3-nitrotyrosine and 3-aminobenzamide

Peripheral nerve degeneration after nerve injury is accompanied with oxidative stress that may activate poly ADP-ribose polymerase (PARP, DNA repair enzyme). PARP overactivation amplifies the neuronal damage either due to energy crisis or through inflammatory process by facilitating nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). Hence investigated the role of PARP inhibitors, 3-Aminobenzamide (3-AB) and 1,5-isoquinolinediol (ISO) in the attenuation of chronic constriction injury (CCI) induced peripheral neuropathy in rats.. 3-AB and ISO (at doses 30 and 3mg/kg i.p., respectively) were tested in rats subjected to standard tests for evaluating hyperalgesia and allodynia. Sciatic functional index (SFI) was assessed by performing walking track analysis. Oxidative stress and inflammation induced biochemical alterations were estimated after 14 days in sciatic nerve and lumbar spinal cord. Molecular changes were explored by immunohistochemistry and DNA fragmentation by TUNEL assay.. Treatment significantly improved sensorimotor responses (p<0.001), SFI (p<0.001) and foot posture. PARP inhibition significantly (p<0.01 and p<0.001) reduced the elevated levels of nitrite, inflammatory markers and also normalized the depleted NAD(total) levels. The protein expression of poly (ADP-ribose) (PAR), NF-κB, cyclooxygenase-2 (COX-2) and nitrotyrosine were significantly (p<0.01 and p<0.001) decreased in both sciatic nerve and lumbar spinal cord, evident through immunohistochemistry.. Present study outcomes fortify the pathological role of PARP overactivation in CCI induced neuropathy and PARP inhibition ameliorated oxidative stress and neuroinflammation associated with CCI induced nerve injury. Therefore, the current study suggests the PARP inhibitors can further be evaluated for designing futuristic strategies for the management of trauma induced neuropathy.

Topics: Animals; Benzamides; Constriction, Pathologic; Cyclooxygenase 2; Hyperalgesia; Inflammation; Male; NAD; Neuritis; Neuroprotective Agents; Oxidative Stress; Pain Measurement; Peripheral Nervous System Diseases; Poly(ADP-ribose) Polymerase Inhibitors; Rats; Rats, Sprague-Dawley; Sensation; Tyrosine; Walking

Poly(ADP-ribose) polymerase (PARP) plays an important role in tissue injury in conditions associated with oxidative stress and inflammation. Because asthma is a chronic inflammatory disorder of the airways, we designed the present experimental study to evaluate the effects of PARP inhibition on allergen-induced asthma-like reaction in ovalbumin-sensitized guinea pigs. Cough and dyspnea in response to ovalbumin aerosol were absent in naive guinea pigs, whereas they became severe in the sensitized animals. In the latter ones, ovalbumin aerosol also induced a rapid increase in PARP activity, bronchiolar constriction, pulmonary air space inflation, mast cell degranulation, poly(ADP-ribose) and nitrotyrosine immunostaining, myeloperoxidase activity, and malondialdehyde in lung tissue, as well as a rise in the amounts of nitrites and tumor necrosis factor-alpha in bronchoalveolar lavage fluid. Pretreatment with the PARP inhibitors 3-aminobenzamide (10 mg/kg b.wt.) or 5-aminoisoquinolinone (0.5 mg/kg b.wt.) given i.p. 3 h before ovalbumin challenge significantly reduced the severity of cough and the occurrence of dyspnea and delayed the onset of respiratory abnormalities. Both PARP inhibitors were also able to prevent the above morphological and biochemical changes of lung tissue or bronchoalveolar lavage fluid induced by ovalbumin challenge. Conversely, p-aminobenzoic acid, the inactive analog of 3-aminobenzamide, had no effects.

Topics: Allergens; Animals; Anti-Asthmatic Agents; Asthma; Benzamides; Bronchoalveolar Lavage Fluid; Enzyme Inhibitors; Guinea Pigs; Immunohistochemistry; Isoquinolines; Lung; Male; Malondialdehyde; Mast Cells; Nitric Oxide; Ovalbumin; Peroxidase; Poly(ADP-ribose) Polymerase Inhibitors; Respiratory Mechanics; Tumor Necrosis Factor-alpha; Tyrosine

