allopurinol and Cardiomyopathies

Heart failure is the major cause of hospitalization, morbidity and mortality worldwide. Previous experimental and clinical studies have suggested that there is an increased production of reactive oxygen species (ROS: superoxide, hydrogen peroxide, hydroxyl radical) both in animals and in patients with acute and chronic heart failure. The possible source of increased ROS in the failing myocardium include xanthine and NAD(P)H oxidoreductases, cyclooxygenase, the mitochondrial electron transport chain and activated neutrophils among many others. The excessively produced nitric oxide (NO) derived from NO synthases (NOS) has also been implicated in the pathogenesis of chronic heart failure (CHF). The combination of NO and superoxide yields peroxynitrite, a reactive oxidant, which has been shown to impair cardiac function via multiple mechanisms. Increased oxidative and nitrosative stress also activates the nuclear enzyme poly(ADP-ribose) polymerase (PARP), which importantly contributes to the pathogenesis of cardiac and endothelial dysfunction associated with myocardial infarction, chronic heart failure, diabetes, atherosclerosis, hypertension, aging and various forms of shock. Recent studies have demonstrated that pharmacological inhibition of xanthine oxidase derived superoxide formation, neutralization of peroxynitrite or inhibition of PARP provide significant benefit in various forms of cardiovascular injury. This review discusses the role of oxidative/nitrosative stress and downstream pathways in various forms of cardiomyopathy and heart failure.

Topics: Animals; Cardiomyopathies; Cardiomyopathy, Dilated; Humans; NADPH Oxidases; Oxidative Stress; Poly(ADP-ribose) Polymerases; Reactive Nitrogen Species; Reactive Oxygen Species; Xanthine Oxidase

Reperfusion of ischemic myocardium is recognized as potentially beneficial because mortality is directly related to infarct size, and the latter is related to the severity and duration of ischemia. However, reperfusion is associated with extension of the injury that is additive to that produced by ischemia alone. The phenomenon of reperfusion injury is caused in large part by oxygen-derived free radicals from both extracellular and intracellular sources. The loci of oxygen-free radical formation include: myocardial sources (mitochondria), vascular endothelial sources (xanthine oxidase and other oxidases), or the inflammatory cellular infiltrate (neutrophils). Experimental studies have shown that free radical scavengers and agents that prevent free radical production can reduce myocardial infarct size in dogs subjected to temporary regional ischemia followed by reperfusion. Superoxide dismutase and catalase, which catalyze the breakdown of superoxide anion and hydrogen peroxide, respectively, limit experimental myocardial infarct size. The free radical scavenging agent N-(2-mercaptopropionyl)glycine (MPG) is reported to be effective in limiting infarct size. The ischemic-reperfused myocardium derives significant protection when experimental animals are pretreated with the xanthine oxidase inhibitor allopurinol. Neutrophils also serve as a significant source of oxygen-derived free radicals at the site of tissue injury. A number of agents have been shown to directly inhibit neutrophil-derived oxygen free radical formation and neutrophil accumulation within the reperfused myocardium. These agents include ibuprofen, nafazatrom, BW755C, prostacyclin, and iloprost. Thus, free radical scavengers and agents that prevent free radical formation can provide significant protection to the ischemic-reperfused myocardium.

Topics: 4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-amine; Allopurinol; Cardiomyopathies; Catalase; Coronary Circulation; Epoprostenol; Free Radicals; Ibuprofen; Iloprost; Neutrophils; Oxygen; Pyrazoles; Pyrazolones; Superoxide Dismutase; Tiopronin

To examine the cardioprotective efficacy of allopurinol in patients undergoing elective coronary artery surgery.. Prospective randomised trial.. London teaching hospital.. Twenty patients with at least moderately good left ventricular function undergoing elective coronary artery surgery and requiring at least two bypass grafts.. Patients were randomised to receive allopurinol (1200 mg in two divided doses) or to act as controls.. The primary determinant of the efficacy of myocardial protection was serial measurement (preoperatively and subsequently at one, six, 24, and 72 hours after the end of cardiopulmonary bypass) of cardiac troponin T (cTnT) a highly sensitive and specific marker of myocardial damage. Additional evidence was provided by serial measurement of the MB-isoenzyme of creatine kinase (CK-MB) and myoglobin, ECG changes, and clinical outcome.. There was no significant difference in age, ejection fraction, number of grafts, bypass times, or cross clamp times between the two groups. In both groups there was a highly significant (p < 0.01) rise in cTnT, CK-MB, and myoglobin. Peak concentrations were reached between one (CK-MB and myoglobin) and six hours (cTnT) after the end of cardiopulmonary bypass. At 72 hours cTnT concentrations were six times higher than baseline concentrations whereas CK-MB and myoglobin were approximately double baseline concentrations. There was no significant difference in cTnT, CK-MB, or myoglobin between the allopurinol and control groups at any time. There was no diagnostic ECG evidence of perioperative infarction in any patient.. Unlike previous reports this study did not show that allopurinol had a cardioprotective effect in patients with good left ventricular function undergoing elective coronary artery surgery.

