Fluoxetine effect on aortic nitric oxide-dependent vasorelaxation in the unpredictable chronic mild stress model of depression in mice.
OBJECTIVE
Major depression is an independent risk factor for the development of cardiovascular diseases. However, the exact mechanism by which depression may induce cardiovascular events is unclear. Endothelial dysfunction has been reported as a possible link between depression and subsequent cardiovascular events as described in depressed subjects. The purpose of this study was to investigate endothelial dysfunction and atherosclerosis formation in the aorta of mice exposed to the unpredictable chronic mild stress (UCMS) procedure.


METHODS
BALB/c mice were exposed to two 7-week UCMS procedures separated by 6 weeks. Treatments (fluoxetine 10 mg/kg; NaCl 0.9%) started at the third week until the end of the seventh week of each procedure. Endothelial function was evaluated by in vitro assessment of acetylcholine-induced vasorelaxation in aortic rings. By using specific inhibitors for nitric oxide (NO)- and prostacyclin-dependent relaxation, we assessed the part played by NO, prostacyclin, and endothelium-derived hyperpolarizing factor (EDHF)-like mediators in endothelium-dependent relaxation. Atherosclerosis was evaluated by histological examination.


RESULTS
Depression-like behavior was increased in the UCMS versus unstressed group and was reversed by chronic fluoxetine treatment. Vascular reactivity study indicated that UCMS induced a decrease in the NO-dependent relaxation that was partially compensated by an EDHF-like dependent relaxation. Because fluoxetine per se increased the NO-dependent relaxation, fluoxetine was able to reverse UCMS effect on the NO component and abolished the EDHF-like component. Atherosclerotic lesion was found in aorta of UCMS and nonstressed animals.


CONCLUSIONS
As an independent risk factor, UCMS reproduced the endothelial alterations observed in depression but was not sufficient to provoke morphological alterations.
Institut National de la Santé et de la Recherche Médicale U930, Team 4 (Affective disorders), Université François-Rabelais de Tours, Parc Grandmont, Batiment O, 37041 Tours Cedex 01, France. Isingrini.elsa@voila.fr
Elsa
E
Isingrini
Catherine
C
Belzung
Jean-Louis
JL
Freslon
Marie-Christine
MC
Machet
Vincent
V
Camus
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D050197:Atherosclerosis / Q000209:etiology / Q000473:pathology; D001685:Biological Factors / Q000502:physiology; D003865:Major Depressive Disorder / Q000503:physiopathology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000503:physiopathology*; D045462:Endothelium-Dependent Relaxing Factors / Q000502:physiology; D011464:Epoprostenol / Q000502:physiology; D005473:Fluoxetine / Q000494:pharmacology*; D016015:Logistic Models; D051379:Mice; D008807:Mice, Inbred BALB C; D009569:Nitric Oxide / Q000502:physiology; D011897:Random Allocation; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D013315:Stress, Psychological / Q000503:physiopathology*; D014664:Vasodilation / Q000187:drug effects* / Q000502:physiology
D000109:Acetylcholine; D001685:Biological Factors; D045462:Endothelium-Dependent Relaxing Factors; D011464:Epoprostenol; D005473:Fluoxetine; D009569:Nitric Oxide; D017367:Selective Serotonin Reuptake Inhibitors; C067410:endothelium-dependent hyperpolarization factor