Oxidative and nitrosative stressor agents can trigger DNA strand breakage, which then activates the nuclear enzyme poly(ADP-ribose) synthetase (PARS). Activation of the enzyme depletes the intracellular concentration of energetic substrates such as nicotinamide adenine dinucleotide (NAD). This process can result in cell dysfunction and cell death. PARS inhibitors have been successfully used in ischemia-reperfusion injury, inflammation and sepsis in several experimental models. In our experimental study, we investigated the role of 3-aminobeanzamide (3-AB), a non-specific PARS inhibitor, on the intestinal mucosal barrier after burn injury. Twenty-four Wistar rats were randomly divided into three groups. The sham group (n = 8) was exposed to 21 degrees C water while the burn group (n = 8) and the burn + 3-AB group (n = 9) were exposed to boiling water for 12s to produce a full thickness burn in 35-40% of total body surface area. In the burn + 3-AB group, 10mg/kg of 3-AB was given intraperitoneally 10min before thermal injury. Twenty-four hours later, tissue samples from mesenteric lymph nodes (MLN), spleen and liver were obtained under sterile conditions for microbiological analysis and ileum samples were obtained for biochemical and histopathological analysis. In burn group, the incidence of bacteria isolated from MLN and spleen was significantly higher than other groups (P < 0.05). 3-AB pre-treatment prevented burn induced bacterial translocation and it significantly reduced burn induced intestinal injury. Tissue malondialdehyde and 3-nitrotyrozine levels were found significantly lower than that of the burn group. These data suggest that the relationship between PARS pathway and lipid peroxidation in intestinal tissue and PARS has a role in intestinal injury caused by thermal injury.

Topics: Animals; Bacterial Translocation; Benzamides; Burns; Enzyme Inhibitors; Intestinal Mucosa; Intestine, Small; Liver; Lymph Nodes; Malondialdehyde; Mesentery; Poly(ADP-ribose) Polymerase Inhibitors; Random Allocation; Rats; Rats, Wistar; Spleen; Tyrosine

Severe hypoglycemia causes neuronal death and cognitive impairment. Evidence suggests that hypoglycemic neuronal death involves excitotoxicity and DNA damage. Poly(ADP-ribose) polymerase-1 (PARP-1) normally functions in DNA repair, but promotes cell death when extensively activated by DNA damage. Cortical neuron cultures were subjected to glucose deprivation to assess the role of PARP-1 in hypoglycemic neuronal death. PARP-1-/- neurons and wild-type, PARP-1+/+ neurons treated with the PARP inhibitor 3,4-dihydro-5-[4-(1-piperidinyl)butoxy]-1(2H)-isoquinolinone both showed increased resistance to glucose deprivation. A rat model of insulin-induced hypoglycemia was used to assess the therapeutic potential of PARP inhibitors after hypoglycemia. Rats subjected to severe hypoglycemia (30 min EEG isoelectricity) accumulated both nitrotyrosine and the PARP-1 product, poly(ADP-ribose), in vulnerable neurons. Treatment with PARP inhibitors immediately after hypoglycemia blocked production of poly(ADP-ribose) and reduced neuronal death by >80% in most brain regions examined. Increased neuronal survival was also achieved when PARP inhibitors were administered up to 2 hr after blood glucose correction. Behavioral and histological assessments performed 6 weeks after hypoglycemia confirmed a sustained salutary effect of PARP inhibition. These results suggest that PARP-1 activation is a major factor mediating hypoglycemic neuronal death and that PARP-1 inhibitors can rescue neurons that would otherwise die after severe hypoglycemia.

Topics: Animals; Astrocytes; Behavior, Animal; Benzamides; Benzopyrans; Cell Death; Cells, Cultured; Cognition Disorders; Disease Models, Animal; Drug Administration Schedule; Enzyme Inhibitors; Hypoglycemia; Isoquinolines; Male; Maze Learning; Mice; Mice, Knockout; Neurons; Poly(ADP-ribose) Polymerase Inhibitors; Rats; Rats, Sprague-Dawley; Receptors, Glutamate; Time Factors; Treatment Outcome; Tyrosine

