Poly(ADP-ribose) polymerase inhibition reverses vascular dysfunction after gamma-irradiation.
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.
Beller
Carsten J
CJ
Department of Cardiac Surgery, University of Heidelberg, Heidelberg, Germany. Carsten.Beller@urz.uni-heidelberg.de
Radovits
Tamás
T
Seres
Leila
L
Kosse
Jens
J
Krempien
Robert
R
Gross
Marie-Luise
ML
Penzel
Roland
R
Berger
Irina
I
Huber
Peter E
PE
Hagl
Siegfried
S
Szabó
Csaba
C
Szabó
Gábor
G
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
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