The parp-1 inhibitor ino-1001 facilitates hemodynamic stabilization without affecting DNA repair in porcine thoracic aortic cross-clamping-induced ischemia/reperfusion.
Inhibition of poly (ADP-ribose) polymerase 1 (PARP-1) improved hemodynamics and organ function in various shock models induced by sepsis or ischemia/reperfusion. PARP-1, however, is also referred to play a pivotal role for the maintenance of genomic integrity. Therefore, we investigated the effect of the PARP-1 blocker INO-1001 on hemodynamics, kidney function, and DNA damage and repair during porcine thoracic aortic cross-clamping. The animals underwent 45 min of aortic cross-clamping after receiving vehicle (n=9) or i.v. INO-1001 (n=9; total dose, 4 mg.kg, administered both before clamping and during reperfusion), data were recorded before clamping, before declamping, and 2 and 4 h after declamping. During reperfusion, continuous i.v. norepinephrine was incrementally adjusted to maintain blood pressure greater than or equal to 80% of the pre-clamping level. The plasma INO-1001 levels analyzed with high-pressure liquid chromatography were 1 to 1.4 micromol/L and 0.4 to 0.6 micromol/L before and after clamping, respectively. Although INO-1001-treated animals required less norepinephrine support, kidney function was comparable in the 2 groups. There was no intergroup difference either in the time course of DNA damage and repair (comet assay) as assessed both in vivo in whole blood before surgery, before clamping, before declamping, 2 h after declamping, and ex vivo in isolated lymphocytes (Ficoll gradient) sampled immediately before clamping and analyzed before, immediately, and 1 and 2 h after exposure to 4 bar 100% O2 for 2 h. There was no difference either in the expression of the cyclin-dependent kinase inhibitor gene, p27, in the kidney (immunohistochemistry). The reduced norepinephrine requirements during reperfusion suggest a positive inotropic effect of INO-1001, as demonstrated by other authors. In our model, INO-1001 proved to be safe with respect to DNA repair.
Hauser
Balázs
B
Sektion Anästhesiologische Pathophysiologie und Verfahrensentwicklung, Universitätsklinikum, Ulm, Germany.
Gröger
Michael
M
Ehrmann
Ulrich
U
Albicini
Maura
M
Brückner
Uwe Bernd
UB
Schelzig
Hubert
H
Venkatesh
Balasubramanian
B
Li
Hongshan
H
Szabó
Csaba
C
Speit
Günter
G
Radermacher
Peter
P
Kick
Jochen
J
D000818:Animals; D001013:Aorta, Thoracic / Q000201:enzymology*; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000096:biosynthesis; D004249:DNA Damage / Q000187:drug effects; D004260:DNA Repair / Q000187:drug effects*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects*; D007211:Indoles / Q000008:administration & dosage* / Q000493:pharmacokinetics; D007668:Kidney / Q000201:enzymology; D009638:Norepinephrine / Q000008:administration & dosage; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D015427:Reperfusion Injury / Q000188:drug therapy / Q000201:enzymology*; D013552:Swine; D014662:Vasoconstrictor Agents / Q000008:administration & dosage
C491685:INO 1001; D007211:Indoles; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D014662:Vasoconstrictor Agents; D050760:Cyclin-Dependent Kinase Inhibitor p27; D011065:Poly(ADP-ribose) Polymerases; D009638:Norepinephrine