Topics: Allopurinol; Cardiomyopathies; Cardiopulmonary Bypass; Coronary Disease; Creatine Kinase; Humans; Isoenzymes; Male; Middle Aged; Myoglobin; Premedication; Treatment Failure; Troponin

Duchenne muscular dystrophy (DMD) associated cardiomyopathy is a major cause of morbidity and mortality. In an in vitro DMD cardiomyocyte model, nicorandil reversed stress-induced cell injury through multiple pathways implicated in DMD. We aimed to test the efficacy of nicorandil on the progression of cardiomyopathy in mdx mice following a 10-day treatment protocol.. A subset of mdx mice was subjected to low-dose isoproterenol injections over 5 days to induce a cardiac phenotype and treated with vehicle or nicorandil for 10 days. Baseline and day 10 echocardiograms were obtained to assess cardiac function. At 10 days, cardiac tissue was harvested for further analysis, which included histologic analysis and assessment of oxidative stress. Paired student's t test was used for in group comparison, and ANOVA was used for multiple group comparisons.. Compared to vehicle treated mice, isoproterenol decreased ejection fraction and fractional shortening on echocardiogram. Nicorandil prevented isoproterenol induced cardiac dysfunction. Isoproterenol increased cardiac fibrosis, which nicorandil prevented. Isoproterenol increased gene expression of NADPH oxidase, which decreased to baseline with nicorandil treatment. Superoxide dismutase 2 protein expression increased in those treated with nicorandil, and xanthine oxidase activity decreased in mice treated with nicorandil during isoproterenol stress compared to all other groups.. In conclusion, nicorandil is cardioprotective in mdx mice and warrants continued investigation as a therapy for DMD associated cardiomyopathy.

Topics: Animals; Cardiomyopathies; Disease Models, Animal; Female; Fibrosis; Isoproterenol; Mice, Inbred mdx; Muscular Dystrophy, Duchenne; Myocytes, Cardiac; NADPH Oxidases; Nicorandil; Reactive Oxygen Species; Stroke Volume; Superoxide Dismutase; Ventricular Function, Left; Xanthine Oxidase

Dystrophin-deficient cardiomyopathy is a growing clinical problem without targeted treatments. We investigated whether nicorandil promotes cardioprotection in human dystrophin-deficient induced pluripotent stem cell (iPSC)-derived cardiomyocytes and the muscular dystrophy mdx mouse heart.. Dystrophin-deficient iPSC-derived cardiomyocytes had decreased levels of endothelial nitric oxide synthase and neuronal nitric oxide synthase. The dystrophin-deficient cardiomyocytes had increased cell injury and death after 2 hours of stress and recovery. This was associated with increased levels of reactive oxygen species and dissipation of the mitochondrial membrane potential. Nicorandil pretreatment was able to abolish these stress-induced changes through a mechanism that involved the nitric oxide-cyclic guanosine monophosphate pathway and mitochondrial adenosine triphosphate-sensitive potassium channels. The increased reactive oxygen species levels in the dystrophin-deficient cardiomyocytes were associated with diminished expression of select antioxidant genes and increased activity of xanthine oxidase. Furthermore, nicorandil was found to improve the restoration of cardiac function after ischemia and reperfusion in the isolated mdx mouse heart.. Nicorandil protects against stress-induced cell death in dystrophin-deficient cardiomyocytes and preserves cardiac function in the mdx mouse heart subjected to ischemia and reperfusion injury. This suggests a potential therapeutic role for nicorandil in dystrophin-deficient cardiomyopathy.

