title: Testosterone worsens endothelial dysfunction associated with hypercholesterolemia and environmental tobacco smoke exposure in male rabbit aorta.
abstract: OBJECTIVE
  To assess the effects of interaction of sex hormones, hypercholesterolemia (HC) and environmental tobacco smoke (ETS) exposure on endothelium-dependent relaxation, we examined vascular reactivity in vitro in an animal model of atherogenesis.
  
  
  BACKGROUND
  Animal and human studies indicate the presence of interactions between classic coronary artery disease risk factors and endothelium-dependent relaxation. Sex hormones have also been shown to influence release of endothelium-derived relaxing factor.
  
  
  METHODS
  New Zealand White rabbits were randomized to receive either an HC diet (n = 8) or ETS exposure plus HC diet (n = 8). Eight rabbits receiving a normal diet, without exposure to ETS, served as the control group. The HC diet consisted of 3% soybean oil and 0.3% cholesterol by weight over 13 weeks. The source of ETS was sidestream smoke of 4 cigarettes/15 min, 6 h/day, 5 days/week over 10 weeks in a smoking chamber. Rabbits were killed, and fresh aortic rings were harvested and maintained in oxygenated Krebs solution in an organ bath at 37 degrees C. Rings were precontracted with norepinephrine and exposed to acetylcholine in increasing doses, and isometric tension was recorded. Rings were also exposed to physiologic concentrations (1 nmol/liter) of either 17-beta-estradiol, testosterone or progesterone before pre-contraction with norepinephrine and relaxation with acetylcholine. Endothelium-independent relaxation was studied using nitroglycerin. The surface area of the ring covered by lipids was measured by Sudan IV staining.
  
  
  RESULTS
  HC and ETS significantly reduced endothelium-dependent relaxation (p = 0.01 and p < 0.0005, respectively) and caused atherogenesis (p < 0.0005 and p = 0.047, respectively) but did not affect endothelium-independent relaxation. Incubation with estradiol and estradiol plus progesterone did not influence endothelium-dependent relaxation. Testosterone reduced endothelium-dependent relaxation (p = 0.049) and augmented the endothelial dysfunction associated with ETS exposure and HC (p = 0.03).
  
  
  CONCLUSIONS
  Both HC and ETS are atherogenic and impair endothelial function but do not affect endothelium-independent relaxation. Physiologic levels of estradiol and estradiol plus progesterone do not affect endothelium-dependent relaxation. Physiologic levels of testosterone impair relaxation and augment the endothelial dysfunction associated with ETS exposure and HC.
authors.affiliation: Division of Cardiology, University of California San Francisco 94143, USA.
authors.forename: S J
authors.initials: SJ
authors.lastname: Hutchison
authors.forename: K
authors.initials: K
authors.lastname: Sudhir
authors.forename: T M
authors.initials: TM
authors.lastname: Chou
authors.forename: R E
authors.initials: RE
authors.lastname: Sievers
authors.forename: B Q
authors.initials: BQ
authors.lastname: Zhu
authors.forename: Y P
authors.initials: YP
authors.lastname: Sun
authors.forename: P C
authors.initials: PC
authors.lastname: Deedwania
authors.forename: S A
authors.initials: SA
authors.lastname: Glantz
authors.forename: W W
authors.initials: WW
authors.lastname: Parmley
authors.forename: K
authors.initials: K
authors.lastname: Chatterjee
mesh_terms: D000818:Animals; D001011:Aorta / Q000502:physiology*; D001161:Arteriosclerosis / Q000503:physiopathology; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000502:physiology*; D004958:Estradiol / Q000502:physiology; D006937:Hypercholesterolemia / Q000503:physiopathology*; D008297:Male; D011374:Progesterone / Q000502:physiology; D011817:Rabbits; D013739:Testosterone / Q000502:physiology*; D014028:Tobacco Smoke Pollution; D014664:Vasodilation / Q000187:drug effects*
chemical_list: D014028:Tobacco Smoke Pollution; D013739:Testosterone; D011374:Progesterone; D004958:Estradiol