Poly(ADP-ribose) polymerase inhibition attenuates biventricular reperfusion injury after orthotopic heart transplantation.
OBJECTIVE
Poly (ADP-ribose) polymerase (PARP) activation plays a key role in free radical induced injury in ischemia/reperfusion. We investigated the effects of INO-1001 a novel PARP inhibitor on postischemic myocardial and endothelial function.


METHODS
In dogs, 12 orthotopic heart transplantations were performed after 4 h ischemic preservation. At the beginning of reperfusion either saline vehicle (control, n=6), or INO-1001 (1 mg/kg, n=6) was applied. Before explantation and after 120 min of reperfusion we measured biventricular pressure-volume relationships by a combined conductance catheter and the adaptation potential of the right ventricle to acute afterload increase by pulmonary banding. Coronary blood flow (CBF), vasoreactivity, PARP-activation and ATP-content were also determined.


RESULTS
INO-1001 led to significantly better recovery of contractility (91+/-3 vs. 44+/-7%, P<0.05) and CBF (44+/-4 vs. 29+/-3 ml/min, P<0.05) and higher increase in CBF after acetylcholine (61+/-10 vs. 27+/-8%, P<0.05). In addition, the inotropic adaptation potential of the right ventricle to an increased afterload was better preserved after INO-1001. ATP content was significantly higher in the INO-1001 group (11.0+/-2.1 vs. 4.5+/-1.1 micromol/g drw). Immunohistology revealed PARP activation in the control group which was abolished by INO-1001 treatment.


CONCLUSIONS
PARP inhibition reduces myocardial and endothelial reperfusion injury after orthotopic heart transplantation.
Szabó
Gábor
G
Department of Cardiac Surgery, University of Heidelberg, Heidelberg, Germany. dzsi@hotmail.com
Soós
Pál
P
Heger
Ulrike
U
Flechtenmacher
Christa
C
Bährle
Susanne
S
Zsengellér
Zsuzsanna
Z
Szabó
Csaba
C
Hagl
Siegfried
S
D000818:Animals; D003326:Coronary Circulation / Q000502:physiology; D004285:Dogs; D004730:Endothelium, Vascular / Q000187:drug effects / Q000503:physiopathology; D016027:Heart Transplantation; D006352:Heart Ventricles / Q000503:physiopathology; D006439:Hemodynamics / Q000502:physiology; D007150:Immunohistochemistry / Q000379:methods; D007211:Indoles / Q000494:pharmacology*; D009200:Myocardial Contraction / Q000187:drug effects; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D010710:Phosphates / Q000032:analysis; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011184:Postoperative Period; D014664:Vasodilation / Q000502:physiology; D018487:Ventricular Dysfunction, Left / Q000503:physiopathology; D018497:Ventricular Dysfunction, Right / Q000503:physiopathology
C491685:INO 1001; D007211:Indoles; D010710:Phosphates; D000067856:Poly(ADP-ribose) Polymerase Inhibitors