Oxidative stress has been shown to be implicated in the pathogenesis of central nervous system injuries such as cerebral ischemia and trauma, and chronic neurodegenerative diseases. In vitro studies show that oxidative stress, particularly peroxynitrite, could trigger DNA strand breaks, which lead to the activation of repairing enzymes including Poly(ADP-ribose) Polymerase-1 (PARP-1). As excessive activation of this enzyme induces cell death, we examined whether such a cascade also occurs in vivo in a model of oxidative stress in rat brain. For this purpose, the mitochondrial toxin malonate, which promotes free radical production, was infused into the left striatum of rats. Immunohistochemistry showed that 3-nitrotyrosine, an indicator of nitrosative stress, and poly(ADP-ribose), a marker of poly(ADP-ribose)polymerase-1 activation, were present as early as 1 h after malonate, and that they persisted for 24 h. The PARP inhibitor, 3-aminobenzamide, significantly reduced the lesion and inhibited PARP-1 activation induced by malonate. These results demonstrate that oxidative stress induced in vivo in the central nervous system leads to the activation of poly(ADP-ribose)polymerase-1, which contributes to neuronal cell death.

Topics: Animals; Apoptosis; Benzamides; Brain; Brain Diseases; Enzyme Activation; Immunohistochemistry; Male; Malonates; Oxidative Stress; Poly Adenosine Diphosphate Ribose; Poly(ADP-ribose) Polymerases; Rats; Rats, Sprague-Dawley; Substantia Nigra; Tyrosine

Activation of the nuclear enzyme poly (ADP-ribose) synthetase (PARS) in response to oxidant-mediated DNA injury has been shown to play an important role in the pathogenesis of reperfusion injury. Here we investigated the role of PARS in myocardial ischemic preconditioning (IPC).. Mice with or without genetic disruption of PARS and rats in the absence or presence of the PARS inhibitor 3-aminobenzamide underwent coronary occlusion and reperfusion with or without IPC.. Both poly(ADP-ribose) synthetase (PARS) deficiency and ischemic preconditioning (IPC) induced protection from reperfusion injury, attenuated inflammatory mediator production, and reduced neutrophil infiltration when compared to the response in wild-type mice. Surprisingly, the protective effect of IPC not only disappeared in PARS-/- mice, but the degree of myocardial injury and inflammatory response was similar to the one seen in wild-type animals. Similarly, in the rat model of IPC, 3-aminobenzamide pretreatment blocked the beneficial effect of IPC. Myocardial NAD+ levels were maintained in the PARS-deficient mice during reperfusion, while depleted in the wild-type mice. The protection against reperfusion injury by IPC was also associated with partially preserved myocardial NAD+ levels, indicating that PARS activation is attenuated by IPC. This conclusion was further strengthened by poly(ADP-ribose) immunohistochemical measurements, demonstrating that IPC markedly inhibits PARS activation during reperfusion.. The mode of IPC's action is related, at least in part, to an inhibition of PARS. This process may occur either by self-auto-ribosylation of PARS during IPC, and/or via the release of endogenous purines during IPC that inhibit PARS activation during reperfusion.

Topics: Animals; Benzamides; Enzyme Inhibitors; Immunohistochemistry; Interleukin-10; Interleukin-12; Ischemic Preconditioning, Myocardial; Male; Mice; Mice, Knockout; Myocardial Reperfusion Injury; Myocardium; NAD; Peroxidase; Poly(ADP-ribose) Polymerase Inhibitors; Poly(ADP-ribose) Polymerases; Rats; Rats, Wistar; Tissue Extracts; Tumor Necrosis Factor-alpha; Tyrosine

Poly(ADP-ribose) synthase (PARS), an abundant nuclear protein, has been described as an important candidate for mediation of neurotoxicity by nitric oxide. However, in cerebral ischemia, excessive PARS activation may lead to energy depletion and exacerbation of neuronal damage. We examined the effect of inhibiting PARS on the (a) degree of cerebral injury, (b) process of inflammatory responses, and (c) functional outcomes in a neonatal rat model of focal ischemia. We demonstrate that administration of 3-aminobenzamide, a PARS inhibitor, leads to a significant reduction of infarct volume: 63 +/- 2 (untreated) versus 28 +/- 4 mm(3) (treated). The neuroprotective effects currently observed 48 h postischemia hold up at 7 and 17 days of survival time and attenuate neurological dysfunction. Inhibition of PARS activity, demonstrated by a reduction in poly(ADP-ribose) polymer formation, also reduces neutrophil recruitment and levels of nitrotyrosine, an indicator of peroxynitrite generation. Taken together, our results demonstrate that PARS inhibition reduces ischemic damage and local inflammation associated with reperfusion and may be of interest for the treatment of neonatal stroke.

