thromboxane-b2 and Albuminuria

Cilostazol improves walking distance in peripheral arterial disease (PAD) patients. The study objectives were to assess the effects of cilostazol on walking distance, followed by the additional assessment of cilostazol on exercise-induced ischaemia-reperfusion injury in such patients.. PAD patients were prospectively recruited to a double-blinded, placebo-controlled trial. Patients were randomised to receive either cilostazol 100mg or placebo twice a day. The primary end-point was an improvement in walking distance. Secondary end-points included the assessment of oxygen-derived free-radical generation, antioxidant consumption and other markers of the inflammatory cascade. Initial and absolute claudication distances (ICDs and ACDs, respectively) were measured on a treadmill. Inflammatory response was assessed before and 30 min post-exercise by measuring lipid hydroperoxide, ascorbate, alpha-tocopherol, beta-carotene, P-selectin, intracellular and vascular cell-adhesion molecules (I-CAM and V-CAM), thromboxane B(2) (TXB(2)), interleukin-6, interleukin-10, high-sensitive C-reactive protein (hsCRP), albumin-creatinine ratio (ACR) and urinary levels of p75TNF receptor. All tests were performed at baseline and 6 and 24 weeks.. One hundred and six PAD patients (of whom 73 were males) were recruited and successfully randomised from December 2004 to January 2006. Patients who received cilostazol demonstrated a more significant improvement in the mean percentage change from baseline in ACD (77.2% vs. 26.6% at 6 weeks, p=0.026 and 161.7% vs. 79.0% at 24 weeks, p=0.048) as compared to the placebo. Cilostazol reduced lipid hydroperoxide levels compared to a placebo-related increase before and after exercise (6 weeks: pre-exercise: -11.8% vs. +5.8%, p=0.003 and post-exercise: -12.3% vs. +13.9%, p=0.007 and 24 weeks: pre-exercise -15.5% vs. +12.0%, p=0.025 and post-exercise: -9.2% vs. +1.9%, p=0.028). beta-Carotene levels were significantly increased in the cilostazol group, compared to placebo, before exercise at 6 and 24 weeks (6 weeks: 34.5% vs. -7.4%, p=0.028; 24 weeks: 34.3% vs. 17.7%, p=0.048). Cilostazol also significantly reduced P-selectin, I-CAM and V-CAM levels at 24 weeks as compared to baseline (p<0.05). There was no difference between treatment groups for ascorbate, alpha-tocopherol, interleukin-6 and -10, hsCRP and p75TNF receptor levels.. Cilostazol significantly improves ACD, in addition to attenuating exercise-induced ischaemia-reperfusion injury, in PAD patients.

Topics: Adult; Aged; Aged, 80 and over; Albuminuria; alpha-Tocopherol; Ascorbate Oxidase; beta Carotene; C-Reactive Protein; Cilostazol; Creatinine; Double-Blind Method; Female; Humans; Intercellular Adhesion Molecule-1; Interleukin-10; Interleukin-6; Intermittent Claudication; Lipid Peroxides; Male; Middle Aged; P-Selectin; Prospective Studies; Receptors, Tumor Necrosis Factor; Reperfusion Injury; Tetrazoles; Thromboxane B2; Vascular Cell Adhesion Molecule-1; Vasodilator Agents; Walking