Topics: Animals; Cardiomyopathies; Cell Line; Disease Models, Animal; Dose-Response Relationship, Drug; Humans; Induced Pluripotent Stem Cells; KATP Channels; Male; Mice, Inbred mdx; Mitochondria, Heart; Muscular Dystrophy, Animal; Myocardial Reperfusion Injury; Myocytes, Cardiac; Nicorandil; Nitric Oxide; Nitric Oxide Donors; Oxidative Stress; Reactive Oxygen Species; Recovery of Function; Signal Transduction; Ventricular Function, Left; Xanthine Oxidase

Increased production of oxygen free radicals and decreased oxidant capacity occur in coronary artery diseases (CAD) This pro-oxidant shift in intracellular redox state may induce cell death by either direct cell membrane damage by lipic peroxidation or apoptosis through activation of transcription factors. These changes occur not only in cardiomyocytes, bu also in cardiac sympathetic nerves, which are very sensitive to oxidative damage. Patients with heart failure encountel reduced peripheralblood flow at rest, during exercise and in response to endothelium-dependentvasodilators. Current treatments of cardiomyopathy, a degenerative condition of the myocardium frequently associated with heart failure have done little to enhance patient survival. Decreased myocardial contractility and altered regulation of peripheral circulation along with oxidative conditions are important contributors to the symptoms and prognosis of the disease process. Nitric oxide formed from L-arginine (2-amino-5 guanidinovaleric acid) metabolism in endothelial cells contributes to regulation of blood flow under these conditions. L-Arginine is the precursor of nitric oxide, an endogenous messenger molecule involved in a variety of endothelium-mediated physiological effects in the vascular system. In the present study, we investigated the effect of oral administration of L-arginine (3 g/day) on the intracellular redox status of the patients of ischemic cardiomyopathy aged 45-60 yrs. The enzymatic and non-enzymatic antioxidant parameters like superoxide dismutase, catalase, total thiols (TSH) and ascorbic acid along with pro-oxidant parameters, such as xanthine oxidase, as well as index of oxidative stress as protein carbonyl content and malondialdehyde (a marker of lipid peroxidation) were investigated in the plasma and RBC lysate. L-Arginine (3 g/day) administration was found to improve the levels of these parameters in the patients and regulate the blood flow, as evident by the improved blood pressure of the patients. Thus, it is inferred that L-arginine attenuates the oxidative stress conditions along with maintaining the blood pressure rate of patients suffering from cardiomyopathy.

Topics: Antioxidants; Arginine; Ascorbic Acid; Cardiomyopathies; Catalase; Coronary Artery Disease; Female; Free Radicals; Humans; Male; Middle Aged; Models, Biological; Myocardial Ischemia; Oxidants; Oxidation-Reduction; Oxidative Stress; Reactive Oxygen Species; Superoxide Dismutase; Thyrotropin; Xanthine Oxidase

Cachexia is a common complication of cancer and may be responsible for 22% of all cancer-related deaths. The exact cause of death in cancer cachexia patients is unknown. Recently, atrophy of the heart has been described in cancer cachexia animal models, which resulted in impaired cardiac function and is likely to contribute to mortality. In cancer patients hyperuricaemia independent of tumour lysis syndrome is often associated with a worse prognosis. Xanthine oxidase (XO) metabolizes purines to uric acid and its inhibition has been shown to improve clinical outcome in patients with chronic heart failure.. The rat Yoshida AH-130 hepatoma cancer cachexia model was used in this study. Rats were treated with 4 or 40 mg/kg/d oxypurinol or placebo starting one day after tumour-inoculation for maximal 15 days. Cardiac function was analyzed by echocardiography on day 11.. Here we show that inhibition of XO by oxypurinol significantly reduces wasting of the heart and preserves cardiac function. LVEF was higher in tumour-bearing rats treated with 4 mg/kg/d (61±4%) or 40 mg/kg/d (64±5%) oxypurinol vs placebo (51±3%, both p<0.05). Fractional shortening was improved by 4 mg/kg/d (43±3%) oxypurinol vs placebo (30±2, p<0.05), while 40 mg/kg/d oxypurinol (41±5%) did not reach statistical significance. Cardiac output was increased in the 4 mg/kg/d dose only (71±11 mL/min vs placebo 38±4 mL/min, p<0.01).. Inhibition of XO with oxypurinol has beneficial effects on cardiac mass and function in a rat model of severe cancer cachexia, suggesting that XO might be a viable drug target in cancer cachexia.

