title: Methamphetamine induces the release of endothelin.
abstract: Methamphetamine is a potent psychostimulant drug of abuse that increases release and blocks reuptake of dopamine, producing intense euphoria, factors that may contribute to its widespread abuse. It also produces severe neurotoxicity resulting from oxidative stress, DNA damage, blood-brain barrier disruption, microgliosis, and mitochondrial dysfunction. Intracerebral hemorrhagic and ischemic stroke have been reported after intravenous and oral abuse of methamphetamine. Several studies have shown that methamphetamine causes vasoconstriction of vessels. This study investigates the effect of methamphetamine on endothelin-1 (ET-1) release in mouse brain endothelial cells by ELISA. ET-1 transcription as well as endothelial nitric oxide synthase (eNOS) activation and transcription were measured following methamphetamine treatment. We also examine the effect of methamphetamine on isolated cerebral arteriolar vessels from C57BL/6 mice. Penetrating middle cerebral arterioles were cannulated at both ends with a micropipette system. Methamphetamine was applied extraluminally, and the vascular response was investigated. Methamphetamine treatment of mouse brain endothelial cells resulted in ET-1 release and a transient increase in ET-1 message. The activity and transcription of eNOS were only slightly enhanced after 24 hr of treatment with methamphetamine. In addition, methamphetamine caused significant vasoconstriction of isolated mouse intracerebral arterioles. The vasoconstrictive effect of methamphetamine was attenuated by coapplication of the endothelin receptor antagonist PD145065. These findings suggest that vasoconstriction induced by methamphetamine is mediated through the endothelin receptor and may involve an endothelin-dependent pathway.
authors.affiliation: Neurotrauma Research, Swedish Medical Center, Englewood, Colorado.
authors.forename: Jeong-Woo
authors.initials: JW
authors.lastname: Seo
authors.affiliation: Neurotrauma Research, Swedish Medical Center, Englewood, Colorado.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Jones
authors.affiliation: Neurotrauma Research, Swedish Medical Center, Englewood, Colorado.
authors.forename: Trisha A
authors.initials: TA
authors.lastname: Hostetter
authors.affiliation: Department of Anesthesiology and Perioperative Medicine, Oregon Health and Science University, Portland, Oregon.
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Iliff
authors.affiliation: Colorado Brain and Spine Institute, Englewood, Colorado.
authors.forename: G Alexander
authors.initials: GA
authors.lastname: West
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001158:Arteries / Q000187:drug effects; D001921:Brain / Q000166:cytology; D002461:Cell Line, Transformed; D002470:Cell Survival / Q000187:drug effects; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D019332:Endothelin-1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D004727:Endothelium / Q000187:drug effects*; D004797:Enzyme-Linked Immunosorbent Assay; D008694:Methamphetamine / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D013997:Time Factors; D014661:Vasoconstriction / Q000187:drug effects
chemical_list: D000697:Central Nervous System Stimulants; D019332:Endothelin-1; D009842:Oligopeptides; D012333:RNA, Messenger; C082887:PD 145065; D008694:Methamphetamine; D052250:Nitric Oxide Synthase Type III
keywords: endothelial cells; endothelin; isolated intracerebral arterioles; methamphetamine; vasoconstriction