title: Tacrolimus preserves vasomotor function and maintains vascular homeostasis.
abstract: BACKGROUND
  Post-transplant immunosuppression is associated with endothelial dysfunction that may lead to vasculopathy. We have previously demonstrated that cyclosporine causes vascular dysfunction. In this we study examined the effect of tacrolimus (Tac) in an identical model.
  
  
  METHODS
  Lewis rats (n = 8 per group) were injected with Tac (low, medium or high dose) or saline (Con) daily for 2 weeks. Segments of thoracic aorta (TAo) were assessed for endothelium-dependent (Edep) and -independent (Eind) vasorelaxation (E(max)) and sensitivity to endothelin (ET)-induced vasoconstriction (C(max)). ET(A) and ET(B) receptor (Rc) expression levels were determined in TAo. Tumor necrosis factor-alpha (TNF-α) and transforming growth factor-beta (TGF-β) expression were determined in myocardial (LV) tissue. Plasma ET levels and tissue oxidative injury were quantified by enzyme-linked immunoassay.
  
  
  RESULTS
  Tac did not impair Edep relaxation when compared with Con (p = 0.69). Impairment of sodium nitroprusside-mediated Eind vasorelaxation was noted with Tac (E(max): Con 69 ± 2%, Tac high 54 ± 2%; p = 0.0001), whereas no such impairment was seen with diltiazem-mediated Eind vasorelaxation (p = 0.06). Tac decreased sensitivity to ET (C(max): Con 222 ± 19%, Tac high 162 ± 11%; p = 0.0002) and ET levels (Con 0.8 ± 0.1 fmol/ml, Tac 0.4 ± 0.1 fmol/ml; p = 0.02). Tac did not alter ET(A) Rc expression (p = 0.28), but increased ET(B) Rc levels (p = 0.02). Oxidative injury was similar in both LV (p = 0.43) and Ao (p = 0.73) tissue. Similarly, TNF-α expression (p = 0.16) was not different between groups, whereas expression of TGF-β demonstrated a significant decrease with Tac treatment (p = 0.02).
  
  
  CONCLUSIONS
  Our findings suggests that tacrolimus has beneficial effects with respect to endothelial function.
authors.affiliation: Heart Transplant Program, Peter Munk Cardiac Centre, University Health Network, Toronto General Hospital, Toronto, Ontario, Canada.
authors.forename: Elissa D
authors.initials: ED
authors.lastname: Tepperman
authors.forename: Laura C
authors.initials: LC
authors.lastname: Tumiati
authors.forename: Danny
authors.initials: D
authors.lastname: Ramzy
authors.forename: Mitesh V
authors.initials: MV
authors.lastname: Badiwala
authors.forename: Rohit
authors.initials: R
authors.lastname: Sheshgiri
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Prodger
authors.forename: Heather J
authors.initials: HJ
authors.lastname: Ross
authors.forename: Vivek
authors.initials: V
authors.lastname: Rao
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000502:physiology; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000502:physiology*; D006706:Homeostasis / Q000187:drug effects* / Q000502:physiology; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008297:Male; D023421:Models, Animal; D009206:Myocardium / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D044022:Receptor, Endothelin A / Q000378:metabolism; D044023:Receptor, Endothelin B / Q000378:metabolism; D016559:Tacrolimus / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology; D014665:Vasodilator Agents / Q000494:pharmacology; D014666:Vasomotor System / Q000187:drug effects* / Q000502:physiology*
chemical_list: D007166:Immunosuppressive Agents; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D014409:Tumor Necrosis Factor-alpha; D014665:Vasodilator Agents; D052250:Nitric Oxide Synthase Type III; D016559:Tacrolimus