Topics: Animals; Cachexia; Cardiomyopathies; Liver Neoplasms; Liver Neoplasms, Experimental; Male; Oxypurinol; Rats; Rats, Wistar; Xanthine Oxidase

An R120G mutation in alphaB-crystallin (CryAB(R120G)) causes desmin-related myopathy (DRM). In mice with cardiomyocyte-specific expression of the mutation, CryAB(R120G)-mediated DRM is characterized by CryAB and desmin accumulations within cardiac muscle, mitochondrial deficiencies, activation of apoptosis, and heart failure (HF). Excessive production of reactive oxygen species (ROS) is often a hallmark of HF and treatment with antioxidants can sometimes prevent the progression of HF in terms of contractile dysfunction and cardiomyocyte survival. It is unknown whether blockade of ROS is beneficial for protein misfolding diseases such as DRM. We addressed this question by blocking the activity of xanthine oxidase (XO), a superoxide-generating enzyme that is upregulated in our model of DRM. The XO inhibitor oxypurinol was administered to CryAB(R120G) mice for a period of 1 or 3 months. Mitochondrial function was dramatically improved in treated animals in terms of complex I activity and conservation of mitochondrial membrane potential. Oxypurinol also largely restored normal mitochondrial morphology. Surprisingly, however, cardiac contractile function and cardiac compliance were unimproved, indicating that the contractile deficit might be independent of mitochondrial dysfunction and the initiation of apoptosis. Using magnetic bead microrheology at the single cardiomyocyte level, we demonstrated that sarcomeric disarray and accumulation of the physical aggregates resulted in significant changes in the cytoskeletal mechanical properties in the CryAB(R120G) cardiomyocytes. Our findings indicate that oxypurinol treatment largely prevented mitochondrial deficiency in DRM but that contractility was not improved because of mechanical deficits in passive cytoskeletal stiffness.

Topics: alpha-Crystallin B Chain; Animals; Apoptosis; Cardiomyopathies; Compliance; Desmin; Disease Models, Animal; Enzyme Inhibitors; Free Radical Scavengers; Hemorheology; Membrane Potential, Mitochondrial; Mice; Mice, Transgenic; Mitochondria, Heart; Mutation; Myocardial Contraction; Myocytes, Cardiac; Oxidative Stress; Oxypurinol; Protein Folding; Reactive Oxygen Species; Sarcomeres; Ventricular Function, Left; Xanthine Oxidase

It is widely recognized that L-NAME exposed rats develop myocardial fibrosis and hypertrophy. The aim of this study was to evaluate the contribution of xanthine oxidase (XO) to these phenomena using allopurinol, isolated or associated with olmesartan. Thirty adult male Wistar rats were divided into 5 groups (n=6) and studied for 5 weeks: L group (L-NAME, 40mg/kg/day); L+A group (L-NAME and allopurinol, 40 mg/kg/day); L+O group (L-NAME and olmesartan, 15mg/kg/day); L+A+O group (L-NAME, allopurinol, and olmesartan); and control group. L-NAME caused arterial hypertension and cardiomyocyte hypertrophy. Hypertension was prevented by olmesartan, but not by allopurinol. There was an increase of left ventricular mass index in the L-NAME group that was prevented by allopurinol, olmesartan and by the combination of both. The increase in mean cardiomyocyte transversal area caused by L-NAME was prevented by the allopurinol and olmesartan combination, or by olmesartan used as monotherapy, but not by allopurinol alone. There was a reduction in the myocardial vascularization index caused by L-NAME which was abolished by allopurinol or by olmesartan, but not by the association. L-NAME caused a reduction in the total number of cardiomyocyte nuclei. This was prevented by olmesartan alone or associated with allopurinol, but not by allopurinol alone. We conclude that XO has an important contribution to adverse cardiac remodeling in L-NAME exposed animals. Moreover, allopurinol acts without interfering with L-NAME induced hypertension. The protective action of this drug is comparable to the results obtained with olmesartan. Antioxidative mechanisms are proposed to account for the pressure independent effects of allopurinol.

