title: Heart rate contributes to the vascular effects of chronic mental stress: effects on endothelial function and ischemic brain injury in mice.
abstract: OBJECTIVE
  Vascular effects of mental stress are only partially understood. Therefore, we studied effects of chronic stress and heart rate (HR) on endothelial function and cerebral ischemia.
  
  
  METHODS
  129S6/SvEv mice were randomized to the I(f)-channel inhibitor ivabradine (10 mg/kg per day) or vehicle and underwent a chronic stress protocol for 28 days.
  
  
  RESULTS
  Stress increased HR from 514 ± 10 bpm to 570 ± 14 bpm, this was prevented by ivabradine (485 ± 7 bpm). Endothelium-dependent relaxation of aortic rings was impaired in mice exposed to stress. HR reduction restored endothelial function to the level of naive controls. Vascular lipid hydroperoxides were increased to 333% ± 24% and vascular NADPH oxidase activity was upregulated to 223 ± 38% in stressed mice, which was prevented by ivabradine. Stress reduced aortic endothelial nitric oxide synthase mRNA expression to 84% ± 3% and increased AT1 receptor mRNA to 168% ± 18%. Both effects were attenuated by HR reduction. In brain tissue, stress resulted in an upregulation of lipid hydroperoxides to 140% ± 11%, which was attenuated by HR reduction. Ivabradine increased brain capillary density in naive and in stressed mice. Mice exposed to chronic stress before induction of ischemic stroke by transient middle cerebral artery occlusion exhibited increased lesion size (33.7 ± 2.3 mm3 versus 23.9 ± 2.4 mm3). HR reduction led to a marked reduction of the infarct volume to 12.9 ± 3.3 mm3.
  
  
  CONCLUSIONS
  Chronic stress impairs endothelial function and aggravates ischemic brain injury. HR reduction protects from cerebral ischemia via improvement of endothelial function and reduction of oxidative stress. These results identify heart rate as a mediator of vascular effects induced by chronic stress.
authors.affiliation: Klinik für Innere Medizin III, Kardiologie, Angiologie und Internistische Intensivmedizin, Universitätsklinikum des Saarlandes, Kirrberger Straße, 66424 Homburg/Saar, Germany. florian.custodis@uks.eu
authors.forename: Florian
authors.initials: F
authors.lastname: Custodis
authors.forename: Karen
authors.initials: K
authors.lastname: Gertz
authors.forename: Mustafa
authors.initials: M
authors.lastname: Balkaya
authors.forename: Vincent
authors.initials: V
authors.lastname: Prinz
authors.forename: Ilka
authors.initials: I
authors.lastname: Mathar
authors.forename: Christoph
authors.initials: C
authors.lastname: Stamm
authors.forename: Golo
authors.initials: G
authors.lastname: Kronenberg
authors.forename: Andrey
authors.initials: A
authors.lastname: Kazakov
authors.forename: Marc
authors.initials: M
authors.lastname: Freichel
authors.forename: Michael
authors.initials: M
authors.lastname: Böhm
authors.forename: Matthias
authors.initials: M
authors.lastname: Endres
authors.forename: Ulrich
authors.initials: U
authors.lastname: Laufs
mesh_terms: D000818:Animals; D001552:Benzazepines / Q000494:pharmacology; D001794:Blood Pressure / Q000502:physiology; D002545:Brain Ischemia / Q000473:pathology / Q000503:physiopathology*; D002560:Cerebrovascular Circulation / Q000502:physiology; D004730:Endothelium, Vascular / Q000473:pathology / Q000503:physiopathology*; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology*; D020244:Infarction, Middle Cerebral Artery; D000077550:Ivabradine; D015227:Lipid Peroxidation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress / Q000502:physiology; D011897:Random Allocation; D013315:Stress, Psychological / Q000503:physiopathology*
chemical_list: D001552:Benzazepines; D000077550:Ivabradine