allopurinol and Carotid-Stenosis

Free radicals contribute to the tissue damage caused by ischaemia-reperfusion. The aim of the present study was to investigate whether preoperative antioxidant therapy (allopurinol) affects free radical levels in cerebral venous blood in connection with surgery for carotid artery stenosis.. Twenty-five patients were randomised into the study. Thirteen were controls and 12 were pretreated with allopurinol the day before surgery. Before, during and after surgery, blood samples were drawn from the ipsilateral jugular vein. Radical levels were measured using the spin trap technique ex vivo using OXANOH as the spin trap. Multivariate statistics were used with Principal Component Analysis and Partial Least Square regression analysis.. Radical levels increased with diabetes, high leukocyte count, high creatinine and a high degree of contralateral stenosis. Radical levels decreased with high age, blood pressure, collateral circulation as well as operation for left-side carotid artery stenosis. After pretreatment with allopurinol, several of the relationships noted in the control group were eliminated, i.e. leukocyte count, side of operation, Betapred pretreatment and collateral circulation.. Radical levels can be determined in connection with surgery for carotid artery stenosis using an ex vivo spin trap method. With preoperative antioxidant therapy the relationships between enhanced radical levels and clinical data, as seen in control subjects, disappeared. This might indicate a beneficial effect of preoperative pretreatment with antioxidants.

Topics: Aged; Aged, 80 and over; Allopurinol; Antioxidants; Carotid Stenosis; Endarterectomy, Carotid; Enzyme Inhibitors; Female; Free Radicals; Humans; Jugular Veins; Male; Middle Aged; Sensitivity and Specificity; Xanthine Oxidase

XO (xanthine oxidase) is a key enzyme of uric acid metabolism and is thought to contribute to oxidative pathways that promote atherosclerotic plaque progression, yet its role in plaque destabilization is not well elucidated. We hypothesized that XO is expressed in carotid plaque from symptomatic patients in association with cardiovascular risk factors.. Patients were stratified by symptoms, defined as presentation with an ipsilateral cerebral ischemic event. Carotid atherosclerotic plaques were obtained from 44 patients with symptomatic plaque and 44 patients without ischemic cerebral events. Protein expression of XO was evaluated by immunohistochemical staining and the percentage of cells expressing XO and CD68 (macrophage marker) compared between the groups. Biochemical and demographic cardiometabolic risk factors of study participants also were measured.. Carotid atherosclerotic plaques from symptomatic patients were associated with significantly higher XO expression versus asymptomatic plaque (median [interquartile range]: 1.24 [2.09] versus 0.16 [0.34]; P<0.001) and with significantly higher circulating uric acid levels (mean±SD: 7.36±2.10 versus 5.37±1.79 mg/dL; P<0.001, respectively). In addition, XO expression in atherosclerotic carotid plaque was inversely associated with serum high-density lipoproteins cholesterol levels (P=0.010, r=−0.30) and directly with circulating uric acid levels (P<0.001, r=0.45). The average percentage of macrophages that expressed XO was significantly higher in symptomatic versus asymptomatic plaques (median [interquartile range]: 93.37% [25] versus 46.15% [21], respectively; P<0.001).. XO overexpression in macrophages is associated with increased serum uric acid and low high-density lipoproteins cholesterol levels and may potentially have a mechanistic role in carotid plaque destabilization. The current study supports a potential role for uric acid synthesis pathway as a target for management of carotid atherosclerosis in humans.

Topics: Aged; Biomarkers; Carotid Arteries; Carotid Artery Diseases; Carotid Stenosis; Endarterectomy, Carotid; Female; Humans; Macrophages; Male; Plaque, Atherosclerotic; Xanthine Oxidase

This study was carried out on carotid artery plaque and plasma of 50 patients. We analyzed uric acid, hypoxanthine, xanthine, and allantoin levels to verify if enzymatic purine degradation occurs in advanced carotid plaque; we also determined free radicals and sulphydryl groups to check if there is a correlation between oxidant status and purine catabolism. Comparing plaque and plasma we found higher levels of free radicals, hypoxanthine, xanthine, and a decrease of some oxidant protectors, such as sulphydryl groups and uric acid, in plaque. We also observed a very important phenomenon in plaque, the presence of allantoin due to chemical oxidation of uric acid, since humans do not have the enzyme uricase. The hypothetical elevated activity of xanthine oxidase in atherosclerosis could be reduced by specific therapies using its inhibitors, such as oxypurinol or allopurinol.

