allopurinol and Arrhythmias--Cardiac

Tumour lysis syndrome is a complication of chemotherapy for haematological malignancies; in particular, aggressive leukaemias and lymphomas. For haematological malignancies, targeted therapies, such as small molecule inhibitors and monoclonal antibodies, have a high anti-tumour activity, are well tolerated, and have a low incidence of associated tumour lysis syndrome. The BCL-2 inhibitor venetoclax has a high anti-tumour activity in chronic lymphocytic leukaemia, achieving deep remissions by potently inducing apoptosis and increasing the risk for tumour lysis syndrome. In this Viewpoint, we discuss the pathophysiology, risk factors, monitoring, changes in laboratory parameters, and clinical manifestations of tumour lysis syndrome, and the prophylaxis and treatments available for this complication. Prophylaxis and treatment strategies have been implemented as standard of care in patients receiving venetoclax to minimise the risk of both laboratory and clinical manifestations of tumour lysis syndrome.

Topics: Acute Kidney Injury; Allopurinol; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Arrhythmias, Cardiac; Bridged Bicyclo Compounds, Heterocyclic; Drug Synergism; Humans; Hyperphosphatemia; Hyperuricemia; Leukemia, Lymphocytic, Chronic, B-Cell; Molecular Targeted Therapy; Neoplasm Proteins; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-bcl-2; Renal Dialysis; Risk Factors; Severity of Illness Index; Sulfonamides; Tumor Lysis Syndrome; Urate Oxidase

The tumor lysis syndrome (TLS) is a life-threatening complication caused by the massive release of nucleic acids, potassium and phosphate into the blood. This complication is the result of tumor cell lysis, which may occur due to treatment of drug sensitive and is characterized by rapid capacity of proliferation, that is often hematological origin. Moreover, the TLS can be observed before starting the treatment due to spontaneous tumor cell death, and frequently worsens when chemotherapy is initiated. TLS has high mortality, so that its prevention continues to be the most important therapeutic measure. In the intensive care unit (ICU), physicians should be aware of the clinical characteristics of TLS, which results in severe electrolyte metabolism disorders, especially hyperkalemia, hyperphosphatemia and hypocalcemia, and acute kidney injury which is a major cause of ICU mortality. An adequate strategy for the management of the TLS, combining hydration, urate oxidase, and an early admission to ICU can control this complication in most patients. The aim of this review is to provide diagnostic tools that allow to the ICU physician to recognize the population at high risk for developing the TLS, and outline a proper strategy for treating and preventing this serious complication.

Topics: Acute Kidney Injury; Allopurinol; Antineoplastic Agents; Arrhythmias, Cardiac; Chelation Therapy; Clinical Trials as Topic; Combined Modality Therapy; Critical Care; Fluid Therapy; Humans; Hyperkalemia; Hyperphosphatemia; Hypocalcemia; Incidence; Multicenter Studies as Topic; Prognosis; Renal Replacement Therapy; Risk Factors; Severity of Illness Index; Tumor Lysis Syndrome; Urate Oxidase

This article assesses whether oxygen-derived free radicals are one of the molecular causes of life-threatening arrhythmias that arise upon reperfusion of the ischemic myocardium. Evidence supporting this proposition has been obtained from studies of the effects of free radical scavengers and antioxidants, free radical generating systems, inhibition of various sources of free radicals and studies investigating the formation of free radicals and their products during early reperfusion. It has been hypothesized that free radical formation causes localised membrane damage to the sarcolemma that results in focal alterations in transmembrane ionic fluxes, particularly potassium. These changes in ionic fluxes may then lead to electrophysiological abnormalities that culminate in ventricular arrhythmias.

Topics: Animals; Arrhythmias, Cardiac; Catecholamines; Coronary Circulation; Coronary Disease; Free Radicals; Humans; Neutrophils; Oxygen; Spin Labels; Xanthine Oxidase

Myocardial ischemia initiates a series of cellular reactions which unless checked will culminate in cell death and tissue necrosis. Although reperfusion provides a means of preventing cell death it is not without hazard. In cases of mild ischemia, where tissue injury is in its reversible phase, reperfusion may precipitate potentially lethal ventricular arrhythmias and in cases of severe injury it may actually accelerate the process of cell death leading to hemorrhage and other forms of severe injury. The identity of mediators of cellular injury, and particularly the critical transition from reversible to irreversible injury, remains controversial. Whereas for a number of years ATP depletion, calcium overload and catecholamines have been considered as key factors in tissue injury, attention has recently been directed towards oxygen-derived free radicals (e.g. superoxide and the hydroxyl radical). In this article we discuss sources of free radicals in the mammalian heart (xanthine oxidase, mitochondria, leucocytes, and catecholamines) and present arguments based on quantitative and temporal considerations that the xanthine oxidase-mediated degradation of hypoxanthine is the most important source of free radicals and as such is the most appropriate target for therapeutic intervention. To support our arguments we present data from two species, the dog and the rat, in which we have shown how allopurinol, the specific inhibitor of xanthine oxidase, can afford a reduction of infarct size in the dog and can dramatically reduce the incidence of potentially lethal reperfusion-induced arrhythmias in the rat. Arising from these and other studies is the proposition that anti-free radical interventions (particularly those directed towards xanthine oxidase inhibition) may provide an important new therapeutic principle in the management of ischemia and reperfusion.

Topics: Allopurinol; Animals; Arrhythmias, Cardiac; Catecholamines; Coronary Disease; Free Radicals; Humans; Leukocytes; Mitochondria, Heart; Myocardial Infarction; Oxygen; Perfusion; Xanthine Oxidase

Several drugs are now known to have useful activity against Trypanosoma cruzi, the causative agent of human American trypanosomiasis (Chagas disease). However, the long-term effects of chemotherapy on the electrocardiographic (ECG) abnormalities associated with this disease have only been assessed for benznidiazole. In the present study, the ECG changes in 299 cases of chronic Chagas disease were followed for 9 years after treatment with itraconazole (N = 136) or allopurinol (N = 163). Among the 97 cases who were found to have ECG abnormalities immediately prior to their treatment, the two drugs appeared equally effective, such abnormalities being corrected in 23 (50%) of the 46 cardiopathy cases given itraconazole and 25 (49%) of the 51 given allopurinol (P > 0.05). Both of these 'cure rates' are much higher than the 8.1% frequency of abnormal-normal conversion observed among 198 'historical controls' (i.e. cases of chronic Chagas disease who had been left untreated; P < 0.05). Itraconazole appeared better than allopurinol at preventing the development of cardiopathy in the cases who appeared electrocardiographically normal at baseline. Among 202 such cases, only two (2.2%) of the 90 treated with itraconazole but 28 (25.0%) of the 112 given allopurinol were found to have developed ECG abnormalities during follow-up (P < 0.05). Therefore, although itraconazole and allopurinol are equally effective at reversing ECG alterations, itraconazole offers better protection against the development of new ECG abnormalities among those with chronic Chagas disease.

Topics: Adolescent; Adult; Allopurinol; Antiprotozoal Agents; Arrhythmias, Cardiac; Chagas Cardiomyopathy; Chagas Disease; Child; Double-Blind Method; Electrocardiography; Female; Heart Block; Humans; Itraconazole; Male; Middle Aged; Patient Compliance

Allopurinol improves endothelial function in chronic heart failure by reducing oxidative stress. We wished to explore if such an effect would attenuate autonomic dysfunction in CHF in line with many other effective therapies in CHF.. We performed a prospective, randomized, double-blind cross-over study in 16 patients with NYHA Class II-IV chronic heart failure (mean age 67 +/- 10 years, 13 male, comparing allopurinol (2 months) at a daily dose of 300 mg (if creatinine < 150 micromol l-1) or 100 mg (if creatinine > 150 micromol l-1) with matched placebo. Mean heart rate and dysrhythmia counts were recorded from 24 h Holter tapes at monthly intervals for 6 months. We assessed autonomic function using standard time domain heart rate variability parameters (HRV): SDNN, SDANN, SDNN index, rMSSD and TI.. Allopurinol had no significant effect on heart rate variability compared with placebo; the results are expressed as a difference in means +/- s.d. with 95% confidence interval (CI) between allopurinol and placebo: SDNN mean = 6.5 +/- 4.8 ms, P = 0.18 and 95% CI (-3.7, 17); TI mean = -2.1 +/- 1.4, P = 0.16 and 95% CI (-5.2, 0.8); SDANN mean = -2.8 +/- 7 ms, P = 0.68 and 95% CI (-18, 12); SDNNi mean = 2 +/- 6.6, P = 0.7 and 95% CI (-12, 16); RMSSD mean = -0.9 +/- 2, P = 0.68 and 95% CI (-5.6, 3.7). For mean heart rate the corresponding results were 0.9 +/- 1.4, P = 0.5 and 95% CI (-2, 3.8). Log 24 h ventricular ectopic counts (VEC) were 0.032 +/- 0.37, P = 0.7 and 95% CI (-0.1, 0.2). Patient compliance with study medication was good since allopurinol showed its expected effect of reducing plasma uric acid (P < 0.001).. Allopurinol at doses, which are known to reduce oxidative stress appear to have no significant effect on resting autonomic tone, as indicated by time domain heart rate variability or on dysrhythmia count in stable heart failure patients.