The pathogenesis of antiphospholipid antibody (aPL) related thrombosis is multifactorial and includes, amongst others, enhanced coagulation activation measured as prothrombin fragment 1 + 2 (F1 + 2), elevated plasma levels of von Willebrand factor (vWF), plasminogen activator inhibitor (PAI) and endothelin-1 (ET-1) as well as heightened thromboxane generation and lipid peroxidation. To evaluate the antioxidant susceptibility of some of the above pathways, probucol (500 mg/d orally, a cholesterol lowering agent bearing antioxidant properties) was administered for a three week period to 14 subjects with aPL and to seven healthy controls. At baseline aPL participants showed higher plasma levels of vWF (P = 0.006), ET-1 (P = 0.0002) and enhanced urinary excretion of 11-dehydro-thromboxane-B2 (TXB2) (P = 0.0004), F2-isoprostanes (marker of lipid peroxidation) (P = 0.02) and albumin (P = 0.04) than controls. In the aPL group baseline IgG anticardiolipin (aCL) titre positively related with urinary TXB2 (r2 = 0.43, P = 0.01) and inversely with urinary NOx (r2 = -0.6, P = 0.005) whereas urinary NOx and TXB2 were negatively correlated (r2 = -0.42, P = 0.01). After the treatment period significant decreases from baseline values were noted for PAI (P = 0.01), ET-1 (P = 0.006), TXB2 (P = 0.02), F2-isoprostanes (P = 0.01) and albuminuria (P = 0.01) in aPL participants but not in controls. These pilot data support oxidative sensitive mechanisms and a potential role for antioxidant treatment in the pathogenesis of aPL induced vasculopathy.

Topics: Adult; Albuminuria; Antibodies, Antiphospholipid; Anticholesteremic Agents; Anticoagulants; Antioxidants; Antiphospholipid Syndrome; Arachidonic Acids; Creatinine; Endothelin-1; Female; Humans; Lipids; Male; Middle Aged; Nitric Oxide; Pilot Projects; Probucol; Prothrombin; Thrombosis; Thromboxane B2; von Willebrand Factor; Warfarin

Picotamide both inhibits thromboxane synthetase and acts as a thromboxane antagonist at the receptor level. We investigated the long-term effect of picotamide on urinary albumin excretion (UAE) at rest and induced by exercise in 30 type 2 diabetic patients who were normotensive and had microalbuminuria while at rest. The subjects of our study had a mean age of 52.5 +/- 1.6 years, BMI of 28.5 +/- 0.7 kg/m2, diabetes duration of 9.1 +/- 1.8 years, and HbA1c of 7.0 +/- 0.8%. The study was a randomized double-blind placebo-controlled trial. The patients were randomly allocated to receive for 1 year either picotamide, 300 mg, 3 tablets/day, or placebo, 3 tablets/day. The patients were asked to visit our outpatient clinic after 1, 3, 6, 9, and 12 months of treatment. At all times, blood pressure, microalbuminuria at rest, blood glucose, serum creatinine, serum picotamide, and creatinine clearance were measured; at baseline and after 6 and 12 months, all patients underwent submaximal physical exercise. After 6 months of picotamide, baseline and exercise-induced microalbuminuria were significantly decreased (up to one-third) as compared with the baseline and placebo level, with no further drops at month 12 of picotamide treatment. On placebo treatment, UAE at rest and after exercise was slightly increased compared with baseline values. The effects of picotamide occurred without significant side effects or changes in either blood pressure levels or glycometabolic control. Our study is the first long-term intervention trial in type 2 diabetes showing that an antithromboxane agent is able to decrease microalbuminuria, which in this disease is a dual marker of macro- and microangiopathy. Our findings suggest an important role for thromboxane in the pathophysiology of microalbuminuria in diabetes; moreover, we hypothesize that antithromboxane agents may have a place in the treatment/prevention of both macro- and microvascular complications in type 2 diabetic patients.

Topics: Administration, Oral; Albuminuria; Blood Pressure; Cohort Studies; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Double-Blind Method; Exercise; Female; Follow-Up Studies; Heart Rate; Humans; Male; Middle Aged; Phthalic Acids; Platelet Aggregation Inhibitors; Thromboxane B2; Time Factors

Albumin excretion rates (AER) were measured in 30 insulin-dependent diabetics during a 16-week double-blind, randomised, placebo-controlled study of the specific thromboxane synthetase inhibitor UK-38,485.6 of 15 subjects in the active group had microalbuminuria (defined as mean pretreatment AER 20-150 micrograms/min); in these patients AER fell from 32 +/- 3 micrograms/min to 11 +/- 1 micrograms/min at 8 weeks and 9 +/- 1 micrograms/min at 16 weeks. The AER rose again (to 29 +/- 8 micrograms/min) within 12 weeks of stopping the drug. There was no significant change in the 10 patients with microalbuminuria who received placebo. There was a strong correlation between change from baseline values and the baseline values themselves in the active, but not in the placebo group, and the change from baseline differed significantly between the two groups. There was no change in glycosylated haemoglobin or mean blood glucose levels during the study. In a separate study UK-38,485 caused significant suppression of thromboxane B2 synthesis in diabetic and non-diabetic subjects.