Topics: Aged; Aged, 80 and over; Allantoin; Allopurinol; Carotid Stenosis; Chemistry, Clinical; Female; Free Radicals; Humans; Hypoxanthine; Male; Middle Aged; Oxidants; Oxypurinol; Purines; Uric Acid; Xanthine

Reactive oxygen species such as superoxide and hydroxyl radicals have been implicated in the pathogenic growth of various cell types. The molecular mechanisms involved in redox-sensitive cell growth control are poorly understood. Stimulation of cultured vascular smooth muscle cells (VSMC) with xanthin/xanthin oxidase (X/XO) increases proliferation, whereas stimulation with hydrogen peroxide and Fe3+NTA (H-Fe) causes growth arrest of VSMC. Differential Display led to the identification of two novel, differentially regulated redox-sensitive genes. The dominant negative helix-loop-helix protein Id3 is induced by X/XO and down-regulated by H-Fe. The transcription factor gut-enriched Kruppel-like factor (GKLF) is induced by H-Fe but not by X/XO. Induction of GKLF and inhibition of Id3 via transfection experiments leads to growth arrest, whereas overexpression of Id3 and inhibition of GKLF cause cell growth. Id3 down-regulation is induced via binding of GKLF to the Id3 promotor and concomitantly reduced Id3 gene transcription rate. GKLF induction by H-Fe is mediated through hydroxyl radicals, p38MAP kinase-, calcium-, and protein synthesis-dependent pathways. Id3 is induced by X/XO via superoxide, calcium, p38, and p42/44 MAP kinase. GKLF induces and Id3 depresses expression of p21WAF1/Cip1, p27KIP1, p53. Induction of Id3 is accomplished by angiotensin II via superoxide release. A vascular injury mouse model revealed that Id3 is overexpressed in proliferating vascular tissue in vivo. These findings reveal novel mechanisms of redox-controlled cellular proliferation involving GKLF and Id3 that may have general implications for our understanding of vascular and nonvascular growth control.

Topics: Angiotensin II; Animals; Carotid Stenosis; Cell Division; Cells, Cultured; DNA-Binding Proteins; Growth Inhibitors; Inhibitor of Differentiation Proteins; Kruppel-Like Factor 4; Kruppel-Like Transcription Factors; Male; Mice; Mice, Inbred C57BL; Muscle, Smooth, Vascular; Neoplasm Proteins; Oxidation-Reduction; Oxidative Stress; Rats; Reactive Oxygen Species; RNA, Messenger; Second Messenger Systems; Transcription Factors; Transcription, Genetic; Xanthine; Xanthine Oxidase

To analyse production of free radicals during operations for stenosis of the internal carotid artery.. University hospital, Sweden.. 10 patients operated on for carotid artery stenosis.. Blood samples were repeatedly drawn from the sigmoid sinus through a catheter in the internal jugular vein on the same side, before, during, and after clamping of the internal carotid artery. OXANOH was added to the blood samples in vitro and the radical production calculated from the amount oxidised to OXANO as electron spin resonance.. The relation between radical production and certain clinical variables investigated by partial least squares regression analysis.. There were several significant relations. High systolic blood pressure and advanced age were associated with low, and severe degree of stenosis with increased, free radical production. Certain anaesthetic drugs as well as blood variables also influenced the production of radicals.. The technique used seems to offer the possibility to find and study methods to reduce free radical production during this kind of operation.

Topics: Age Factors; Aged; Aged, 80 and over; Allopurinol; Carotid Stenosis; Enzyme Inhibitors; Female; Free Radicals; Humans; Male; Middle Aged; Monitoring, Physiologic; Multivariate Analysis; Regression Analysis; Spin Trapping; Vascular Surgical Procedures; Xanthine Oxidase

Topics: Adult; Aged; Aortic Aneurysm, Abdominal; Arteriosclerosis; Carotid Stenosis; Chromatography, High Pressure Liquid; Humans; Middle Aged; Uric Acid; Xanthine Oxidase