Topics: Aged; Allopurinol; Arrhythmias, Cardiac; Cardiac Output, Low; Cross-Over Studies; Data Interpretation, Statistical; Double-Blind Method; Female; Free Radical Scavengers; Heart Rate; Humans; Male; Placebos; Uric Acid

During cardiac operations, the heart is subjected to total ischemia and reperfusion, causing serious operative and postoperative complications such as arrhythmias, heart failure, and infarctions that may be partly due to free radical generation. Thus, allopurinol was tested to see if it could reduce cardiac complications during open heart operations. Ninety patients undergoing elective coronary artery bypass grafting were studied prospectively. Fortyfive patients were treated with allopurinol and 45 patients acted as controls. Treatment requiring arrhythmias in the allopurinol group was 6.6% compared with 33.3% in the control group (p less than 0.01). The percentage of patients requiring inotropes was significantly lower in the allopurinol group than in the control group (4.4% versus 26.6%; p less than 0.01). Perioperative myocardial infarction did not occur in the allopurinol group but was seen in 8 patients (17.7%) in the control group. Intraaortic balloon pumping was used in 5 control patients (11.1%) but not in the allopurinol group. This study shows that allopurinol decreases significantly the incidence of cardiac complications in open heart operations.

Topics: Adult; Aged; Allopurinol; Arrhythmias, Cardiac; Cardiotonic Agents; Coronary Artery Bypass; Female; Humans; Male; Middle Aged; Myocardial Infarction; Prospective Studies

224 patients with coronary heart disease, hypertension, disturbances of cardiac rhythm or hyperkinetic heart syndrome were treated with the cardioselective beta-blocker Talinolol (Cordanum) for a period up to 3 years. In 239 examinations in intravenous or peroral application of this medicament we controlled among others the appearance of side effects. This test was carried out with the help of standardised questionings and clinical controls. Apart from registrations of ECG and blood pressure clinico-chemical investigations were included and in the long-term experiment also tests by dermatologists, otorhinolaryngologists and ophthalmologists. In the total number of patients the proportion of side appearances was 17,6%, in the long-term experiment (100 patients with on an average 12.9 months) 7%. The symptoms most frequently cited in the initial phase, such as fatigue, weakness, insomnia and nausea receded within 4 weeks apart from few exceptions. There did not appear any essential bradycardic disturbances of the cardiac rhythm, just as little were references to disadvantageous reactions in the sense of a practolol syndrome.

Topics: Adolescent; Adrenergic beta-Antagonists; Adult; Aged; Allopurinol; Angina Pectoris; Arrhythmias, Cardiac; Double-Blind Method; Fatigue; Female; Headache; Humans; Hypertension; Male; Middle Aged; Phenylurea Compounds; Propanolamines; Sleep Initiation and Maintenance Disorders

Febuxostat is a xanthine oxidase inhibitor used to reduce the formation of uric acid and prevent gout attacks. Previous studies have suggested that febuxostat was associated with a higher risk of cardiovascular events, including atrial fibrillation, compared with allopurinol, another anti-hyperuricemia drug. Whereas in our clinical practice, we identified 2 cases of febuxostat-associated ventricular tachycardia (VT) events. The proarrhythmogenic effects of febuxostat on human cardiomyocytes and underlined mechanisms remain poorly understood. In this study, we employed real-time cell analysis and calcium transient to investigate the effects of febuxostat on the cytotoxicity and electrophysiology properties of human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Up to 10 μM febuxostat treatment did not show toxicity to cell viability. However, 48-h febuxostat exposure generated dose-dependent increased irregular calcium transients and decreased calcium transient amplitude. Furthermore, RNA-seq analysis indicated that the MAPK signaling pathway was enriched in the febuxostat-treated group, especially the protein kinases c-Jun N-terminal kinase (JNK). Western blotting of 3 main protein kinases demonstrated that JNK activation is related to febuxostat-induced arrhythmia rather than extracellular signal regulated kinases (ERK) or p38. The dysfunctional calcium dynamics of febuxostat-treated hiPSC-CMs could be ameliorated by SP600125, the inhibitor of JNK. In conclusion, our study demonstrated that febuxostat increases the predisposition to ventricular arrhythmia by dysregulating calcium dynamics.

Topics: Allopurinol; Arrhythmias, Cardiac; Calcium; Extracellular Signal-Regulated MAP Kinases; Febuxostat; Humans; Induced Pluripotent Stem Cells; JNK Mitogen-Activated Protein Kinases; Myocytes, Cardiac; Uric Acid; Xanthine Oxidase

Ischemia/reperfusion (I/R) injury triggers cardiac dysfunctions via creating reactive oxygen species (ROS). Because xanthine oxidase (XO) is one of the major enzymes that generate ROS, inhibition of XO is expected to suppress ROS-induced I/R injury. However, it remains unclear whether XO inhibition really yields cardioprotection during I/R. The protective effects of the XO inhibitors, topiroxostat and allopurinol, on cardiac I/R injury were evaluated.Methods and Results:Using isolated rat hearts, ventricular functions, occurrence of arrhythmias, XO activities and thiobarbituric acid reactive substances (TBARS) productions and myocardial levels of adenine nucleotides before and after I/R, and cardiomyocyte death markers during reperfusion, were evaluated. Topiroxostat prevented left ventricular dysfunctions and facilitated recovery from arrhythmias during I/R. Allopurinol and the antioxidant, N-acetylcysteine (NAC), exhibited similar effects at higher concentrations. Topiroxostat inhibited myocardial XO activities and TBARS productions after I/R. I/R decreased myocardial levels of ATP, ADP and AMP, but increased that of xanthine. While topiroxostat, allopurinol or NAC did not change myocardial levels of ATP, ADP or AMP after I/R, all of the agents decreased the level of xanthine. They also decreased releases of CPK and LDH during reperfusion.. Topiroxostat showed protective effects against I/R injury with higher potency than allopurinol or NAC. It dramatically inhibited XO activity and TBARS production, suggesting suppression of ROS generation.

Topics: Allopurinol; Animals; Arrhythmias, Cardiac; Myocardial Reperfusion Injury; Nitriles; Protective Agents; Pyridines; Rats; Reactive Oxygen Species; Thiobarbituric Acid Reactive Substances; Ventricular Dysfunction, Left; Xanthine Dehydrogenase

There are no published human studies investigating whether the use of allopurinol, the most commonly used medication for the treatment of hyperuricemia in gout, the most common type of inflammatory arthritis in adults, has any beneficial effects on ventricular electrophysiology. The objective of our study was to assess whether allopurinol use is associated with a reduction in the risk of ventricular arrhythmias (VA).. We used the 5% random sample of Medicare beneficiaries from 2006-2012 to examine new allopurinol use and the risk of incident VA. Multivariable Cox regression analyses were adjusted for demographics (age, race, sex), comorbidity, cardiac medications, and conditions associated with VA. We calculated hazard ratios (HR) and 95% confidence intervals (CI).. Of the 28,755 episodes of new allopurinol use, 2538 were associated with incident VA (8.8%). Among patients with incident VA, 54% were male, 78% were White, 75% had gout as the underlying diagnosis, and the mean Charlson-Romano comorbidity score was 4.8. The crude incidence of VA per 1,000,000 person-days declined as the duration of allopurinol use increased: 1-180 days, 151; 181 days to 2 years, 105; and > 2 years, 85. In multivariable-adjusted analyses, compared to non-use, allopurinol use was associated with lower HR of VA of 0.82 (95% CI, 0.76-0.90). Compared to allopurinol non-use, longer allopurinol use durations were significantly associated with lower multivariable-adjusted HR for VA: 1-180 days, 0.96 (95% CI, 0.85-1.08); 181 days to 2 years, 0.76 (95% CI, 0.68-0.85); and > 2 years, 0.72 (95% CI, 0.60-0.87). Multiple sensitivity analyses adjusting for cardiac conditions, anti-arrhythmic drugs and alternate definitions confirmed our findings with minimal/no attenuation of estimates.. Allopurinol use and use duration of more than 6 months were independently associated with a lower risk of VA. Future studies need to assess the pathophysiology of this potential benefit.