Topics: Adult; Albuminuria; Clinical Trials as Topic; Creatinine; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Double-Blind Method; Female; Humans; Imidazoles; Male; Middle Aged; Oxidoreductases; Thromboxane B2; Thromboxane-A Synthase

We have previously shown nutritional intervention with fish oil (n-3 PUFA) to reduce numerous complications associated with the metabolic syndrome (MetS) in the JCR:LA-corpulent (cp) rat. In the present study, we sought to explore the potential role of fish oil to prevent glomerulosclerosis in JCR:LA-cp rats via renal eicosanoid metabolism and lipidomic analysis. Male lean and MetS JCR:LA-cp rats were fed a lipid-balanced diet supplemented with fish oil (5 or 10 % of total fat). After 16 weeks of feeding, albuminuria was significantly reduced in MetS rats supplemented with 5 or 10 % fish oil ( - 53 and - 70 %, respectively, compared with the untreated MetS rats). The 5 % fish oil diet resulted in markedly lower glomerulosclerosis ( - 43 %) in MetS rats and to a lesser extent in those supplemented with 10 % fish oil. Interestingly, untreated MetS rats had higher levels of 11- and 12-hydroxyeicosatetraenoic acids (HETE) v. lean rats. Dietary fish oil reduced these levels, as well as other (5-, 9- and 15-) HETE. Whilst genotype did not alter prostanoid levels, fish oil reduced endogenous renal levels of 6-keto PGF1α (PGI2 metabolite), thromboxane B2 (TxB2), PGF2α and PGD2 by approximately 60 % in rats fed 10 % fish oil, and TxB2 ( - 50 %) and PGF2α ( - 41 %) in rats fed 5 % fish oil. In conclusion, dietary fish oil prevented glomerular damage in MetS rats and mitigated the elevation in renal HETE levels. These results suggest a potential role for dietary fish oil to improve dysfunctional renal eicosanoid metabolism associated with kidney damage during conditions of the MetS.

Topics: 6-Ketoprostaglandin F1 alpha; Albuminuria; Animals; Dietary Fats; Dietary Supplements; Dinoprost; Disease Models, Animal; Fish Oils; Genotype; Hydroxyeicosatetraenoic Acids; Kidney Diseases; Kidney Glomerulus; Male; Metabolic Syndrome; Prostaglandin D2; Prostaglandins; Rats; Rats, Inbred Strains; Thromboxane B2

Recent studies indicate that not all diabetic subjects benefit from aspirin therapy. Our objective is to characterize diabetic subjects with aspirin resistance using urine thromboxane, and VerifyNow measures. Our results suggest that cardiovascular disease, microalbuminuria, poor diabetes control, and increased waist circumference help identify aspirin resistance in diabetes.

Topics: Albuminuria; Aspirin; Cohort Studies; Diabetic Angiopathies; Drug Resistance; Female; Glycated Hemoglobin; Humans; Insulin Resistance; Male; Middle Aged; Nephelometry and Turbidimetry; Platelet Aggregation; Platelet Aggregation Inhibitors; Thromboxane B2; Waist Circumference

