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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...

Increased inducible nitric oxide synthase (iNOS) expression is a component of the immune response and has been demonstrated in cardiomyocytes in septic shock, myocarditis, transplant rejection, ischemia, and dilated cardiomyopathy. To explore whether the consequences of such expression are adaptive or pathogenic, we have generated a transgenic mouse model conditionally targeting the expression of a human iNOS cDNA to myocardium. Chronic cardiac-specific upregulation of iNOS in transgenic mice led to increased production of peroxynitrite. This was associated with a mild inflammatory cell infiltrate, cardiac fibrosis, hypertrophy, and dilatation. While iNOS-overexpressing mice infrequently developed overt heart failure, they displayed a high incidence of sudden cardiac death due to bradyarrhythmia. This dramatic cardiac phenotype was rescued by specific attenuation of transgene activity. These data implicate cardiomyocyte iNOS overexpression as sufficient to cause cardiomyopathy, bradyarrhythmia, and sudden cardiac death.

We conclude that hypercholesterolemia but not hypertriglyceridemia leads to increased formation of superoxide and peroxynitrite, and thereby results in cardiac dysfunction in hearts of human apoB100 transgenic mice.