Topics: Adult; Aged; Aged, 80 and over; Allopurinol; Arrhythmias, Cardiac; Comorbidity; Female; Gout; Humans; Incidence; Male; Medicare; Middle Aged; Risk Factors; Time Factors; United States

Ventricular arrhythmias induced by ischemic heart disease are the main cause of sudden cardiac death. Ischemia can cause life-threatening arrhythmias by modulating connexin 43 (Cx43), a principal cardiac gap junction channel protein. The present study investigates whether nitrite can attenuate ischemia-induced ventricular arrhythmias and dephosphorylation of Cx43 in a rat model.. Rats were medicated with normal saline (control, n = 10), nitrite (0.015, 0.15, and 1.5 mg/kg, n = 9 or 10 each), and 0.15 mg/kg nitrite with either the nitric oxide scavenger 2-(4-carboxyphenyl)-4, 4, 5, 5-tetramethylimidazoline-1-oxyl-3-oxide, sodium salt (cPTIO; n = 9) or allopurinol (xanthine oxidoreductase inhibitor, n = 9). We determined the severity of ventricular arrhythmias based on arrhythmia scores and levels of phosphorylated Cx43.. The median arrhythmia score may have been lower in the group given 0.15 mg/kg nitrite (4 [interquartile range {IQR}, 4-5]) than that in the control group (7.5 [IQR, 5.25-8]; P = 0.013). There was no difference among the control, the given 0.015 mg/kg nitrite (7 [IQR, 5-8]), and 1.5 mg/kg nitrite (7 [IQR, 5.5-7.75]; P = 0.95). The arrhythmia scores in the cPTIO (6 [IQR, 5-8]; P = 0.030) and allopurinol (7 [IQR, 5-8]; P = 0.005) groups may have been higher than that in 0.15 mg/kg nitrite group. Immunoblotting revealed that the level of phosphorylated Cx43 in the group given 0.15 mg/kg nitrite, but not in the other treated groups, was significantly higher compared with the control group (P = 0.007).. Nitrite may have attenuated acute ischemia-induced ventricular arrhythmias and Cx43 dephosphorylation in rats. Nitric oxide, which might be generated by xanthine oxidoreductase via nitrite reduction, appears to play a crucial role in this antiarrhythmic effect.

Topics: Allopurinol; Animals; Arrhythmias, Cardiac; Blood Gas Analysis; Connexin 43; Cyclic N-Oxides; Dose-Response Relationship, Drug; Enzyme Inhibitors; Free Radical Scavengers; Hemodynamics; Imidazoles; Male; Myocardial Ischemia; Nitric Oxide; Phosphorylation; Rats; Rats, Wistar; Sodium Nitrite; Ventricular Dysfunction

Hyperuricemia has been shown to be associated with ventricular arrhythmias. However, the mechanisms remained unknown. We assessed whether different urate-lowering agents can attenuate arrhythmias through lowering urate itself or inhibiting xanthenes oxidize (XO) activity in infarcted rats. Male Wistar rats after ligating coronary artery were randomized to either allopurinol, or febuxostat, chemically unrelated inhibitors of XO, benzbromarone or vehicle for 4 weeks. Post-infarction was associated with increased oxidant stress, as measured by myocardial superoxide, isoprostane, XO activity and dihydroethidine fluorescence staining. Measurement of myocardial norepinephrine levels revealed a significant elevation in vehicle-treated infarcted rats compared with sham-operated rats. Sympathetic hyperinnervation was blunted after administering both XO inhibitors, assessed by immunofluorescent analysis, Western blotting and real-time quantitative RT-PCR. Besides, the XO inhibitors-attenuated nerve growth factor levels were reversed in the presence of peroxynitrite generator. Arrhythmic scores in the XO inhibitors-treated infarcted rats were significantly lower than that in vehicle. For similar levels of urate lowering, the uricosuric agent benzbromarone had no beneficial effects on oxidative stress, sympathetic hyperinnervation or arrhythmia vulnerability. Chronic use of XO inhibitors, but not uricosuric agent, down-regulated sympathetic innervation probably through a superoxide-dependent pathway and plays a role in the beneficial effect on arrhythmogenic response.

Topics: Animals; Arrhythmias, Cardiac; Febuxostat; GAP-43 Protein; Male; Myocardial Infarction; Myocardium; Nerve Growth Factor; Rats; Rats, Wistar; Superoxides; Tyrosine 3-Monooxygenase; Uric Acid; Uricosuric Agents; Xanthine Oxidase

In myocardial infarction (MI), repolarization alternans is a potent arrhythmia substrate that has been linked to Ca2+ cycling proteins, such as sarcoplasmic reticulum Ca2+ ATPase (SERCA2a), located in the sarcoplasmic reticulum. MI is also associated with oxidative stress and increased xanthine oxidase (XO) activity, an important source of reactive oxygen species (ROS) in the sarcoplasmic reticulum that may reduce SERCA2a function. We hypothesize that in chronic MI, XO-mediated oxidation of SERCA2a is a mechanism of cardiac alternans.. Male Lewis rats underwent ligation of the left anterior descending coronary artery (n=54) or sham procedure (n=24). At 4 weeks, optical mapping of intracellular Ca2+ and ROS was performed. ECG T-wave alternans (ECG ALT) and Ca2+ transient alternans (Ca2+ALT) were induced by rapid pacing (300-120 ms) before and after the XO inhibitor allopurinol (ALLO, 50 µmol/L). In MI, ECG ALT (2.32±0.41%) and Ca2+ ALT (22.3±4.5%) were significantly greater compared with sham (0.18±0.08%, P<0.001; 0.79±0.32%, P<0.01). Additionally, ROS was increased by 137% (P<0.01) and oxidation of SERCA2a by 30% (P<0.05) in MI compared with sham. Treatment with ALLO significantly decreased ECG ALT (-77±9%, P<0.05) and Ca2+ ALT (-56±7%, P<0.05) and, importantly, reduced ROS (-65%, P<0.01) and oxidation of SERCA2a (-38%, P<0.05). CaMKII inhibition and general antioxidant treatment had no effect on ECG ALT and Ca2+ ALT.. These results demonstrate, for the first time, that in MI, increased ROS from XO is a significant cause of repolarization alternans. This suggests that targeting XO ROS production may be effective at preventing arrhythmia substrates in chronic MI.

Topics: Allopurinol; Animals; Anti-Arrhythmia Agents; Antioxidants; Arrhythmias, Cardiac; Calcium Signaling; Cardiac Pacing, Artificial; Disease Models, Animal; Enzyme Inhibitors; Male; Myocardial Infarction; Myocytes, Cardiac; Oxidation-Reduction; Oxidative Stress; Rats, Inbred Lew; Reactive Oxygen Species; Sarcoplasmic Reticulum; Sarcoplasmic Reticulum Calcium-Transporting ATPases; Time Factors; Xanthine Oxidase

This study was to explore whether repeated non-invasive limb ischemic pre-conditioning (NLIP) can confer an equivalent cardioprotection against myocardial ischemia-reperfusion (I/R) injury in acute diabetic rats to the extent of conventional myocardial ischemic pre-conditioning (MIP) and whether or not the delayed protection of NLIP is mediated by reducing myocardial oxidative stress after ischemia-reperfusion. Streptozotocin-induced diabetic rats were randomized to four groups: Sham group, the I/R group, the MIP group and the NLIP group. Compared with the I/R group, both the NLIP and MIP groups showed an amelioration of ventricular arrhythmia, reduced myocardial infarct size, increased activities of total superoxide dismutase (SOD), manganese-SOD and glutathione peroxidase, increased expression of manganese-SOD mRNA and decreased xanthine oxidase activity and malondialdehyde concentration (All p < 0.05 vs I/R group). It is concluded that non-invasive limb ischemic pre-conditioning reduces oxidative stress and attenuates myocardium ischemia-reperfusion injury in diabetic rats.

