title: Poly(ADP-ribose) polymerase inhibition reverses vascular dysfunction after gamma-irradiation.
abstract: OBJECTIVE
  The generation of reactive oxygen species during gamma-irradiation may induce DNA damage, leading to activation of the nuclear enzyme poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) culminating in endothelial dysfunction. In the present study, we assessed the effect of PARP inhibition on changes in vascular function after acute and short-term irradiation.
  
  
  METHODS
  In the acute experiments, aortic rings were exposed to 20 Gy of gamma-irradiation. The aortae were harvested after 1 or 7 days. Two additional groups received the ultrapotent PARP inhibitor, INO-1001, for 1 or 7 days after irradiation. The aortic rings were precontracted by phenylephrine and relaxation to acetylcholine and sodium nitroprusside were studied.
  
  
  RESULTS
  The vasoconstrictor response to phenylephrine was significantly lower both acutely and 1 and 7 days after irradiation. Vasorelaxation to acetylcholine and sodium nitroprusside was not impaired acutely after irradiation. One and seven days after irradiation, vasorelaxation to acetylcholine and sodium nitroprusside was significantly enhanced. Treatment with INO-1001 reversed vascular dysfunction after irradiation.
  
  
  CONCLUSIONS
  Vascular dysfunction was observed 1 and 7 days after irradiation, as evidenced by reduced vasoconstriction, coupled with endothelium-dependent and -independent hyperrelaxation. PARP inhibition restored vascular function and may, therefore, be suitable to reverse vascular dysfunction after irradiation.
authors.affiliation: Department of Cardiac Surgery, University of Heidelberg, Heidelberg, Germany. Carsten.Beller@urz.uni-heidelberg.de
authors.forename: Carsten J
authors.initials: CJ
authors.lastname: Beller
authors.forename: Tamás
authors.initials: T
authors.lastname: Radovits
authors.forename: Leila
authors.initials: L
authors.lastname: Seres
authors.forename: Jens
authors.initials: J
authors.lastname: Kosse
authors.forename: Robert
authors.initials: R
authors.lastname: Krempien
authors.forename: Marie-Luise
authors.initials: ML
authors.lastname: Gross
authors.forename: Roland
authors.initials: R
authors.lastname: Penzel
authors.forename: Irina
authors.initials: I
authors.lastname: Berger
authors.forename: Peter E
authors.initials: PE
authors.lastname: Huber
authors.forename: Siegfried
authors.initials: S
authors.lastname: Hagl
authors.forename: Csaba
authors.initials: C
authors.lastname: Szabó
authors.forename: Gábor
authors.initials: G
authors.lastname: Szabó
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001013:Aorta, Thoracic; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects*; D004789:Enzyme Activation; D005720:Gamma Rays; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D009599:Nitroprusside / Q000494:pharmacology; D010656:Phenylephrine / Q000494:pharmacology; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley; D014661:Vasoconstriction / Q000187:drug effects / Q000528:radiation effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects / Q000528:radiation effects; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: C491685:INO 1001; D007211:Indoles; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D009599:Nitroprusside; D010656:Phenylephrine; D052250:Nitric Oxide Synthase Type III; D000109:Acetylcholine