title: Tobacco smoke chemicals attenuate brain-to-blood potassium transport mediated by the Na,K,2Cl-cotransporter during hypoxia-reoxygenation.
abstract: Smoking tobacco, including cigarettes, has been associated with an increased incidence and relative risk for cerebral infarction in both men and women. Recently, we have shown that nicotine and cotinine attenuate abluminal (brain facing) K(+) uptake mediated by the Na,K,2Cl-cotransporter (NKCC) in bovine brain microvessel endothelial cells (BBMECs) after hypoxic/aglycemic exposure (stroke conditions). The purpose of the current study was to explore the effects of nicotine and tobacco smoke chemicals on K(+) movement through the blood-brain barrier during both hypoxia/aglycemia and reoxygenation. BBMECs were exposed to nicotine/cotinine, nicotine-containing cigarette smoke extract (N-CSE), or nicotine-free cigarette smoke extract (NF-CSE) in quantities designed to mimic plasma concentrations of smokers. Stroke conditions were mimicked in vitro in BBMECs through 6 h of hypoxia/aglycemia with or without 12 h of reoxygenation, after which NKCC-mediated K(+) uptake and paracellular integrity were measured with (86)Rb and [(14)C]sucrose, respectively. In addition, K(+) concentrations in brain extracellular fluid were estimated in (86)Rb-injected rats that were administered nicotine, N-CSE, or NF-CSE and on whom global ischemia/reperfusion by in vivo four-vessel occlusion was performed. Both in vitro and in vivo paradigms showed nicotine, the major alkaloid present in tobacco smoke, to be the determining factor of an inhibited response of abluminal NKCC in BBMECs during and after stroke conditions. This was measured as a decrease in abluminal brain endothelial cell NKCC activity and as an increase in brain extracellular K(+) concentration measured as the brain extracellular fluid (86)Rb/plasma ratio after in vivo four-vessel occlusion with reperfusion.
authors.affiliation: Dept. of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, 1300 South Coulter, Amarillo, TX 79106, USA.
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Paulson
authors.forename: Karen E
authors.initials: KE
authors.lastname: Roder
authors.forename: Ghia
authors.initials: G
authors.lastname: McAfee
authors.forename: David D
authors.initials: DD
authors.lastname: Allen
authors.forename: Cornelis J
authors.initials: CJ
authors.lastname: Van der Schyf
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Abbruscato
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001923:Brain Chemistry / Q000187:drug effects*; D002417:Cattle; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D002534:Hypoxia, Brain / Q000378:metabolism*; D017551:Microdialysis; D011188:Potassium / Q000378:metabolism*; D012414:Rubidium Radioisotopes; D012906:Smoke / Q000032:analysis*; D028021:Sodium-Potassium-Chloride Symporters / Q000378:metabolism*; D013395:Sucrose / Q000378:metabolism; D014026:Nicotiana
chemical_list: D001786:Blood Glucose; D012414:Rubidium Radioisotopes; D012906:Smoke; D028021:Sodium-Potassium-Chloride Symporters; D013395:Sucrose; D011188:Potassium