Topics: Animals; Arrhythmias, Cardiac; Blood Pressure; Diabetes Mellitus, Experimental; Extremities; Gene Expression; Glutathione Peroxidase; Hemodynamics; Ischemic Preconditioning; Male; Malondialdehyde; Models, Animal; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; Oxidative Stress; Rats; Rats, Wistar; Streptozocin; Superoxide Dismutase; Xanthine Oxidase

We previously demonstrated in rats that noninvasive delayed limb ischemic preconditioning (LIPC) induced by three cycles of 5-min occlusion and 5-min reperfusion of the left hind limb per day for three days confers the same cardioprotective effect as local ischemic preconditioning of the heart, but the mechanism has not been studied in depth. The aim of this project was to test the hypothesis that delayed LIPC enhances myocardial antioxidative ability during ischemia-reperfusion by a mitochondrial K(ATP) channel (mito K(ATP))-dependent mechanism. Rats were randomized to five groups: ischemia-reperfusion (IR)-control group, myocardial ischemic preconditioning (MIPC) group, LIPC group, IR-5HD group and LIPC-5HD group. The MIPC group underwent local ischemic preconditioning induced by three cycles of 5-min occlusion and 5-min reperfusion of the left anterior descending coronary arteries. The LIPC and LIPC-5HD groups underwent LIPC induced by three cycles of 5-min occlusion and 5-min reperfusion of the left hind limb using a modified blood pressure aerocyst per day for three days. All rats were subjected to myocardial ischemia-reperfusion injury. The IR-5HD and LIPC-5HD groups received the mito K(ATP) channel blocker 5-hydroxydecanoate Na (5-HD) before and during the myocardial ischemia-reperfusion injury. Compared with the IR-control group, both the LIPC and MIPC groups showed an amelioration of ventricular arrhythmia, reduced myocardial infarct size, increased activities of total superoxide dismutase, manganese-superoxide dismutase (Mn-SOD) and glutathione peroxidase, increased expression of Mn-SOD mRNA and decreased xanthine oxidase activity and malondialdehyde concentration. These beneficial effects of LIPC were prevented by 5-HD. In conclusion, delayed LIPC offers similar cardioprotection as local IPC. These results support the hypothesis that the activation of mito K(ATP) channels enhances myocardial antioxidative ability during ischemia-reperfusion, thereby contributing, at least in part, to the anti-arrhythmic and anti-infarct effects of delayed LIPC.

Topics: Animals; Arrhythmias, Cardiac; Decanoic Acids; Glutathione Peroxidase; Hydroxy Acids; Ischemic Preconditioning; Male; Malondialdehyde; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; Potassium Channel Blockers; Potassium Channels; Rats; Rats, Wistar; Superoxide Dismutase; Xanthine Oxidase

Superoxide has been shown to play a major role in ventricular remodeling and arrhythmias after myocardial infarction. However, the source of increased myocardial superoxide production and the role of superoxide in sympathetic innervation remain to be further characterized. Male Wistar rats, after coronary artery ligation, were randomized to vehicle, allopurinol, or apocynin for 4weeks. To determine the role of peroxynitrite in sympathetic reinnervation, we also used 3-morpholinosydnonimine (a peroxynitrite generator). The postinfarction period was associated with increased oxidative stress, as measured by myocardial superoxide, nitrotyrosine, xanthine oxidase activity, NADPH oxidase activity, and dihydroethidium fluorescent staining. Measurement of myocardial norepinephrine levels revealed a significant elevation in vehicle-treated infarcted rats compared with sham. Sympathetic hyperinnervation was blunted after administration of allopurinol. Arrhythmic scores in the allopurinol-treated infarcted rats were significantly lower than those in vehicle. For similar levels of ventricular remodeling, apocynin had no beneficial effects on oxidative stress, sympathetic hyperinnervation, or arrhythmia vulnerability. Allopurinol-treated hearts had significantly decreased nerve growth factor expression, which was substantially increased after coadministration of 3-morpholinosydnonimine. These results indicate that xanthine oxidase but not NADPH oxidase largely mediates superoxide production after myocardial infarction. Xanthine oxidase inhibition ameliorates sympathetic innervation and arrhythmias possibly via inhibition of the peroxynitrite-mediated nerve growth factor pathway.

Topics: Acetophenones; Allopurinol; Animals; Arrhythmias, Cardiac; Coronary Vessels; Ethidium; Male; Molsidomine; Myocardial Infarction; Myocardium; NADPH Oxidases; Nerve Growth Factor; Oxidative Stress; Peroxynitrous Acid; Rats; Rats, Wistar; Superoxides; Sympathetic Nervous System; Tyrosine; Xanthine Oxidase

Eleven years after they had been given itraconazole or allopurinol for the treatment of chronic American trypanosomiasis, 109 adult patients were checked for electrocardiographic abnormalities and evidence of Trypanosoma cruzi infection. The parasitological investigations included xenodiagnosis, in which the faeces of Triatoma infestans that had fed on the patients were checked under the microscope for flagellates. In addition, a PCR-based assay and a hybridization assay were used to test blood samples from the patients, and faeces from the Tri. infestans that had fed on the patients, for Try. cruzi DNA. For the data analysis, the patients were divided into four groups known as normal/normal, abnormal/normal, normal/abnormal and abnormal/abnormal, according to whether the patients had been found to have normal or abnormal electrocardiograms (ECG) shortly before the first treatment and to have normal or abnormal ECG when checked at the 11-year follow-up. The 51 normal/normal and 24 normal/abnormal patients were assumed to have been in the 'indeterminate' phase of the disease when they were treated, whereas the 16 abnormal/normal and 18 abnormal/abnormal patients all had evidence of chagasic cardiopathy at that time. When checked 11 years post-treatment, 40 (78.4%), 17 (70.8%), 14 (87.5%) and 17 (94.4%) of these patients, respectively, were each found positive for Try. cruzi in at least one of the parasitological tests. The hybridization assay, whether applied to human blood or bug faeces, appeared a significantly more sensitive test than the PCR-based assays or microscopically assessed xenodiagnosis (P<0.05). Only the 21 patients who appeared to be negative for Try. cruzi could be considered parasitologically cured (although all still appeared to have anti-Try. cruzi antibodies in their blood). Only 13 of these parasitologically cured patients (seven of those treated with itraconazole and six of those given allopurinol) had normal ECG at the 11-year follow-up. In Chile at least, itraconazole, which caused fewer adverse effects than the allopurinol while being no less effective at preventing cardiopathy, appears to be the drug of choice to treat chronic American trypanosomiasis in adults.

Topics: Adult; Allopurinol; Animals; Arrhythmias, Cardiac; Chagas Disease; Chronic Disease; DNA, Protozoan; Double-Blind Method; Electrocardiography; Female; Follow-Up Studies; Humans; Itraconazole; Male; Middle Aged; Polymerase Chain Reaction; Trypanosoma cruzi; Xenodiagnosis

To examine the role of allopurinol as a cardioprotectant during coronary artery bypass graft (CABG) surgery.. A search of MEDLINE (1966-October 2002) was performed using the following terms: allopurinol, xanthine oxidase, oxygen free radical, and coronary artery bypass. References evaluated were limited to English-language and human studies, yielding 41 citations, 13 of which were found suitable. The 5 largest studies are discussed.. Multiple studies with various doses have evaluated the effects of allopurinol on outcomes in CABG patients. These studies found that allopurinol can reduce in hospital mortality, improve cardiac performance, reduce incidence of arrhythmias, reduce markers of ischemia and free-radical generation, and reduce the need for inotropic support. However, these findings were not consistent between all studies.. Allopurinol may reduce the incidence of CABG complications. Although the optimal dose has not been determined, reviewed literature suggests that patients should receive at least 600 mg one day prior to surgery, as well as at least 600 mg on the day of surgery.