Topics: Allopurinol; Angiotensin II Type 1 Receptor Blockers; Animals; Blood Pressure; Cardiomyopathies; Disease Models, Animal; Enzyme Inhibitors; Hypertension; Imidazoles; Male; Myocardium; NG-Nitroarginine Methyl Ester; Olmesartan Medoxomil; Rats; Rats, Wistar; Tetrazoles; Time Factors; Uric Acid; Ventricular Remodeling; Xanthine Oxidase

Oxidative stress is involved in the pathogenesis of cocaine-induced cardiomyopathy. In the present study, we aimed to determine the enzymatic sources of reactive oxygen species (ROS) production, namely NADPH oxidase and xanthine oxidoreductase (XOR) in male Wistar rats treated for 7 days with cocaine (2x7.5 mg/kg/day, ip) or cocaine with a NADPH oxidase inhibitor (apocynin, 50 mg/kg/day, po) or a XOR inhibitor (allopurinol, 50 mg/kg/day, po). Cocaine-induced cardiac dysfunction is associated with an increase in NADPH oxidase and XOR activities (59% and 29%, respectively) and a decrease in catalase activity. Apocynin or allopurinol treatment prevents the cocaine-induced cardiac alteration by restoration of cardiac output, stroke volume and fractional shortening. This is associated with a reduction of the myocardial production of superoxide anions and an enhancement of catalase activity. Surprisingly, apocynin treatment prevents XOR up-regulation supporting the hypothesis that NADPH oxidase-derived ROS play a role in modulating ROS production by XOR. These data suggest that NADPH and xanthine oxidase act synergically to form myocardial ROS and clearly demonstrate that their inhibition may be critical in preventing the initiation and progression of cocaine-induced LV dysfunction.

Topics: Acetophenones; Allopurinol; Anesthetics, Local; Animals; Cardiomyopathies; Cocaine; Enzyme Inhibitors; Male; Myocardium; NADPH Oxidases; Rats; Rats, Wistar; Reactive Oxygen Species; Up-Regulation; Ventricular Dysfunction, Left; Xanthine Dehydrogenase

Reactive oxygen species, in particular superoxide, have been closely linked to the underlying pathophysiology of ischemic cardiomyopathy: superoxide not only mediates mechanoenergetic uncoupling of the myocyte but also adversely impacts on myocardial perfusion by depleting endothelial-derived nitric oxide bioavailability. Xanthine oxidase generates superoxide upon oxidation of hypoxanthine and xanthine and has been detected in cardiac myocytes and coronary endothelial cells of patients with ischemic heart disease. Here we investigated the effects of oxypurinol, a xanthine oxidase inhibitor, on myocardial contractility in patients with ischemic cardiomyopathy. Twenty patients (19 males, 66+/-8 years) with stable coronary disease, severely suppressed systolic function (left ventricular ejection fraction 22+/-2%), and nonelevated uric acid plasma levels received a single intravenous dose of oxypurinol (400 mg). Cardiac MRI studies, performed before and 5.2+/-0.9 h after oxypurinol administration, revealed a reduction in end-systolic volumes (-9.7+/-4.2%; p=0.03) and an increase in left ventricular ejection fraction (+17.5+/-5.2%; p=0.003), whereas 6 patients (6 males, 63+/-3.8 years, ejection fraction 26+/-5%) who received vehicle only did not show significant changes in any of the parameters studied. Oxypurinol improves left ventricular function in patients with ischemic cardiomyopathy. These results underscore the significance of reactive oxygen species as important pathophysiological mediators in ischemic heart failure and point toward xanthine oxidase as an important source of reactive species that serve to modulate the myocardial redox state in this disease.

Topics: Aged; Cardiomyopathies; Cardiotonic Agents; Enzyme Inhibitors; Female; Humans; Hypoxanthine; Magnetic Resonance Imaging, Cine; Male; Middle Aged; Myocardial Contraction; Myocardial Ischemia; Oxypurinol; Reactive Oxygen Species; Uric Acid; Xanthine; Xanthine Oxidase

Oral desensitization with allopurinol presents a problem for patients with allopurinol hypersensitivity and gout that needs to be controlled rapidly. To our knowledge, only 1 case report of intravenous (i.v.) desensitization has been previously published.. To present a case report of a patient with cutaneous reactions to allopurinol who underwent i.v. allopurinol desensitization.. Intravenous infusion of allopurinol was performed using an escalating, 19-dose protocol.. No adverse reactions were precipitated by 2 i.v., escalating dose procedures, allowing continuation of effective treatment of the patient's hyperuricemia.. This case of safe and effective desensitization with allopurinol by the i.v. route should emphasize the need for a trial of this protocol in additional patients in whom rapid desensitization would be advantageous.

