title: Inhibition of brain swelling after ischemia-reperfusion by β-adrenergic antagonists: correlation with increased K+ and decreased Ca2+ concentrations in extracellular fluid.
abstract: Infarct size and brain edema following ischemia/reperfusion are reduced by inhibitors of the Na+, K+, 2Cl-, and water cotransporter NKCC1 and by β1-adrenoceptor antagonists. NKCC1 is a secondary active transporter, mainly localized in astrocytes, driven by transmembrane Na+/K+ gradients generated by the Na+,K+-ATPase. The astrocytic Na+,K+-ATPase is stimulated by small increases in extracellular K+ concentration and by the β-adrenergic agonist isoproterenol. Larger K+ increases, as occurring during ischemia, also stimulate NKCC1, creating cell swelling. This study showed no edema after 3 hr medial cerebral artery occlusion but pronounced edema after 8 hr reperfusion. The edema was abolished by inhibitors of specifically β1-adrenergic pathways, indicating failure of K+-mediated, but not β1-adrenoceptor-mediated, stimulation of Na+,K+-ATPase/NKCC1 transport during reoxygenation. Ninety percent reduction of extracellular Ca2+ concentration occurs in ischemia. Ca2+ omission abolished K+ uptake in normoxic cultures of astrocytes after addition of 5 mM KCl. A large decrease in ouabain potency on K+ uptake in cultured astrocytes was also demonstrated in Ca2+-depleted media, and endogenous ouabains are needed for astrocytic K+ uptake. Thus, among the ionic changes induced by ischemia, the decrease in extracellular Ca2+ causes failure of the high-K+-stimulated Na+,K+-ATPase/NKCC1 ion/water uptake, making β1-adrenergic activation the only stimulus and its inhibition effective against edema.
authors.affiliation: Laboratory of Brain Metabolic Diseases, Institute of Metabolic Disease Research and Drug Development China Medical University, No. 92 Beier Road, Heping District, Shenyang 110001, China.
authors.forename: Dan
authors.identifier: 0000-0003-0659-6813
authors.initials: D
authors.lastname: Song
authors.affiliation: Laboratory of Brain Metabolic Diseases, Institute of Metabolic Disease Research and Drug Development China Medical University, No. 92 Beier Road, Heping District, Shenyang 110001, China.
authors.forename: Junnan
authors.initials: J
authors.lastname: Xu
authors.affiliation: Laboratory of Brain Metabolic Diseases, Institute of Metabolic Disease Research and Drug Development China Medical University, No. 92 Beier Road, Heping District, Shenyang 110001, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Du
authors.affiliation: Laboratory of Brain Metabolic Diseases, Institute of Metabolic Disease Research and Drug Development China Medical University, No. 92 Beier Road, Heping District, Shenyang 110001, China.
authors.forename: Enzhi
authors.initials: E
authors.lastname: Yan
authors.affiliation: Laboratory of Brain Metabolic Diseases, Institute of Metabolic Disease Research and Drug Development China Medical University, No. 92 Beier Road, Heping District, Shenyang 110001, China ; Departments of Psychiatry and Pharmacology, University of Saskatchewan, Saskatoon, SK, Canada.
authors.forename: Leif
authors.identifier: 0000-0001-7878-9863
authors.initials: L
authors.lastname: Hertz
authors.affiliation: Departments of Psychiatry and Pharmacology, University of Saskatchewan, Saskatoon, SK, Canada.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Walz
authors.affiliation: Laboratory of Brain Metabolic Diseases, Institute of Metabolic Disease Research and Drug Development China Medical University, No. 92 Beier Road, Heping District, Shenyang 110001, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Peng
mesh_terms: D058671:Adrenergic beta-1 Receptor Antagonists / Q000627:therapeutic use; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000473:pathology; D001929:Brain Edema / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002118:Calcium / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects; D045604:Extracellular Fluid / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D051379:Mice; D011188:Potassium / Q000378:metabolism*; D051381:Rats; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism; D064506:Solute Carrier Family 12, Member 2 / Q000378:metabolism
chemical_list: D058671:Adrenergic beta-1 Receptor Antagonists; C578877:SLC12A2 protein, human; D064506:Solute Carrier Family 12, Member 2; D000254:Sodium-Potassium-Exchanging ATPase; D011188:Potassium; D002118:Calcium