Microalbuminuria is a predictor of adverse outcome in hypertension.We evaluated in vivo platelet activation, by urinary 11-dehydrothromboxane (TX)B2 and plasma P-selectin, in hypertensives with or without microalbuminuria, and its possible association with oxidative stress, by urinary 8-iso-prostaglandin (PG)F2alpha and endothelial dysfunction. Sixty essential hypertensive patients, with (n=30) or without (n=30) microalbuminuria, and 30 controls were studied. Endothelial function was assessed by nitric oxide products, intercellular adhesion molecule (ICAM)-1, and asymmetric dimethylarginine (ADMA) levels. Urinary 11-dehydro-TXB2 excretion was higher in microalbuminuric (median 805 pg/mg creatinine) compared to nonmicroalbuminuric patients or controls (414 and 291 pg/mg, respectively; P<0.0001). Plasma P-selectinwas significantly higher in patients with microalbuminuria (median 136 ng/ml) as compared to those without microalbuminuria or controls (85 and 65 ng/ml; P<0.0001). Urinary 8-iso-PGF2alpha excretion was also enhanced in microalbuminuric (median 279 pg/mg creatinine) compared to nonmicroalbuminuric patients or controls (157 and 146 pg/mg, respectively; P<0.0001). A significant impairment in endothelial function was found in microalbuminuric patients, with decreased nitric oxide and increased ICAM-1 and ADMA levels. Multivariate regression analysis showed that urinary 8-iso-PGF2alpha excretion (beta=0.49; P<0.0001) and microalbuminuria (beta=0.36; P<0.001) were independently related to 11-dehydro-TXB2 in hypertensives. Vitamin E supplementation (900 mg daily for 1 month) in 10 hypertensives with microalbuminuria was associated with normalization in median 11-dehydro-TXB2 and 8-iso-PGF2alpha. We conclude that lipid peroxidation is a major determinant of persistent platelet activation in hypertensive patients with microalbuminuria.

Topics: Aged; Albuminuria; Arginine; Biomarkers; Disease Progression; Endothelium; Female; Humans; Hypertension; Intercellular Adhesion Molecule-1; Lipid Peroxidation; Male; Middle Aged; Nitric Oxide; Oxidative Stress; P-Selectin; Platelet Activation; Prostaglandins A; Thromboxane B2; Vitamin E

Actions of the lipid mediator thromboxane (Tx) A2 acting through the TP receptor contribute to the pathogenesis of cardiovascular disease. To further explore the role of TxA2 in hypertension, we examined the consequences of deficiency of the TP receptor on the course of hypertension associated with endothelial dysfunction and salt sensitivity. To this end, the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME) was administered to TP-deficient (Tp-/-) and wild-type (Tp+/+) control mice in drinking water for 21 wk along with a high-salt (HS; 6% NaCl) diet. Administration of L-NAME increased urinary excretion of TxB2 to a similar extent in both Tp+/+ and Tp-/- animals. L-NAME also caused significant and sustained elevations in blood pressure that reached a maximum between weeks 3 and 6. However, the severity of hypertension was attenuated in the Tp-/- mice throughout the study period (P<0.001). At the end of the study, the wild-type mice developed significant cardiac hypertrophy (23.6+/-2% increase in heart-to-body weight ratio). The severity of cardiac hypertrophy was attenuated in the TP-deficient group (11.1+/-2.6%; P<0.05). In contrast, kidney hypertrophy was exaggerated in the Tp-/- mice compared with controls (37.1+/-5.4 vs. 12.3+/-2.3%; P<0.01). Moreover, the severity of glomerulosclerosis, tubule vacuolization, and interstitial chronic inflammation was also enhanced in the Tp-/- group (P<0.01). Thus, in L-NAME hypertension, TP receptors contribute to elevated blood pressure and cardiac hypertrophy. In this model, TP receptors also provided unexpected protection against kidney injury.