Topics: Allopurinol; Cardiomyopathies; Desensitization, Immunologic; Drug Hypersensitivity; Female; Gout; Heart Transplantation; Humans; Infusions, Intravenous; Middle Aged

The aim of this experimental study was to investigate the effects of erdosteine, an antioxidant agent, on doxorubicin (DXR)-induced cardio-toxicity through nitric oxide (NO) levels, collagen synthesis, xanthine oxidase (XO) and adenosine deaminase (ADA) activities in rats. Rats were treated with erdosteine (10 mg/kg b.wt. per day, orally) or saline starting 2 days before administrating a single dose of DXR (20 mg/kg i.p.) or saline. At the 10th day of the DXR administration, hearts were removed under anesthesia for biochemical measurements. Enzyme activities as well as OH-proline and NO levels were found to be significantly increased in DXR group compared with the control group. All of the parameters studied except ADA activity were decreased significantly approximating to the control levels upon erdosteine administration. In conclusion, erdosteine seems to be an alternative agent for protection of cardiac tissue against DXR-induced cardio-toxicity through its regulatory effect on XO activity and NO level.

Topics: Adenosine Deaminase; Animals; Antibiotics, Antineoplastic; Antioxidants; Cardiomyopathies; Doxorubicin; Hydroxyproline; Male; Nitric Oxide; Random Allocation; Rats; Rats, Sprague-Dawley; Thioglycolates; Thiophenes; Xanthine Oxidase

Oxidative stress has been implicated in the pathophysiology of myocardial failure. We tested the hypothesis that oxidative stress can regulate extracellular matrix in cardiac fibroblasts. Neonatal and adult rat cardiac fibroblasts in vitro were exposed to H(2)O(2) (0.05-5 microM) or the superoxide-generating system xanthine (500 microM) plus xanthine oxidase (0.001-0.1 mU/ml) (XXO) for 24 h. In-gel zymography demonstrated that H(2)O(2) and XXO each increased gelatinase activity corresponding to matrix metalloproteinases (MMP) MMP-13, MMP-2, and MMP-9. H(2)O(2) and XXO decreased collagen synthesis (collagenase-sensitive [(3)H]proline incorporation) without affecting total protein synthesis ([(3)H]leucine incorporation). H(2)O(2) and XXO decreased the expression of procollagen alpha(1)(I), alpha(2)(I), and alpha(1)(III) mRNA but increased the expression of fibronectin mRNA, suggesting a selective transcriptional effect on collagen synthesis. H(2)O(2), but not XXO, also decreased the expression of nonfibrillar procollagen alpha(1)(IV) and alpha(2)(IV) mRNA. To determine the role of endogenous antioxidant systems, cells were treated with the superoxide dismutase (SOD) inhibitor diethyldithiocarbamic acid (DDC, 100 microM) to increase intracellular superoxide or with the glucose-6-phosphate dehydrogenase inhibitor dehydroisoandrosterone 3-acetate (DHEA; 10 microM) to increase intracellular H(2)O(2). DDC and DHEA decreased collagen synthesis and increased MMP activity, and both effects were inhibited by an SOD/catalase mimetic. Thus increased oxidative stress activates MMPs and decreases fibrillar collagen synthesis in cardiac fibroblasts. Oxidative stress may play a role in the pathogenesis of myocardial remodeling by regulating the quantity and quality of extracellular matrix.

Topics: Animals; Animals, Newborn; Cardiomyopathies; Cells, Cultured; Collagen; Dehydroepiandrosterone; Ditiocarb; Fibroblasts; Glucosephosphate Dehydrogenase; Heart; Hydrogen Peroxide; Matrix Metalloproteinases; Mice; Myocardium; Oxidative Stress; Reactive Oxygen Species; Superoxide Dismutase; Xanthine; Xanthine Oxidase

Studies of myocardial edema and diastolic dysfunction in rat heart transplantation have been flawed by ischemic injury. This study uses improved methods to prevent ischemic contracture.. Hearts of 30 ACI rats were transplanted into the abdomen of Lewis rats by use of cold University of Wisconsin solution for improved preservation. Left ventricular diastolic properties were expressed as volume at standardized pressure intervals.. On posttransplantation day 3, mean left ventricular volume at 15 mm Hg in allografts (290 +/- 9 microl, SEM) was not significantly different vs isografts (299 +/- 32 microl), allografts on day 0 (337 +/- 28 ml) or day 1 (324 +/- 20 microl), or native hearts (334 +/- 19 microl). However, volume was reduced to 173 +/- 17 microl on day 4 and to 70 +/- 23 microl on day 5 (p < 0.05). Similar findings were obtained for volume at 5 and 10 mm Hg. Allograft myocardial water content on day 3, 76.3% +/- 5%, similar to allografts on day 0 and 1 and to isografts on day 3, increased to 77.6% +/- 8% on day 4 (NS) and 79.4% +/- 6% on day 5 (p < 0.05 vs day 0). Histologically, rejection in allografts was mild on day 3, moderate on day 4, and severe on day 5.. Reduced left ventricular filling volume during rejection is only partially explained by edema. Abnormalities of diastolic properties previously attributed to the unloaded state of nonworking heart models may actually reflect inadequate peritransplantation myocardial protection.

