Abstract-The aim of the present study was to investigate the effects of the novel poly(ADP-ribose) polymerase (PARP) inhibitor PJ34 (N-(6-oxo-5,6-dihydro-phenanthridin-2-yl)-N,N-dimethylacetamide) on myocardial and endothelial function after hypothermic ischemia and reperfusion in a heterotopic rat heart transplantation model. After a 1-hour ischemic preservation, reperfusion was started either after application of placebo or PJ34 (3 mg/kg). The assessment of left ventricular pressure-volume relations, total coronary blood flow, endothelial function, myocardial high energy phosphates, and histological analysis were performed at 1 and 24 hours of reperfusion. After 1 hour, myocardial contractility and relaxation, coronary blood flow, and endothelial function were significantly improved and myocardial high energy phosphate content was preserved in the PJ34-treated animals. Improved transplant function was also seen with treatment with another, structurally different PARP inhibitor, 5-aminoisoquinoline. The PARP inhibitors did not affect baseline cardiac function. Immunohistological staining confirmed that PJ34 prevented the activation of PARP in the transplanted hearts. The activation of P-selectin and ICAM-1 was significantly elevated in the vehicle-treated heart transplantation group. Thus, pharmacological PARP inhibition reduces reperfusion injury after heart transplantation due to prevention of energy depletion and downregulation of adhesion molecules and exerts a beneficial effect against reperfusion-induced graft coronary endothelial dysfunction. (Circ Res. 2002;90:100-106.)Key Words: transplantation Ⅲ reperfusion injury Ⅲ PARP inhibition Ⅲ endothelial function Ⅲ rat I schemia/reperfusion injury is a common condition during cardiac surgery. Myocardial performance within the first hours after the surgical procedure determines the patient's state not only during the postoperative period but also in the long-term outcome, especially after heart transplantation when an extended time of ischemia is followed by reperfusion. Most studies about the effects of myocardial ischemia and reperfusion focus on myocardial injury and the recovery of contractile function. It is now appreciated that the survival of the heart as a whole depends in part on the ability of the microcirculation to deliver and distribute blood flow adequately during reperfusion. Recent studies show the importance of protecting the microvasculature to attenuate reperfusion injury. 1 Therefore, novel therapeutic strategies concentrate on management modalities that prevent both myocardial and endothelial injury during reperfusion.Ischemia/reperfusion injury initiates a pathophysiological cascade including an inflammatory response with liberation of cytokines and free radicals. A recently discovered mechanism of cell injury, the poly-ADP-ribose polymerase (PARP) pathway (see Sims et al 2 and Schraufstter et al 3 ;overview in Szabó 4 ) is involved in the pathogenesis of various forms of ischemia/reperfusion injury. In 1997, Thiemermann et al 5 and Zing...
Thus, inosine improves myocardial and endothelial function during early reperfusion after heart transplantation with a persisting beneficial effect against reperfusion induced graft coronary endothelial dysfunction. The effects of inosine are mediated at least partly by modulation of the peroxynitrite-poly(ADP-ribose) polymerase pathway.
Objective: Previous studies suggested that endothelin-1 (ET-1) may play a pathophysiological role in myocardial ischemia / reperfusion injury. This study was designed to investigate the effects of the selective ET-A receptor antagonist BQ123 and the selective ET-B receptor antagonist BQ788 on myocardial and endothelial function after reversible deep hypothermic ischemia in a heterotopic rat heart transplantation model. Methods: Isogenic intraabdominal heterotopic transplantation was performed in Lewis rats. After 1 h of cold ischemic preservation reperfusion was started either after application of placebo (control), BQ123 (3 mmol / kg / min), BQ788 (3 mmol / kg / min), ET-1 (8 pmol / kg / min) or simultaneous infusion of BQ123 or BQ788 and ET-1, respectively (n512 each). An implanted balloon was used to obtain pressure-volume relations of the transplanted heart. Myocardial blood flow (MBF) was assessed by the hydrogen-clearance method. Measurements were taken after 1 and 24 h of reperfusion. Endothelium-dependent vasodilation to acetylcholine (ACH) and endothelium-independent vasodilation to sodium nitroprusside were also determined. Results: Both BQ123 and BQ788 significantly improved myocardial and endothelial functional recovery during early reperfusion, whereas ET-1 significantly impaired myocardial and endothelial function. Simultaneous infusion of ET-1 diminished the effects of BQ123 and BQ788. Although myocardial function and baseline MBF were similar in all groups after 24 h of reperfusion, endothelium dependent vasodilation to ACH was still significantly higher in the BQ123 and BQ788 groups and lower in the ET-1 groups ( p,0.05). Conclusions: These results suggest that endogenous ET release is involved in the pathogenesis of reperfusion injury after heart transplantation. ET-A and ET-B receptor antagonists may be useful to reduce ischemia / reperfusion injury.
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