Topics: Allopurinol; Arrhythmias, Cardiac; Clinical Trials as Topic; Coronary Artery Bypass; Free Radical Scavengers; Humans; Reactive Oxygen Species

1. The potential for the N-hydroxyguanidine compound PR5 (N-(3, 4-dimethoxy-2-chlorobenzylideneamino)-N'-hydroxyguanidine) as a cardioprotective agent in heart ischaemia and reperfusion injury was investigated using rat models. 2. Administration of 1-10 mg kg-1 of PR5 5 min before 10 min of left coronary artery occlusion, followed by 20 min reperfusion, strongly inhibited reperfusion burst of arrhythmias and markedly improved the survival of the animals (e.g. ventricular fibrillation incidence 93 vs 43% (P<0.05); mortality 47 vs 0% (P<0.05), for controls and for 3 mg kg-1 of PR5, respectively). 3. Administration of 3 mg kg-1 of PR5 1 min before reperfusion to rats subjected to 10 min occlusion, 20 min reperfusion was most effective in reducing arrhythmias and decreasing mortality (43 vs 0%, P<0.05), but effects were also seen when PR5 was administered 0, 1 and 5 min after start of reperfusion. 4. Coronary occlusion/reperfusion (10 - 20 min) increased malondialdehyde (MDA) of rat hearts (0.88+/-0.13 for sham vs 1.45+/-0.12 nmol mg-1 protein for ischaemic; P<0.05). In rats where 3 mg kg-1 PR5 were administered 1 min before reperfusion the increase was attenuated (MDA being 1.04+/-0.12; P<0.05 vs ischaemic). 5. PR5 caused a substantial reduction of the infarction size in rats subjected to 180 min left coronary artery occlusion, followed by 120 min of reperfusion; the necrotic zone being 326+/-32 mg for controls vs 137+/-21 mg for animals treated with 3x3 mg kg-1 of PR5 (P<0.01). 6. PR5 reduced the elevation of the ST-segment of the ECGs, as well as caused pronounced attenuation of the rapid blood pressure drop seen at the start of reperfusion following coronary artery occlusion. 7 We conclude that the N-hydroxyguanidine PR5 provides remarkable protection against ischaemia and reperfusion induced myocardial necrosis and life-threatening arrhythmias. These effects of PR5 are discussed in relation to a recently discovered ability of N-hydroxyguanidines to function as electron acceptors at the xanthine oxidase enzyme.

Topics: Animals; Antihypertensive Agents; Arrhythmias, Cardiac; Cardiovascular Agents; Dose-Response Relationship, Drug; Enzyme Inhibitors; Guanabenz; Guanidines; Hydroxylamines; Male; Malondialdehyde; Myocardial Ischemia; Myocardial Reperfusion Injury; Myocardium; Oxidation-Reduction; Rats; Rats, Wistar; Reperfusion Injury; Xanthine Oxidase

Ventricular arrhythmias were studied in rat isolated hearts subjected to coronary artery occlusion and reperfusion. Free radicals in the perfusate were detected by continuous flow luminol-enhanced chemiluminescence. Administration of purine (2.3 mM) and xanthine oxidase (0.12 U ml-1 min-1) did not significantly modify the severity of reperfusion-induced arrhythmias but did generate free radicals. No free radical generation was detected during the period of coronary artery occlusion or reperfusion. Superoxide dismutase (SOD) 20-80 U ml-1 did not alter the severity of reperfusion arrhythmias but, in the presence of 80 U ml-1 SOD, occlusion-induced arrhythmias were augmented. SOD did not produce any effect on haemodynamics at the concentrations tested. Ventricular arrhythmias and cardiac haemodynamics were also not significantly changed by the combination of scavengers, SOD (10 U ml-1), catalase (100 U ml-1) and mannitol (20 mM). These data suggest that the superoxide free radical is unlikely to be the primary cause of reperfusion induced arrhythmias in rat isolated hearts subjected to regional ischaemia.

Topics: Animals; Arrhythmias, Cardiac; Catalase; Coronary Disease; Free Radical Scavengers; Free Radicals; In Vitro Techniques; Luminescent Measurements; Male; Mannitol; Oxygen Compounds; Purines; Rats; Rats, Wistar; Reperfusion Injury; Superoxide Dismutase; Xanthine Oxidase

The ability of allopurinol to protect against reperfusion injury in the heart has usually been attributed to its xanthine oxidase (XO)-inhibiting properties. Human myocardium however, has exhibited low levels of XO activity. To investigate the effects of allopurinol in an XO-free model and determine whether pretreatment is necessary, 12 domestic pigs (15 kg to 20 kg) underwent occlusion of the left circumflex for 8 minutes followed by reperfusion for 4 hours. One group received allopurinol infusion (5 mg/kg IV) at occlusion over 45 minutes and a control group (n = 6) received a saline infusion (same volume). Left ventricular and aortic pressure, electrocardiograms, and regional wall motion (sonomicrometry) were monitored throughout the process. Regional blood flow (microspheres) were obtained before, during, and 5, 10, and 30 minutes after ischemia. Occlusion decreased transmural flow at the midpapillary level by 75% (0.28 versus 1.10 mL/minute/g). The allopurinol-treated group exhibited a mild, generalized hyperemia at 5 minutes (ischemic zone: 1.44 versus 1.10 mL/min/g, which returned to control levels at 10 and 30 minutes. In contrast, the control group was associated with only 80% restoration of resting blood flow at 5 minutes (0.84 versus 1.10 mL/min/g), which stabilized at 63% of control levels at 10 and 30 minutes. When evaluated for the propensity of arrhythmias using an arbitrary arrhythmia score, the allopurinol group demonstrated no myocardial ectopy when compared with the focal ectopy routinely encountered in the control group at all time intervals.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Allopurinol; Animals; Aorta; Arrhythmias, Cardiac; Blood Pressure; Coronary Circulation; Electrocardiography; Hyperemia; Injections, Intravenous; Myocardial Contraction; Myocardial Reperfusion Injury; Myocardial Stunning; Swine; Ventricular Function, Left; Ventricular Pressure; Xanthine Oxidase

Although the formation of oxygen-derived free radicals (or reactive oxygen species; ROS) and the release of endogenous opioid peptides (EOP) have been independently reported to be the major arrhythmogenic factors in ischemic hearts, possible relations between these two factors have seldom been investigated. Thus, we studied whether the ROS and EOP were related in the progression of ischemia-induced arrhythmias. Isolated rat hearts perfused in the Langendorff mode were treated with dynorphin A1-13 (kappa EOP receptor agonist), and/or allopurinol (xanthine oxidase inhibitor), before the onset of ischemia induced by ligating the left coronary arteries. Ischemic period lasted for 30 min, during which cardiac rhythms were recorded. At the end of ischemia, hearts were analyzed for the glutathione and ascorbate levels. Allopurinol (100 nmoles/heart) was effective in reducing the severity of arrhythmia (arrhythmia score: Mean +/- SEM 3.00 +/- 0.80 for allopurinol, 5.75 +/- 0.41 for placebo, p < 0.01), while dynorphin (10 micrograms/heart) potentiated the arrhythmia (6.71 +/- 0.52, p < 0.05 vs. placebo). Coadministration of allopurinol and dynorphin was capable of reducing arrhythmia (5.57 +/- 0.65) when compared with the administration of dynorphin alone (6.71 +/- 0.52, p < 0.05). Tissue oxidative stress was evaluated by the concentrations of glutathione (GSH) and ascorbate. Allopurinol did not significantly elevate tissue GSH concentrations (1.46 +/- 0.05 mumoles/g wet wt) in ischemic hearts, while dynorphin alone significantly decreased the GSH concentrations (0.96 +/- 0.08, p < 0.05) when compared with the placebo (1.32 +/- 0.03). The dynorphin-induced GSH decrease cannot be reversed by coadministration with allopurinol (0.90 +/- 0.104). Allopurinol significantly elevated tissue ascorbate levels (0.16 +/- 0.01) when compared with placebo (0.10 +/- 0.01, p < 0.05). Interestingly, dynorphin alone also elevated the tissue ascorbate concentrations (0.16 +/- 0.02). Coadministration of allopurinol and dynorphin further spiked the ascorbate levels (0.28 +/- 0.05, p < 0.01). In conclusion, the results suggested that ischemia-induced arrhythmia mechanisms might involve the formation of superoxide and other ROS, which were probably generated from the release of EOP (or EOP/EOP receptor interactions). Superoxide, the formation of which can be inhibited by allopurinol that exerted antiarrhythmic effect, was probably scavenged by ascorbate in myocardial ischemia. The ROS r

Topics: Allopurinol; Animals; Arrhythmias, Cardiac; Ascorbic Acid; Dynorphins; Female; Free Radicals; Glutathione; In Vitro Techniques; Models, Cardiovascular; Myocardial Ischemia; Opioid Peptides; Oxidative Stress; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species