Topics: Animals; Animals, Newborn; Benzamides; Brain Ischemia; Cell Death; Cerebral Infarction; Encephalitis; Female; Male; Motor Activity; Neurologic Examination; Neuroprotective Agents; Neutrophils; Nitrates; Poly(ADP-ribose) Polymerase Inhibitors; Polymers; Rats; Rats, Wistar; Reperfusion Injury; Signal Transduction; Stroke; Time Factors; Tyrosine

To assess the contribution of poly (adenosine 5'-diphosphate ribose) synthetase (PARS) to the development of bacterial lipopolysaccharide (LPS)-induced acute lung injury and vascular failure in pigs.. Four groups of anesthetized, paralyzed, and mechanically ventilated domestic white pigs. Group 1 served as control, whereas Escherichia coli LPS (20 microg/kg/h) was continuously infused in group 2. Group 3 received 20 mg/kg injection of 3-aminobenzamide (a selective inhibitor of PARS activity) 15 minutes before LPS infusion. Only 3-aminobenzamide and not LPS was injected in group 4. All animals were examined for 180 minutes. Systemic and pulmonary hemodynamics and lung mechanics were measured during the experimental period. Lung wet/dry ratio, bronchoalveolar lavage (BAL) protein levels and cell counts and lung nitrotyrosine (footprint of peroxynitrite) immunostaining were also measured in a few animals.. LPS infusion evoked a progressive decline in systemic arterial pressure, a small increase in cardiac output, and biphasic elevation of pulmonary arterial pressure. Lung compliance declined progressively, whereas lung and total respiratory resistance rose significantly after LPS infusion. Prominent nitrotyrosine immunostaining was detected around small airways and pulmonary endothelium of LPS-infused animals. No significant changes in lung wet/dry ratio and BAL protein levels and cell counts were produced by LPS infusion. Pretreatment with 3-aminobenzamide did not alter the systemic and pulmonary hemodynamic responses to LPS infusion but eliminated the rise in pulmonary and total respiratory resistance.. We concluded that PARS activation plays an important role in the changes of lung mechanics associated with LPS-induced acute lung injury but had no role in vascular failure.

Topics: Animals; Benzamides; Bronchoalveolar Lavage Fluid; Disease Models, Animal; Enzyme Inhibitors; Escherichia coli Infections; Female; Hemodynamics; Immunohistochemistry; Lipopolysaccharides; Male; Poly(ADP-ribose) Polymerase Inhibitors; Poly(ADP-ribose) Polymerases; Proteins; Pulmonary Circulation; Respiratory Distress Syndrome; Respiratory Mechanics; Shock, Septic; Swine; Tyrosine

Crohn's disease is a chronic disease characterized by oxidant-induced tissue injury and increased intestinal permeability. A consequence of oxidative damage is the accumulation of DNA strand breaks and activation of poly(ADP-ribose) polymerase (PARP), which subsequently catalyzes ADP-ribosylation of target proteins. In this study, we assessed the role of PARP in the colitis seen in interleukin (IL)-10 gene-deficient mice. IL-10 gene-deficient mice demonstrated significant alterations in colonic cellular energy status in conjunction with increased permeability, proinflammatory cytokine release, and nitrosative stress. After 14 days of treatment with the PARP inhibitor 3-aminobenzamide, IL-10 gene-deficient mice demonstrated normalized colonic permeability; reduced tumor necrosis factor-alpha and interferon-gamma secretion, inducible nitric oxide synthase expression, and nitrotyrosine levels; and significantly attenuated inflammation. Time course studies demonstrated that 3-aminobenzamide rapidly altered cellular metabolic activity and decreased cellular lactate levels. This was associated with normalization of colonic permeability and followed by a downregulation of proinflammatory cytokine release. Our data demonstrate that inhibition of PARP activity results in a marked improvement of colonic inflammatory disease and a normalization of cellular metabolic function and intestinal permeability.