Topics: Albuminuria; Animals; Blood Pressure; Cardiomegaly; Disease Models, Animal; Drinking; Eating; Enzyme Inhibitors; Hypertension, Renal; Isoprostanes; Male; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; NG-Nitroarginine Methyl Ester; Nitric Oxide; Receptors, Thromboxane A2, Prostaglandin H2; Renin-Angiotensin System; Sodium, Dietary; Thromboxane B2

The mechanisms involved in development of cardiovascular complications associated with diabetes mellitus are not well elucidated. Among the vasoactive factors that may play a role in development of these complications are angiotensin II and thromboxane B2 (TXB2). We hypothesized that diabetes increases renal production of TXB2 through stimulation of angiotensin type-1 receptor.. We used a microdialysis technique to monitor changes in renal interstitial fluid (RIF) TXB2 in conscious streptozotocin-induced diabetes rat model. The RIF levels of angiotensin II and TXB2 were monitored before and during 6 weeks after development of diabetes and during treatment with the angiotensin type-1 receptor blocker valsartan at 10 mg/kg. Measurement of the urinary albumin excretion (UAE) was used to monitor the development and progression of diabetic nephropathy.. The UAE was 81.62 +/- 1.31 ng/min, 184.75 +/- 9.41 ng/min (P < .01), and 229.84 +/- 4.49 ng/min (P < .0001) at baseline, week 3, and week 6, respectively, after induction of diabetes. Basal levels of RIF angiotensin II were 4.28 +/- 0.02 pg/mL and significantly increased to 6.24 +/- 0.31 pg/mL (P < .001) and 7.66 +/- 0.05 pg/mL (P < .001) at 3 and 6 weeks after development of diabetes. Similarly, basal RIF TXB2 was 197 +/- 27 pg/mL and increased to 488 +/- 80 pg/mL (P < .01) and 703 +/- 130 pg/mL (P < .01) at 3 and 6 weeks after development of diabetes. Valsartan caused further increase in RIF angiotensin II levels. In contrast, valsartan decreased RIF TXB2 levels at baseline to 85 +/- 11 pg/mL (P < .01), at 3 weeks to 141 +/- 17 pg/mL (P < .01), and at 6 weeks to 255 +/- 45 pg/mL (P < .01) after development of diabetes.. These results demonstrate that diabetes mellitus is accompanied by increased renal production of angiotensin II and TXB2. The increase in TXB2 is mediated through stimulation of angiotensin type-1 receptor.

Topics: Albuminuria; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Animals; Blood Glucose; Blood Pressure; Body Weight; Diabetes Mellitus, Experimental; Extracellular Fluid; Kidney; Rats; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 1; Tetrazoles; Thromboxane B2; Valine; Valsartan

To determine cytochrome P450 (CYP450) and cyclooxygenase (COX) expression and metabolite regulation and renal damage in the early stages of obesity-related hypertension and diabetes.. Obese and lean Zucker rats at 10 to 12 weeks of age were studied. Blood pressure was measured in the conscious state using radiotelemetry. Blood glucose levels and body weight were measured periodically. Protein expression of CYP450 and COX enzymes in the kidney cortex, renal microvessels, and glomeruli was studied. The levels of CYP450 and COX metabolites in urine were measured, and urinary albumin excretion, an indicator of kidney damage, was measured.. Body weight and blood glucose averaged 432 +/- 20 grams and 105 +/- 5 mg/dl, respectively, in obese Zucker rats as compared with 320 +/- 8 grams and 91 +/- 5 mg/dl, respectively, in age-matched 10- to 12-week-old lean Zucker rats. Renal microvascular CYP4A and COX-2 protein levels were increased 2.3- and 17.0-fold, respectively, in obese Zucker rats. The protein expression of CYP2C11 and CYP2C23 was decreased 2.0-fold in renal microvessels isolated from obese Zucker rats when compared with lean Zucker rats. The urinary excretion rate of thromboxane B(2) was increased significantly in obese Zucker as compared with lean Zucker rats (22.0 +/- 1.8 vs. 13.4 +/- 1.0 ng/d). Urinary albumin excretion, an index of kidney damage, was increased in the obese Zucker rat at this early age.. These results suggest that increased CYP4A and COX-2 protein levels and decreased CYP2C11 and CYP2C23 protein levels occur in association with microalbuminuria during the onset of obesity-related hypertension and type 2 diabetes.