Topics: Adenosine; Allopurinol; Animals; Cardiomyopathies; Cardioplegic Solutions; Diastole; Edema; Glutathione; Graft Rejection; Heart Transplantation; Insulin; Male; Organ Preservation; Organ Preservation Solutions; Raffinose; Rats; Rats, Inbred ACI; Rats, Inbred Lew; Transplantation, Heterotopic; Ventricular Dysfunction, Left

Topics: Allopurinol; Animals; Cardiomyopathies; Cytoplasm; Diltiazem; Gerbillinae; Hydroxybutyrates; Isoproterenol; Lipid Metabolism; Male; Myocardium

Oxygen-derived free radicals are thought to injure the ischemic heart during coronary microvascular embolization.. To test this idea, microspheres (15 microns in diameter) were repetitively administered into the left anterior descending coronary artery to cause microvascular embolization in dogs. Myocardial contractile and metabolic dysfunctions were significantly attenuated after treatments with recombinant human superoxide dismutase, an acyl derivative of ascorbic acid (CV3611, 2-O-octadecylascorbic acid), and xanthine oxidase inhibitor (allopurinol). The free radical scavengers and inhibitor enhanced the coronary hyperemic flow response during embolization, and the total number of microspheres causing maximal embolization was increased by these drugs. When 8-phenyltheophylline was additionally administered with superoxide dismutase, these beneficial effects were abolished, indicating that coronary effects of these drugs may be due to increased release of adenosine during coronary microvascular embolization.. We conclude that oxygen radicals worsen the ischemic injury in coronary microembolization.

Topics: Allopurinol; Animals; Ascorbic Acid; Body Water; Cardiomyopathies; Coronary Disease; Dogs; Edema; Embolism; Free Radical Scavengers; Free Radicals; Microcirculation; Microspheres; Oxygen; Superoxide Dismutase; Theophylline

It has been suggested that cardiac injury by catecholamines may be the result of coronary constriction leading to ischemic damage. Allopurinol (ALLO) has been shown to reduce the extent of myocardial necrosis in various systems. Hence the possibility that ALLO might limit norepinephrine (NE) injury was tested. Rabbit hearts were infused with NE (3 micrograms/min/kg) for 90 minutes, with or without ALLO (50 micrograms/min/kg). Control specimens infused with saline solution plus ALLO were also prepared. Hearts were excised 48 hours later and studied as isovolumic isolated heart preparations. Peak systolic pressure, coronary flow, and myocardial oxygen consumption were significantly reduced in the hearts infused with NE but not in the NE + ALLO hearts. Myocardial adenosine triphosphate and glycogen concentrations were 29% and 26% lower in the NE hearts compared with control hearts. These reductions were absent in the NE + ALLO group. Moreover, rates of creatine phosphokinase and lactic dehydrogenase release were sharply elevated in the NE hearts but not in those also given ALLO. These findings are consistent with the changes observed histologically. The amount of myocardial damage was less in the ALLO + NE group compared with the NE group (p less than 0.02). This appears to be the first report to demonstrate that ALLO reduces myocyte damage by NE. Possible mechanisms include decreased free radical production, scavenging of free radicals, and preservation of the adenine nucleotide pool. Because xanthine oxidase activity is absent in the rabbit, the latter two mechanisms are more likely explanations for the findings.