Topics: Animals; Benzamides; Chronic Disease; Colitis; Disease Models, Animal; Energy Metabolism; Enzyme Inhibitors; Inflammatory Bowel Diseases; Interferon-gamma; Interleukin-10; Intestinal Absorption; Intestinal Mucosa; Mice; Mice, Inbred Strains; Mice, Knockout; Neutrophils; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerases; Proteins; Tumor Necrosis Factor-alpha; Tyrosine

The aim of the present study was to investigate the role of poly (ADP-ribose) synthetase (PARS) in a model of acute local inflammation (zymosan-activated plasma (ZAP)-induced paw edema), in which the oxyradicals, nitric oxide and peroxynitrite, are known to play a crucial role. Injection of zymosan-activated plasma (ZAP) into the rat paw induced edema formation. The maximal increase in paw volume was observed at three hours after administration (maximal in paw volume: 1.29+/-0.09 ml). At this time point, there was a marked increase in neutrophil infiltration in the paw, as measured by an increase in myeloperoxidase (MPO) activity in the paw tissue (260+/-25 mU/100 mg wet tissue). However, ZAP-induced paw edema was significantly reduced in a dose-dependent manner by treatment with 3-aminobenzamide (3-AB) or nicotinamide (NIC), two inhibitors of PARS, at 1, 2, 3, 4 hours after ZAP injection. PARS inhibition also caused a significant reduction of MPO activity. The paw tissues were also examined immunohistochemically for the presence of nitrotyrosine (a footprint for peroxynitrite formation). At 3 h following ZAP injection, staining for nitrotyrosine were also found to be localised within discrete cells in the inflamed paw tissue. Treatment with PARS inhibitor prevented the appearance of nitrotyrosine in the tissues. Our results suggest that in paw edema induced by ZAP, inhibition of PARS exert potent anti-inflammatory effects.

Topics: Animals; Benzamides; Complement Activation; Dose-Response Relationship, Drug; Edema; Enzyme Inhibitors; Free Radicals; Immunohistochemistry; Inflammation; Male; Niacinamide; Nitrates; Peroxidase; Poly(ADP-ribose) Polymerase Inhibitors; Poly(ADP-ribose) Polymerases; Rats; Rats, Wistar; Tyrosine; Zymosan

The effect of 3-aminobenzamide, an inhibitor of poly (ADP-ribose) synthetase activity, was evaluated in a rat model of laryngeal injury induced by endotracheal intubation for 1 h. At 1 h after extubation, the laryngeal damage was characterized by areas of mucosal necrosis, submucosal edema, swelling of subglottic glands, and submucosal infiltration of inflammatory cells. Activity of myeloperoxidase, a marker of neutrophil infiltration, was also markedly increased into the damaged tissue. Immunohistochemistry for nitrotyrosine, an index of nitrosative stress, showed an intense staining in the inflamed larynx. Treatment with 3-aminobenzamide (10 mg/kg intraperitoneally) significantly reduced the appearance of mucosal damage and was associated with a significant reduction of tissue myeloperoxidase activity and nitrotyrosine immunoreactivity in the larynx. The results of this study suggest that poly (ADP-ribose) synthetase may play a role in the inflammatory process after laryngeal intubation and extubation, and administration of 3-aminobenzamide may be a beneficial therapeutic approach.

Topics: Animals; Benzamides; Enzyme Inhibitors; Immunohistochemistry; Intubation, Intratracheal; Laryngeal Mucosa; Larynx; Male; Neutrophils; Peroxidase; Poly(ADP-ribose) Polymerase Inhibitors; Rats; Rats, Wistar; Tyrosine; Wounds and Injuries

Peritoneal administration of zymosan in the rat induced a severe inflammatory process characterised by an increase in the plasma levels of nitrite and nitrate, stable metabolites of nitric oxide (NO) and in the levels of peroxynitrite, as measured by the oxidation of the fluorescent dye dihydrorhodamine 123, at 18 hours zymosan challenge. Immunohistochemical examination demonstrated a marked increase in the immunoreactivity to nitrotyrosine, a specific "footprint" of peroxynitrite, in the aorta of zymosan-shocked rats. In ex vivo experiments, thoracic aorta rings of zymosan-treated rats showed a reduced contraction to noradrenaline and reduced responsiveness to the relaxant effect to acetylcholine (vascular hyporeactivity and endothelial dysfunction, respectively). Treatment of zymosan-shocked rats with 3-aminobenzamide or Nicotinamide, inhibitors of poly ADP-ribosil synthetase (PARS) activity reduced the production of peroxynitrite and significantly prevented the cardiovascular dysfunction. Our data suggest that peroxynitrite and PARS activation play a role in the zymosan-induced cardiovascular derangements in the rat.