Topics: Albuminuria; Animals; Aryl Hydrocarbon Hydroxylases; Blood Glucose; Body Weight; Cyclooxygenase 2; Cytochrome P-450 CYP2J2; Cytochrome P-450 Enzyme System; Cytochrome P450 Family 2; Diabetes Mellitus, Type 2; Hypertension; Isoenzymes; Kidney; Kidney Cortex; Kidney Glomerulus; Male; Microcirculation; Obesity; Prostaglandin-Endoperoxide Synthases; Rats; Rats, Zucker; Steroid 16-alpha-Hydroxylase; Thromboxane B2

To study the modifying effect and mechanism of Tangshenning Recipe on micro-albuminuria in rats with early diabetic nephropathy (DN).. Male Wistar rats were randomly divided into the normal group (n=8) and model group (n=24). Intraperitoneal injecting of streptozotocin (STZ) plus complete Freund's adjuvant (CFA) was applied once a week for 3 times to induce the DN rats model. Three weeks later, the model group rats were randomly divided into pathologic group (n=8), monopril group (n=8) and Tangshenning Recipe group(n=8) according to the 24 h U-Alb. Each group's renal hemodynamics index and SOD, GSH, MDA in renal tissue were determined by radioimmunoassay (RIA) and colorimetric method respectively.. The levels of plasmatic TXB(2), the ratio of TXB(2) and 6-keto-PGF1alpha, and the CGRP in pathologic group were significantly higher than those in normal group. The levels of plasmatic ET decreased obviously, SOD decreased and MDA increased significantly in the rats' renal tissue of pathologic group. The levels of plasmatic TXB(2), the ratio of TXB(2) and 6-keto-PGF1alpha decreased significantly in both Tangshenning Recipe group and monopril group, and the therapeutic effect of Tangshenning Recipe group was better than that of monopril group. SOD was higher and MDA was lower in Tangshenning Recipe group than that in pathologic group.. The results indicates that Tangshenning Recipe can lower the micro-albuminuria in early DN rats, the mechanism of which probably lies in the modification of glycometabolism, the ratio of TXB(2) and 6-keto-PGF1alpha, the plasmatic CGRP and the renal lipid preoxidation.

Topics: 6-Ketoprostaglandin F1 alpha; Albuminuria; Animals; Diabetic Nephropathies; Disease Models, Animal; Drugs, Chinese Herbal; Glutathione; Male; Malondialdehyde; Phytotherapy; Radioimmunoassay; Random Allocation; Rats; Rats, Wistar; Superoxide Dismutase; Thromboxane B2; Treatment Outcome

Although it is well known that dietary lipids affect the course of glomerulonephritis in rats and humans, the precise mechanisms involved have not been fully elucidated. The aim of this study was to investigate the effects of different types of dietary lipids (fish oil and vegetable oil) on daunomycin (DM)-induced nephropathy in mice fed on soybean oil (SO) or cod liver oil (CLO). Urinary protein excretion, serum albumin, creatinine, total cholesterol, and TG were measured, and glomerular histological changes were evaluated. Antioxidant enzymes were also measured, along with the levels of lipid peroxide, GSH, thromboxane (Tx) B2, and 6-keto prostaglandin F1alpha in renal cortical tissue. Dietary CLO significantly reduced urinary albumin excretion and ameliorated the histological changes induced by DM. The increase of tissue lipid peroxide levels seen in SO-fed mice was suppressed in CLO-fed mice, whereas CLO-fed mice showed higher GSH levels than SO-fed mice throughout the experiment. In addition, renal tissue GSH peroxidase activity was significantly higher at 72 h after DM injection in CLO-DM mice than in SO-DM mice. Both renal cortical TxB2 and 6-keto PGF1alpha levels were significantly lower in CLO-DM mice than in SO-DM mice. These results suggest that inhibition of oxidative damage by dietary CLO played an important role in the prevention of DM nephropathy in this mouse model. The effect of CLO was closely associated with the inhibition of Tx synthesis.