In order to evaluate the protective effect of University of Wisconsin (UW) solution in heart transplantation, a retrospective comparative study with histidine-tryptophane-ketoglutarate (HTK) solution was initiated. In group I, we included 160 patients with HTK preservation, while group II consisted of 50 patients who had their transplant protected with UW solution. All patients received standard quadruple drug therapy for immunosuppression. The average ischaemic time of the donor hearts in group I was 142+/-44 min, ranging from 83 to 235 min. Acute immediate perioperative graft failure occurred in six cases (3.8%). Statistical analysis including the chi-square test, revealed a significant increase in the incidence of acute perioperative graft failure when compared with duration of ischaemic time (P < 0.01). Within the first 30 postoperative days, 24 patients died (15% early mortality). The same statistical correlation was evident between the incidence of early mortality and duration of graft ischaemic time. The 30-day and 6-month survival rates were 81% and 78%, respectively. The average ischemic time of the donor hearts in group II was 193+/-50 min ranging from 100 to 360 min, which was significantly longer in comparison with the group I (P < 0.05). Acute perioperative graft failure occurred once (2%); the patient was retransplanted successfully. Five patients died within the first 30 postoperative days (10% early mortality). There was no correlation between length of ischaemic time and incidence of acute graft failure or early mortality. The 30-day and 6-month survival rates were 90% and 88%, respectively and, thus, better when compared with group I. In both groups similar results were achieved with regard to postoperative NYHA status of the patients and incidence of cardiac arrhythmias. Myocardial preservation with HTK solution showed satisfying results as long as the ischaemic time did not exceed 4 h. The early functional results achieved with UW graft protection were excellent, even with ischaemic times longer than 4 h and not depending on lenght of ischaemic period.

Topics: Adenosine; Allopurinol; Arrhythmias, Cardiac; Chi-Square Distribution; Female; Glucose; Glutathione; Graft Survival; Heart; Heart Transplantation; Humans; Insulin; Ischemia; Male; Mannitol; Middle Aged; Organ Preservation Solutions; Postoperative Complications; Postoperative Period; Potassium Chloride; Procaine; Raffinose; Reoperation; Retrospective Studies; Survival Rate; Time Factors; Treatment Failure

The effects of perfusate calcium reduction, allopurinol and dimethylthiourea on reperfusion-induced arrhythmias and purine wash-out in isolated rabbit and rat hearts were compared. The overall incidence of reperfusion-induced ventricular tachycardia (VT) was 88% and 94% and that of ventricular fibrillation (VF) was 44% and 88% in the control rabbit and rat hearts, respectively. VF was reduced to 10% and 0% in rat and rabbit hearts subjected to perfusate calcium reduction (0.4 mM for 1 min before ischemia and for 1 min before and throughout reperfusion), respectively. In allopurinol, 1 mM, perfused rat hearts the overall incidence of VF was not changed and only the incidence of a sustained VF (that lasting for at least 10 min) was reduced. VT and VF were prevented in allopurinol-perfused rabbit hearts. Dimethylthiourea, 10 mM, reduced the incidence of VF in rat hearts to 16% and did not significantly affect VT and VF in rabbit hearts. In untreated rat hearts, the major purine compounds washed out upon reperfusion were inosine, hypoxanthine, xanthine and urate. Allopurinol augmented the wash-out of adenosine and abolished that of xanthine and urate. In untreated rabbit hearts, the major purine washed out were inosine, adenosine and hypoxanthine. Allopurinol did not cause further increase in adenosine wash-out in rabbit hearts. We speculate that: (1) calcium mediated arrhythmogenic mechanism is operating both in reperfused rat and rabbit heart; (2) free radical mediated mechanism is of an importance only in rat heart; (3) neither a decreased free radical production secondary to xanthine oxidase inhibition nor the augmentation of adenosine wash-out is a likely explanation for the antiarrhythmic effect of allopurinol in reperfused hearts; and (4) high level of myocardial adenosine accumulation during ischemia, probably secondary to low xanthine oxidase activity, may play a role of a natural defence mechanism in ischemic/reperfused rabbit heart.

Topics: Adenosine; Allopurinol; Animals; Arrhythmias, Cardiac; Calcium; Female; Free Radicals; Heart; Incidence; Male; Myocardium; Oxidation-Reduction; Purines; Rabbits; Rats; Rats, Wistar; Receptors, Purinergic P1; Reperfusion Injury; Tachycardia, Ventricular; Thiourea; Xanthine Oxidase

The aim was to examine the effects of exogenous oxygen derived free radicals on myocardial capillary permeability for a small hydrophilic indicator, postischaemic vascular tone, and the occurrence of arrhythmias in the canine heart in vivo.. Free radicals were generated by simultaneous intracoronary infusion of hypoxanthine and xanthine oxidase into normally perfused myocardium, and at reperfusion following five minutes of coronary occlusion, respectively, in 20 anaesthetised open chest dogs. Myocardial capillary extraction for 99mTc-DTPA, plasma flow rate, and the interstitial washout rate constant were measured by the single injection, residue detection method, and the capillary permeability-surface area product (PS) was calculated. The maximum plasma flow during reactive hyperaemia was measured by the local 133Xe washout method.. Hypoxanthine and xanthine oxidase infusion into normally perfused myocardium induced a 15% decrease in capillary extraction (p = 0.05), a 24% decrease in PS (p < 0.01), and a 23% decrease in the interstitial washout rate constant (NS) two minutes after the end of the infusion. When hypoxanthine and xanthine oxidase were infused into postischaemic myocardium, 86% of animals developed sustained ventricular arrhythmias, in contrast to none in control experiments (p < 0.05). The maximum plasma flow was 363% of preocclusive values in control experiments v 268% in hypoxanthine + xanthine oxidase experiments (p < 0.05).. In normally perfused hearts, intracoronary infusion of hypoxanthine and xanthine oxidase induce a decreased capillary extraction, suggesting a reduced capillary surface area. In postischaemic myocardium these substances cause a decreased vasodilatation in the initial phase of reactive hyperaemia, and induce ventricular arrhythmias.

Topics: Animals; Arrhythmias, Cardiac; Capillary Permeability; Dogs; Female; Hypoxanthines; Male; Myocardial Reperfusion Injury; Myocardium; Reactive Oxygen Species; Vascular Resistance; Xanthine Oxidase

Electrophysiological effects of allopurinol on arrhythmias were studied in isolated segments of guinea pig right ventricular free walls paced from endocardium. A high-gain electrocardiogram as well as transmembrane electrical activity from endo- and epicardium were recorded. Tissues were exposed to simulated ischemia for 15 min and then were reperfused with normal Tyrode solution. Sustained or nonsustained ventricular tachycardia, bigeminy, and trigeminy with characteristics of transmural reentry occurred in early reperfusion in 75% of 20 control preparations. Arrhythmias were associated with prolongation of transmural conduction time and abbreviation of endocardial effective refractory period (ERP). Allopurinol strongly reduced the incidence of reperfusion arrhythmias (20-33%) between 10 and 100 microM, whereas either lower or higher concentrations (5 or 500 microM) were less effective (43 and 50%). Antiarrhythmic efficacy correlated with significant attenuation of reperfusion-induced transmural conduction delay (P less than 0.05 or 0.01). Allopurinol did not affect endocardial conduction times nor did it significantly alter endocardial action potential duration or ERP. Our results indicate that allopurinol exerts antiarrhythmic efficacy during reperfusion by selectively attenuating defects related to anisotropic tissue properties.

Topics: Action Potentials; Allopurinol; Animals; Arrhythmias, Cardiac; Coronary Disease; Electrophysiology; Guinea Pigs; Heart; Heart Conduction System; In Vitro Techniques; Male; Myocardial Reperfusion Injury; Pericardium; Reaction Time; Refractory Period, Electrophysiological; Reperfusion

The pathogenesis of post-ischaemic depression of contractility in myocardium was examined in isovolumic rat heart. 31P-NMR was used to monitor changes in ATP, creatine phosphate (CrP), inorganic phosphate (Pi), and [H+] during brief periods of ischaemia and reperfusion with and without allopurinol treatment. During 5, 10, or 15 min of total global ischaemia, the decline in function (rate-pressure product) correlated inversely with [Pi] (r = 0.92, P less than 0.01). Cardiac function exhibited a slow progressive recovery during 20 min of reperfusion, ultimately reaching only 85%, 78%, and 69% of its pre-ischaemic value following 5, 10, and 15 min of global ischaemia respectively. Following each ischaemic period [ATP], [CrP], [Pi], and [H+] all recovered to control levels within 5-10 min of initiating reperfusion. Allopurinol (2 mM) treatment of hearts made ischaemic for 15 min significantly improved contractile recovery to 89 +/- 7%. Allopurinol also exhibited significant anti-arrhythmic activity during the reperfusion period, decreasing the incidence of premature contractions and the duration of tachy-arrhythmias. Allopurinol had no effect on the final repletion of [ATP] and [CrP], or the recovery of [Pi] and [H+], although the rate of ATP repletion was elevated in the initial 5 min of reperfusion. These results show that neither depletion of the cytosolic high-energy phosphate pool, nor sustained elevations in [Pi] or [H+] are important in the production of post-ischaemic contractile impairment. The beneficial action of allopurinol suggests that xanthine oxidase derived oxygen free-radicals may be involved in the sustained contractile dysfunction following brief ischaemic episodes.