Topics: Animals; Aortic Diseases; Benzamides; Enzyme Activation; Enzyme Inhibitors; Immunohistochemistry; Injections, Intraperitoneal; Male; Niacinamide; Nitrates; Oxidants; Poly(ADP-ribose) Polymerase Inhibitors; Poly(ADP-ribose) Polymerases; Rats; Rats, Sprague-Dawley; Shock, Cardiogenic; Tyrosine; Zymosan

The mechanisms by which immature thymocyte apoptosis is induced during negative selection are poorly defined. Reports demonstrated that cross-linking of T-cell receptor leads to stromal cell activation, expression of inducible nitric oxide synthase (iNOS) and, subsequently, to thymocyte apoptosis. Therefore we examined, whether NO directly or indirectly, through peroxynitrite formation, causes thymocyte apoptosis. Immuno-histochemical detection of nitrotyrosine revealed in vivo peroxynitrite formation in the thymi of naive mice. Nitrotyrosine, the footprint of peroxynitrite, was predominantly found in the corticomedullary junction and the medulla of naive mice. In the thymi of mice deficient in the inducible isoform of nitric oxide synthase, considerably less nitrotyrosine was found. Exposure of thymocytes in vitro to low concentrations (10 microM) of peroxynitrite led to apoptosis, whereas higher concentrations (50 microM) resulted in intense cell death with the characteristics of necrosis. We also investigated the effect of poly (ADP-ribose) synthetase (PARS) inhibition on thymocyte apoptosis. Using the PARS inhibitor 3-aminobenzamide (3-AB), or thymocytes from PARS-deficient animals, we established that PARS determines the fate of thymocyte death. Suppression of cellular ATP levels, and the cellular necrosis in response to peroxynitrite were prevented by PARS inhibition. Therefore, in the absence of PARS, cells are diverted towards the pathway of apoptotic cell death. Similar results were obtained with H2O2 treatment, while apoptosis induced by non-oxidative stimuli such as dexamethasone or anti-FAS antibody was unaffected by PARS inhibition. In conclusion, we propose that peroxynitrite-induced apoptosis may play a role in the process of thymocyte negative selection. Furthermore, we propose that the physiological role of PARS cleavage by apopain during apoptosis may serve as an energy-conserving step, enabling the cell to complete the process of apoptosis.

Topics: Animals; Apoptosis; Benzamides; Caspase 1; Caspase 3; Caspases; Cell Death; Cells, Cultured; Cysteine Endopeptidases; DNA Fragmentation; Enzyme Activation; Enzyme Inhibitors; Flow Cytometry; Hydrogen Peroxide; Immunohistochemistry; Mice; Nitrates; Nitric Oxide; Poly(ADP-ribose) Polymerase Inhibitors; Poly(ADP-ribose) Polymerases; Thymus Gland; Tyrosine

Peroxynitrite and hydroxyl radical, reactive oxidants produced during reperfusion, are potent triggers of DNA single strand breakage. DNA injury triggers the activation of the nuclear enzyme poly (ADP-ribose) synthetase (PARS), which contributes to cellular energetic depletion. Using 3-aminobenzamide, an inhibitor of PARS, we investigated the role of PARS in the pathogenesis of myocardial reperfusion injury in a rat model.. Occlusion of the left main coronary artery (one hour) followed by reperfusion (one hour) in the anesthetized rat caused severe cardiac necrosis, neutrophil infiltration, and increased plasma creatine phosphokinase activity. There was significant peroxynitrite production during reperfusion, as indicated by a massive increase in nitrotyrosine in the necrotic myocardium. Reperfusion was also associated with a significant loss of myocardial ATP. In vivo administration of the PARS inhibitor 3-aminobenzamide (10 mg/kg i.v.) to rats subjected to myocardial ischemia and reperfusion, reduced myocardial infarct size and blunted the increase in plasma creatine phosphokinase activity and myeloperoxidase activity in infarcted hearts. In addition, 3-aminobenzamide partially preserved the myocardial ATP levels. In vitro, pharmacological inhibition of PARS also ameliorated peroxynitrite-induced cytotoxicity in rat cardiac myocytes and human endothelial cells.. 3-aminobenzamide has significant protective effects in myocardial reperfusion injury. We hypothesize that activation of PARS activation plays a role in the pathophysiology of acute myocardial infarction.

Topics: Adenosine Triphosphate; Animals; Benzamides; Cells, Cultured; Creatine Kinase; Endothelium, Vascular; Enzyme Inhibitors; In Vitro Techniques; Male; Myocardial Reperfusion Injury; Myocardium; Peroxidase; Poly(ADP-ribose) Polymerase Inhibitors; Rats; Rats, Wistar; Tyrosine