title: A differential impact of lithium on endothelium-dependent but not on endothelium-independent vessel relaxation.
abstract: Lithium is drug for bipolar disorders with a narrow therapeutic window. Lithium was recently reported to prevent stroke and protect vascular endothelium but tends to accumulate particularly in the brain and kidney. Here, adverse effects are common; however mechanisms are still vaguely understood. If lithium could also negatively influence the endothelium is unclear. We hypothesize that at higher lithium levels, the effects on endothelium reverses--that lithium also impairs endothelial-dependent relaxation of blood vessels. Vessel grafts from de-nerved murine aortas and porcine middle cerebral arteries were preconditioned using media supplemented with lithium chloride or acetate (0.4-100 mmol/L). Native or following phenylephrine-induced vasoconstriction, the relaxation capacity of preconditioned vessels was assessed by isometric myography, using acetylcholine to test the endothelium-dependent or sodium nitroprusside to test the endothelium-independent vasorelaxation, respectively. At the 0.4 mmol/L lithium concentration, acetylcholine-induced endothelium-dependent vessel relaxation was slightly increased, however, diminished in a concentration-dependent manner in vessel grafts preconditioned with lithium at higher therapeutic and supratherapeutic concentrations (0.8-100 mmol/L). In contrast, endothelium-independent vasorelaxation remained unaltered in preconditioned vessel grafts at any lithium concentration tested. Lithium elicits opposing effects on endothelial functions representing a differential impact on the endothelium within the narrow therapeutic window. Lithium accumulation or overdose reduces endothelium-dependent but not endothelium-independent vasorelaxation. The differentially modified endothelium-dependent vascular response represents an additional mechanism contributing to therapeutic or adverse effects of lithium.
authors.affiliation: Division of Neurosurgery, St Michael's Hospital, Keenan Research Centre for Biomedical Science and the Li Ka Shing Knowledge Institute of St. Michael's Hospital, Department of Surgery, University of Toronto, Toronto, Ontario, Canada; Department of Neurology, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany. Electronic address: Bert.Bosche@gmail.com.
authors.forename: Bert
authors.initials: B
authors.lastname: Bosche
authors.affiliation: Institute of Neurophysiology, Center of Physiology and Pathophysiology, University of Cologne, Cologne, Germany.
authors.forename: Marek
authors.initials: M
authors.lastname: Molcanyi
authors.affiliation: Institute of Physiology, Medical Faculty Carl Gustav Carus, Technical University of Dresden, Dresden, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Noll
authors.affiliation: Division of Geriatric Psychiatry, Department of Psychiatry, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada; Department of Psychiatry, Geri-PARTy Research Group, Jewish General Hospital, McGill University, Montréal, Québec, Canada.
authors.forename: Soham
authors.initials: S
authors.lastname: Rej
authors.affiliation: Institute of Physiology, Medical Faculty Carl Gustav Carus, Technical University of Dresden, Dresden, Germany.
authors.forename: Birgit
authors.initials: B
authors.lastname: Zatschler
authors.affiliation: Department of Neurology, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany.
authors.forename: Thorsten R
authors.initials: TR
authors.lastname: Doeppner
authors.affiliation: Institute of Neurophysiology, Center of Physiology and Pathophysiology, University of Cologne, Cologne, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Hescheler
authors.affiliation: Pharmacogenetics Research Clinic, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health & Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Müller
authors.affiliation: Division of Neurosurgery, St Michael's Hospital, Keenan Research Centre for Biomedical Science and the Li Ka Shing Knowledge Institute of St. Michael's Hospital, Department of Surgery, University of Toronto, Toronto, Ontario, Canada.
authors.forename: R Loch
authors.initials: RL
authors.lastname: Macdonald
authors.affiliation: Institute of Physiology, Medical Faculty Carl Gustav Carus, Technical University of Dresden, Dresden, Germany.
authors.forename: Frauke V
authors.initials: FV
authors.lastname: Härtel
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D018692:Antimanic Agents / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007537:Isometric Contraction / Q000187:drug effects; D018021:Lithium Chloride / Q000494:pharmacology*; D047028:Macrocyclic Compounds / Q000494:pharmacology; D051379:Mice; D019001:Nitric Oxide Synthase / Q000378:metabolism; D010080:Oxazoles / Q000494:pharmacology; D010656:Phenylephrine / Q000494:pharmacology; D018709:Statistics, Nonparametric; D013552:Swine; D013997:Time Factors; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology*
chemical_list: D018692:Antimanic Agents; D004791:Enzyme Inhibitors; D047028:Macrocyclic Compounds; D010080:Oxazoles; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; C108642:xestospongin D; D010656:Phenylephrine; D019001:Nitric Oxide Synthase; D018021:Lithium Chloride; D000109:Acetylcholine
keywords: Adverse effects of lithium; Bipolar disorder; Cerebrovascular autoregulation; Endothelial function; Endothelium; Lithium; Stroke; Vascular autoregulation; Vascular relaxation