Topics: Adenosine Triphosphate; Allopurinol; Animals; Arrhythmias, Cardiac; Coronary Disease; Energy Metabolism; In Vitro Techniques; Male; Myocardial Contraction; Myocardial Reperfusion Injury; Myocardium; Phosphocreatine; Rats; Rats, Inbred Strains

Topics: Allopurinol; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Humans; Myocardial Infarction; Myocardial Reperfusion; Thrombolytic Therapy

Isolated rat hearts (n = 15 per group) were subjected to regional ischemia (10 min) and reperfusion. Superoxide dismutase (SOD; 8 X 10(3), 2 X 10(4), 4 X 10(4), 6 X 10(4), 8 X 10(4), 1.2 X 10(5), or 1.6 X 10(5) IU/l) given early (i.e., throughout the experiment) reduced the incidence of reperfusion-induced ventricular fibrillation (VF), the dose-response characteristics describing an asymmetric U-shaped curve. The optimal dose of SOD (8 X 10(4) IU/l) reduced VF incidence from its control value of 87 to 27% (P less than 0.05). Given late (i.e., 2 min before reperfusion), this dose of SOD exerted a reduced but nonetheless significant antifibrillatory effect. Early administration of catalase (1 X 10(3), 1 X 10(4), 2.5 X 10(4), 5 X 10(4), 1 X 10(5), 1.5 X 10(5), or 1 X 10(6) IU/l) reduced VF incidence in a linear dose-dependent manner, from its control value of 87 to 7% with 1 X 10(6) IU/l (P less than 0.05). Late administration of this dose reduced VF incidence from its control value of 87 to 27% (P less than 0.05). Allopurinol (0.07, 0.15, 0.37, 0.73, 1.10, or 1.47 mM added to the perfusate throughout the experiment) significantly reduced VF incidence over a wide range of doses, but low and high doses were ineffective. Pretreatment with allopurinol (0, 0.01, 0.02, 0.05, 0.10, 0.20, or 0.50 g.kg-1.day-1 per os 48, 24, and 1 h before study) reduced VF incidence from its control value of 93 to less than 50% at several doses.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Allopurinol; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Catalase; Coronary Disease; Dose-Response Relationship, Drug; Free Radicals; Male; Myocardial Contraction; Myocardial Reperfusion Injury; Rats; Superoxide Dismutase; Time Factors

A novel series of 2-O-alkylascorbic acids (5a-u) was synthesized, and their scavenging activities against active oxygen species as well as their suppressive effects on the arrhythmias in rat heart ischemia-reperfusion models were evaluated. Some 2-O-alkylascorbic acids (5e-1) exhibited potent inhibiting activities against lipid peroxidation in rat brain homogenates and in alleviating effects in the ischemia-reperfusion models. Studies on the structure-activity relationship demonstrated that a free 3-enolic hydroxyl group and the longer alkyl chains substituted on the 2-hydroxyl group of ascorbic acid were beneficial for the biological and pharmacological activities. 2-O-Octadecylascorbic acid (5k, CV-3611), one of the most potent and promising compounds, markedly inhibited lipid peroxidation (IC50 = 4.3 X 10(-6) M) and alleviated myocardial lesions induced by ischemia-reperfusion at an oral dose of 1 mg/kg in rats.

Topics: Animals; Arrhythmias, Cardiac; Ascorbic Acid; Heart Rate; Ligation; Linoleic Acid; Linoleic Acids; Lipid Peroxides; Male; Micelles; Oxygen; Rats; Structure-Activity Relationship

We have assessed whether the xanthine oxidase inhibitor, allopurinol, can afford maximal protection against the formation of reperfusion-induced arrhythmias or whether the addition of free radical scavengers and anti-oxidants can increase this protection. Using an anesthetized rat preparation with transient coronary artery occlusion, we have compared the ability of allopurinol pretreatment alone to that of a combination therapy of allopurinol, superoxide dismutase, and catalase to reduce the incidence of reperfusion-induced arrhythmias. While both regimes reduced the incidence of reperfusion-induced ventricular fibrillation (from 87% to 40%, p less than 0.05 by allopurinol alone; and to 13%, p less than 0.01 by combination therapy), and both treatments eliminated mortality, only combination therapy reduced the incidence of reperfusion-induced ventricular tachycardia (from 87% to 40%, p less than 0.05). Furthermore, using an arrhythmia score analysis, combination therapy was shown to offer significantly greater protection than allopurinol alone. This additional protection afforded by combination therapy was also demonstrated by significant decreases in log10 duration of fibrillation and log10 number of premature ventricular complexes compared with allopurinol alone. Both allopurinol and combination therapy also significantly delayed the ischemia-induced increases in ST segment elevation, although there was no difference between the two drug-treated groups. We conclude from these results that allopurinol does not offer maximal protection against reperfusion-induced arrhythmias and that the addition of more general anti-oxidant therapy can increase this protection.

Topics: Allopurinol; Animals; Antioxidants; Arrhythmias, Cardiac; Enzyme Therapy; Male; Myocardial Reperfusion Injury; Rats; Rats, Inbred Strains; Superoxide Dismutase

We have assessed whether oxygen-derived free radicals produced by xanthine oxidase may be an important trigger mechanism in the genesis of reperfusion-induced arrhythmias. We have examined (i) the effects of inhibition of xanthine oxidase by both folic acid solution and amflutizole; (ii) the effects of the inhibitor of xanthine dehydrogenase to xanthine oxidase conversion, soybean trypsin inhibitor; (iii) the effects of administration of superoxide dismutase and catalase, both singly and in combination and (iv) in an isolated rat heart preparation we have investigated the ability of free radical scavengers to reduce reperfusion arrhythmias caused by the infusion of xanthine oxidase and hypoxanthine. The prior administration of folic acid solution, amflutizole, superoxide dismutase, catalase, and superoxide dismutase plus catalase all reduced the incidence of reperfusion-induced arrhythmias and resultant mortality, caused by reperfusion after a transient period of coronary artery occlusion in the anaesthetised rat. Prior administration of soybean trypsin inhibitor significantly reduced mortality. In an isolated, perfused rat heart preparation with temporary coronary artery occlusion, addition of xanthine oxidase-hypoxanthine to the perfusion medium increased the incidence of reperfusion arrhythmias and decreased the total duration of sinus rhythm during reperfusion. Further addition of superoxide dismutase or L-methionine increased significantly the total duration of sinus rhythm. These results suggest that in the rat heart xanthine oxidase may be involved in the genesis of reperfusion-induced arrhythmias.

