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: Bert Bosche, Marek Molcanyi, Thomas Noll, Soham Rej, Birgit Zatschler, Thorsten R Doeppner, Jürgen Hescheler, Daniel J Müller, R Loch Macdonald, Frauke V Härtel
• Journal: Progress in neuro-psychopharmacology & biological psychiatry (Prog Neuropsychopharmacol Biol Psychiatry) Vol. 67 Pg. 98-106 (Jun 03 2016) ISSN: 1878-4216 [Electronic] England
• PMID: 26875501 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2016 Elsevier Inc. All rights reserved.

Chemical References

• Antimanic Agents
• Enzyme Inhibitors
• Macrocyclic Compounds
• Oxazoles
• Vasoconstrictor Agents
• Vasodilator Agents
• xestospongin D
• Phenylephrine
• Nitric Oxide Synthase
• Lithium Chloride
• Acetylcholine

Topics

• Acetylcholine (pharmacology)
• Animals
• Antimanic Agents (pharmacology)
• Dose-Response Relationship, Drug
• Endothelium, Vascular (drug effects)
• Enzyme Inhibitors (pharmacology)
• Isometric Contraction (drug effects)
• Lithium Chloride (pharmacology)
• Macrocyclic Compounds (pharmacology)
• Mice
• Nitric Oxide Synthase (metabolism)
• Oxazoles (pharmacology)
• Phenylephrine (pharmacology)
• Statistics, Nonparametric
• Swine
• Time Factors
• Vasoconstrictor Agents (pharmacology)
• Vasodilation (drug effects)
• Vasodilator Agents (pharmacology)