Topics: Adenosine Triphosphate; Allopurinol; Animals; Cardiomyopathies; Coronary Circulation; Creatine Kinase; Glycogen; L-Lactate Dehydrogenase; Myocardium; Norepinephrine; Oxygen Consumption; Rabbits

This study was designed to evaluate the effect of an exogenous free radical generating system consisting of purine plus xanthine oxidase on the isolated rat heart and in particular to assess the possible contribution of arachidonic acid or its metabolites to toxicity produced by this drug combination. Purine plus xanthine oxidase produced a time-dependent depression in cardiac contractility which was associated with stimulated release of lactate dehydrogenase (LDH). Electron microscopic analysis revealed a distinct separation of the glycocalyx from the sarcolemmal membrane with no apparent intracellular defects. Purine plus xanthine oxidase was a potent stimulus for 6-keto-prostaglandin F1 alpha (6K-PGF1 alpha) synthesis but leukotriene production was undetectable under any condition. Eicosatetraynoic acid, which totally prevents the metabolism of arachidonic acid, accelerated the loss in force and increased LDH release invoked by purine plus xanthine oxidase, but produced no noticeable change in sarcolemmal ultrastructure. Cyclooxygenase inhibitors produced little influence although pretreatment with either acetylsalicylic acid or ibuprofen decreased contractility toward the end of purine plus xanthine oxidase perfusion. Nordihydroguarietic acid, a purported inhibitor of 5'-lipoxygenase accelerated the loss in force produced by purine plus xanthine oxidase. The nordihydroguarietic acid effects were associated with reduced 6K-PGF1 alpha efflux but LDH release was unaffected. We also examined whether modification of arachidonic acid release through changes in calcium concentration was associated with altered response to purine plus xanthine oxidase. Lowering the calcium concentration to 0.41 mM (from 1.25 mM control) reduced markedly 6K-PGF1 alpha, efflux as well as LDH release. Although the latter is suggestive of protection, hypocalcemic perfusion resulted in a greater loss in force due to free radical generation. Furthermore, cells from these hearts exhibited a greater degree of glycocalyx separation. Increasing the calcium concentration to 2.50 mM produced no further toxic manifestations in the response to purine plus xanthine oxidase, although the release of 6K-PGF1 alpha was increased. Our results suggest complex toxicity induced by an exogenously generated free radical system. The injury produced by this method is restricted to sarcolemmal changes, the latter being dependent on the external calcium concentration. The study further suggests that accu

Topics: 5,8,11,14-Eicosatetraynoic Acid; Allopurinol; Animals; Anti-Inflammatory Agents, Non-Steroidal; Arachidonic Acid; Arachidonic Acids; Calcium; Cardiomyopathies; Catalase; Eicosanoic Acids; Free Radicals; In Vitro Techniques; Male; Masoprocol; Myocardial Contraction; Myocardium; Oxygen; Purines; Rats; Rats, Inbred Strains; Superoxide Dismutase; Xanthine Oxidase

The effectiveness of 24-hour hypothermic machine perfusion with TP-V (a hyperosmolar colloid solution containing dextrose, sucrose and ATP-MgCl2) alone, or in combination with oxygen free radical scavengers, was evaluated in isolated-perfused canine heart-lungs. Heart-lungs were perfused at 4 degrees C in either TP-V (n = 6), TP-V/Allopurinol (500 mg/L) (n = 6), or TP-V/Allopurinol (500 mg/L) & Catalase (5000 U/L) (n = 5). Lung inflation was maintained with 100% nitrogen. Following preservation, the heart-lungs were perfused with an albumin-mannitol perfusate for 3 hours at 37 degrees C, for functional, hemodynamic, and laboratory determinations. Cold preservation with TP-V/Allopurinol, and TP-V/Allopurinol & Catalase resulted in physiologically normal LDH levels during the 3-hour normothermic isolated perfusion test period. Significantly lower enzyme activity for CPK was evident at 0 (p less than .005) and 3 hours (p less than .05) of perfusion, while no significant differences in lactate production were seen among the groups. In addition, pH, PCO2, PO2, and left ventricular, aortic, and coronary artery pressures all remained within normal physiologic range, with no significant differences seen among the three groups. 99m Technetium scans demonstrated adequate patency among the heart-lungs, with better flow seen in those perfused with TP-V/Allopurinol & Catalase. Histological specimens confirmed a decrease in myocardial and pulmonary damage when Allopurinol and/or Catalase was used. It appears that oxygen free radical scavengers provide some protection from canine heart-lungs which have been hypothermically preserved for 24 hours.

Topics: Allopurinol; Animals; Cardiomyopathies; Catalase; Coronary Vessels; Dogs; Free Radicals; Hypothermia, Induced; Ischemia; Lung; Lung Diseases; Organ Preservation; Oxygen; Perfusion; Superoxides