Topics: Albuminuria; Animals; Body Weight; Cod Liver Oil; Daunorubicin; Dietary Fats; Dinoprost; Glutathione; Kidney; Kidney Diseases; Lipid Peroxides; Male; Mice; Mice, Inbred Strains; Soybean Oil; Thromboxane B2

To quantify the inflammatory and renal parameters in comparative cohorts of patients undergoing surgical or endovascular repair of abdominal aortic aneurysms (AAAs).. Forty-three patients (41 men; ages 58-81 years) underwent endovascular or conventional aneurysm surgery according to aortic morphology. All patients received a standard general anesthetic and had 12 serial blood and urine samples collected during the perioperative period. Samples underwent analysis for the cytokines interleukin (IL) 1beta tumor necrosis factor-alpha (TNF-alpha), and IL-6. White cell and platelet activation were estimated indirectly by measuring sL-selectin and 11-dehydrothromboxane B2, respectively. The urinary albumin:creatinine ratio (ACR) and N-acetyl-beta-D-glucosaminidase (NAG) activity were estimated to assess renal injury. Fibrinogen and fibrinogen degradation products were calculated to assess activation of the clotting cascade.. Twenty-three patients underwent endovascular AAA repair and 20 had conventional surgery. Concentrations of IL-6 (p < 0.002) and TNF-alpha (p < 0.0004) were significantly higher in the conventional group. The ACR (p < 0.002) and urinary NAGs (p < 0.0009) were also significantly higher in this group, suggesting greater renal injury. Platelet activity was significantly greater in the endovascular group (p < 0.01), perhaps indicating thrombus organization within the aneurysm sac.. These data suggest that the inflammatory response associated with conventional aneurysm repair is largely obviated by endovascular techniques. This may potentially translate to a lower incidence of multiple organ failure after endovascular surgery.

Topics: Acetylglucosaminidase; Aged; Aged, 80 and over; Albuminuria; Aortic Aneurysm, Abdominal; Blood Platelets; Creatinine; Female; Fibrin Fibrinogen Degradation Products; Humans; Inflammation; Interleukin-1; Interleukin-6; Kidney; L-Selectin; Male; Middle Aged; Minimally Invasive Surgical Procedures; Prospective Studies; Thromboxane B2; Tumor Necrosis Factor-alpha

1. The obese fa/fa Zucker rat is a genetic model of obesity and insulin resistance which develops a number of metabolic and endocrine features of non-insulin-dependent diabetes, including hypertension, proteinuria and glomerular sclerosis. 2. We have investigated the urinary excretion of the metabolites of thromboxane (thromboxane B2) and prostacyclin (6-keto prostaglandin F1 alpha), and of endothelin and cyclic GMP as markers for changes in the balance of renal haemodynamic factors in the obese Zucker rat. 3. Obese fa/fa Zucker rats were hypertensive compared with their lean counterparts (161 +/- 3 and 138 +/- 3 mmHg respectively, P < 0.01); obese animals were also markedly proteinuric (16.7 +/- 6.7 versus 1.1 +/- 0.1 mg/ml) and albuminuric (8.3 +/- 2.9 versus 0.4 +/- 0.25 mg/ml) and excreted less creatinine than lean animals (all P < 0.01). Urinary excretion of endothelin was greater in obese rats (123 +/- 24 versus 62 +/- 10 pg/15 h, P < 0.05) as was the level of pre-proendothelin mRNA, but excretion of cyclic GMP was depressed (12.5 +/- 1.6 versus 27.2 +/- 3.1 nmol/ 15 h, P < 0.01). Histological examination of kidneys from obese animals showed evidence of focal glomerulosclerosis and cortical tubular damage. 4. These results show that increased urinary endothelin is associated with proteinuria and early stage nephropathy in this animal model of non-insulin-dependent diabetes mellitus. This finding, coupled with a decreased excretion of cyclic GMP, suggests that these increased renal vasoconstrictor/vasodilator forces might contribute to the renal functional changes in non-insulin-dependent diabetes mellitus.