Topics: Allopurinol; Animals; Arrhythmias, Cardiac; Catalase; Coronary Disease; Folic Acid; Free Radicals; Heart; Hypoxanthines; Male; Perfusion; Rats; Rats, Inbred Strains; Superoxide Dismutase; Thiazoles; Trypsin Inhibitors; Xanthine Oxidase

Topics: Animals; Arrhythmias, Cardiac; Coronary Circulation; Coronary Disease; Free Radicals; Hydroxides; Hydroxyl Radical; Superoxides; Xanthine Oxidase

Standard microelectrode techniques were used to study the effects of a free radical generating system on action potentials recorded from guinea pig ventricular myocardium. Free radicals were generated by mixing xanthine oxidase (0.02-0.04 mu/ml) with the superfusate-modified Locke's solution containing purine 2.3 mM. The system was validated by demonstrating that it could reduce cytochrome C at a rate of 15.9 +/- 1.5 mol/l/min. This rate was decreased to 3.0 +/- 0.3 (p less than 0.001) in the presence of superoxide dismutase (12 mg/100 ml), and the reaction was absent if xanthine oxidase and purine were premixed for 60 minutes prior to adding cytochrome C. Superfusion of guinea pig ventricular strips with the free radical generating system (20-30 minutes) resulted in a highly significant reduction in resting potential from -79.3 +/- 1.8 mV to -70.9 +/- 1.4 mV (p less than 0.0001, n = 6) and in action potential amplitude from 110.9 +/- 2.2 mV to 101.7 +/- 4.0 mV (p less than 0.0001). There was an accompanying fall in maximum rate of depolarization (Vmax) from 254.1 +/- 17.7 V/sec to 207.1 +/- 18.6 V/sec (p less than 0.01) and no significant change in action potential duration. These changes were accompanied by spontaneous activity in 3 of 6 preparations and reversed after 20-30 minutes washing in Locke's solution. They were largely abolished by adding superoxide dismutase (12 mg/100 ml) to the superfusate and completely absent if the xanthine oxidase and purine were premixed for 60 minutes before superfusing the myocardium. We conclude that the phenomena observed may contribute to the genesis of reperfusion arrhythmias.

Topics: Action Potentials; Animals; Arrhythmias, Cardiac; Coronary Circulation; Coronary Disease; Female; Free Radicals; Guinea Pigs; Heart; Isotonic Solutions; Male; Membrane Potentials; Oxygen; Purines; Superoxides; Xanthine Oxidase

The effects of in vitro generated oxygen free radicals on transmembrane potentials in guinea pig papillary muscles were investigated. Superfusion of the muscle with the oxygen free radical generating medium (1 mM xanthine + 10 U/l xanthine oxidase) for 40 min altered significantly neither the resting nor the action potentials characteristics. We propose that electrophysiological changes leading to the reperfusion-induced arrhythmias may be secondary to an inhomogenous change in the coronary myocardial perfusion produced by the radicals.

Topics: Animals; Arrhythmias, Cardiac; Coronary Disease; Female; Free Radicals; Guinea Pigs; In Vitro Techniques; Male; Membrane Potentials; Oxygen; Papillary Muscles; Xanthine; Xanthine Oxidase; Xanthines

The possible role of free radicals in the genesis of occlusion and reperfusion-induced arrhythmias was studied by determining the effects of the xanthine oxidase inhibitor allopurinol (400 mg p.o. 24 h before experimentation +25 mg kg-1 i.v.) and the free radical scavenger N-t-butyl-alpha-phenyl nitrone (PBN; 50 mg kg-1 i.v.) on these arrhythmias in chloralose anaesthetized greyhounds. Neither of the drugs had any major effects on haemodynamic variables, although allopurinol caused a significant increase in heart rate. The mean number of extrasystoles observed during ischaemia in dogs given allopurinol or PBN was not significantly different from those seen in controls. Further, the incidence of ventricular fibrillation during either occlusion or reperfusion was unchanged by either drug and there was thus no improvement in survival. These results suggest that, in this model of myocardial ischaemia and reperfusion, free radicals may not play a major role in the genesis of life-threatening arrhythmias.

Topics: Allopurinol; Animals; Arrhythmias, Cardiac; Blood Gas Analysis; Coronary Circulation; Coronary Disease; Cyclic N-Oxides; Dogs; Female; Free Radicals; Hemodynamics; Hydrogen-Ion Concentration; Lactates; Male; Nitrogen Oxides

The effect of the xanthine oxidase inhibitor, allopurinol, on myocardial ultrastructure after left circumflex coronary artery occlusion (40 min) with or without reperfusion (60 min) was examined in rabbits. Pretreatment of rabbits for 7 days with allopurinol (0.1% in the drinking water) resulted in a lower incidence of ventricular fibrillation in both ischemic and reperfusion phases. However, the number of Q waves, ST-segment elevation and premature ventricular contractions were similar in both groups of animals. Examination of hearts from allopurinol-treated animals revealed a distinct decrease in ultrastructural alterations following ischemia and reperfusion. Among the subcellular organelles studied, allopurinol had a preferential protective effect on the mitochondria both during the ischemic and reperfusion phases. In the allopurinol-treated animals, most mitochondria were intact and the cristae network preserved. Our study suggests that the preservation of mitochondrial structural and functional integrity by allopurinol may be an important determinant of its protective actions in myocardial ischemic/reperfusion injury.

Topics: Allopurinol; Animals; Arrhythmias, Cardiac; Coronary Disease; Electrocardiography; Male; Microscopy, Electron; Mitochondria, Heart; Myocardium; Rabbits

Topics: Allopurinol; Animals; Arrhythmias, Cardiac; Coronary Circulation; Coronary Disease; Free Radicals; Oxygen; Rats; Ventricular Fibrillation; Xanthine Oxidase

We have investigated the possibility that xanthine oxidase-linked free radical production has a role in the genesis of arrhythmias during ischemia and reperfusion. In this study, rats were treated with allopurinol (20 mg/kg, orally, 24 hours before study, plus 20 mg/kg, iv, 15 minutes prior to study). Using an anesthetized open-chest preparation with either coronary artery occlusion for 30 minutes, or 5 minutes followed by 10 minutes reperfusion, we monitored and compared the rhythm disturbances in experimental vs. placebo-treated rats (n = 18 in each group). Allopurinol treatment reduced the incidence of ventricular tachycardia during ischemia from 88% to 50% (P less than 0.05) and the number of premature ventricular complexes from 471 +/- 120 to 116 +/- 46 (P less than 0.02), but the treatment had no effect upon the incidence or duration of ventricular fibrillation or upon mortality. In contrast, far more dramatic protection was observed during reperfusion after 5 minutes of ischemia. Allopurinol treatment reduced the incidence of ventricular fibrillation from 67% to 11% (P less than 0.01), reduced the mean duration of fibrillation from 230 +/- 70 to 14 +/- 1 seconds (P less than 0.05), and reduced mortality by half (10/18 to 4/18), although this did not reach a level of statistical significance. In addition, the mean duration of tachycardia was reduced from 83 +/- 26 to 38 +/- 8 seconds (P less than 0.05). Allopurinol pretreatment thus affords some protection against ischemia-induced arrhythmias, but a higher degree of protection against reperfusion-induced arrhythmias. Allopurinol inhibits xanthine oxidase activity, and, in turn, this inhibits superoxide radical production.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Allopurinol; Animals; Arrhythmias, Cardiac; Arteries; Coronary Disease; Coronary Vessels; Free Radicals; Hemodynamics; Ligation; Male; Perfusion; Rats; Rats, Inbred Strains; Xanthine Oxidase

Total starvation is effective for acute weight reduction in obesity. However, in 200 patients, most of whom also had internal diseases, 8% exhibited sometimes severe complications, i.e. reversible cerebral ischemia in 3 hypertensive patients when the blood pressure was lowered to the normal range by natriuresis of fasting; breakdown of water and electrolyte homeostasis with circulatory collapse, vomiting and vertigo; acute crises of paroxysmal nocturnal hemoglobinuria and porphyria respectively and increase of transaminases up to 200 mu/ml, or cardiac arrhythmias. Relative (?) contraindications for total fasting appear to be clinical sings of arteriosclerosis such as vascular bruits, angina pectoris and intermittent claudication. In case of doubt, the method should only be used in hospital.

Topics: Acetone; Adult; Allopurinol; Arrhythmias, Cardiac; Diet, Reducing; Edema; Female; Humans; Ischemic Attack, Transient; Male; Middle Aged; Obesity; Spironolactone; Starvation; Transaminases; Urea; Water-Electrolyte Imbalance

Topics: Adult; Allopurinol; Arrhythmias, Cardiac; Blood Glucose; Cardiomegaly; Cholesterol; Diphosphates; Electrocardiography; Heart Defects, Congenital; Humans; Lipids; Male; Orotic Acid; Phosphates; Phospholipids; Ribose; Triglycerides; Uric Acid; Uricosuric Agents

Topics: Aged; Alcoholism; Allopurinol; Arrhythmias, Cardiac; Chloral Hydrate; Colchicine; Digoxin; Drug Synergism; Gastrointestinal Hemorrhage; Gout; Hospitals, Teaching; Humans; Liver Diseases; Male; Middle Aged; Nitroglycerin; Patient Care Team; Pharmacists; Pharmacy Service, Hospital; Quinidine; Warfarin; Washington