Q000097:blood; D009573:Nitrites / Q000097:blood; D012756:Sheep; D014409:Tumor Necrosis Factor-alpha / Q000097:blood; D014655:Vascular Resistance / Q000187:drug effects / Q000502:physiology; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology; D014665:Vasodilator Agents / Q000097:blood / Q000494:pharmacology
chemical_list: D008070:Lipopolysaccharides; D009566:Nitrates; D009573:Nitrites; D014409:Tumor Necrosis Factor-alpha; D014665:Vasodilator Agents; C082161:lipopolysaccharide A; D001920:Bradykinin