Topics: 6-Ketoprostaglandin F1 alpha; Albuminuria; Animals; Cyclic GMP; Diabetes Mellitus; Diabetes Mellitus, Type 2; Endothelin-1; Immunohistochemistry; Kidney; Male; Obesity; Rats; Rats, Zucker; RNA, Messenger; Statistics, Nonparametric; Thromboxane B2

In this study, we investigated the effect of captopril (CPT) on glomerular filtration rate (GFR), effective renal plasma flow (ERPF), filtration fraction (FF), urinary albumin excretion (UAE) and daily urinary excretion of thromboxane B2 (TXB2) and 6-keto- prostaglandin F1a (6-keto-PGF1a) in 29 normotensive non-insulin-dependent diabetes (NIDDM) patients without clinically discernible nephropathy. Before treatment, urinary excretion 6-keto-PGF1a was significantly increased (P < 0.05) in 29 NIDDM patients compared with 25 health subjects matched for age and sex. The values of GFR and FF were significantly higher (P < 0.01 and P < 0.005, respectively) in NIDDM than in normal volunters, whereas ERPF was comparable in both groups. Meanwhile we observed that UAE of early NIDDM was increased before treatment. After CPT treatment, GFR, FF, UAE and urinary excretion of 6-keto-PGF1a were significantly reduce (all P < 0.005) compared with those of NIDDM before treatment. These data indicated that CPT is effective in lowering glomerular filtration pressure and ameliorating microalbuminuria in the normotensive early NIDDM.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Aged; Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Captopril; Diabetes Mellitus, Type 2; Female; Glomerular Filtration Rate; Humans; Male; Matched-Pair Analysis; Middle Aged; Prostaglandins; Renal Plasma Flow; Thromboxane B2

It has been postulated that ischaemia-reperfusion occurs in intermittent claudication resulting in neutrophil activation and release of soluble mediators, increasing systemic vascular permeability and enhancing atherogenesis.. We measured neutrophil deformability, plasma thromboxane levels, and urinary microalbumin excretion in 30 male claudicants, and 10 age- and sex-matched controls, before and after exercise to maximum walking distance. Blood was taken from an antecubital vein.. There was an increase in urinary microalbumin excretion after exercise in claudicants. Statistically significant increases in the median and 90th percentile transit times (markers of neutrophil deformability) for isolated neutrophils from blood drawn 5 min after exercise in the claudicants were observed with no change in control subjects. Plasma thromboxane concentrations in claudicants increased within 10 min post-exercise. Plasma concentrations in controls were significantly lower throughout the study period. In the claudicant group, a positive correlation between the percentage change in the median transit time for neutrophils, and the percentage change in plasma thromboxane at 60 min post-exercise was found.. The results lend further support to the concept of ischaemia-reperfusion events in patients with intermittent claudication, leading to a systemic increase in vascular permeability as a result of endothelial injury or dysfunction (a crucial step in atherogenesis), associated with thromboxane production and neutrophil activation. We suggest that the above changes may contribute to the increased mortality seen in such patients.

Topics: Adult; Aged; Albuminuria; Humans; Intermittent Claudication; Male; Middle Aged; Neutrophil Activation; Physical Exertion; Thromboxane B2; Walking

Urinary excretion of selected markers for renal injury, as well as urinary excretion rates of the thromboxane metabolite, 11-keto-thromboxane B2 (11k-TXB2), was studied in 36 male patients undergoing coronary bypass surgery using cardiopulmonary bypass (CPB). In all patients, excretion of both tubular (N-acetyl-beta-D-glucosaminidase [beta NAG]; alpha 1-microglobulin [alpha 1-MG]) and glomerular markers (albumin [Alb]; transferrin [Trf]; immunoglobulin G [IgG]) sharply increased on Day 1 after CPB, and they remained elevated throughout the observation period of 5 days. Urinary excretion rates of 11k-TXB2 markedly increased on Day 1 after surgery, and they rapidly decreased thereafter. In 12 of the 36 patients, a temporary increase of serum creatinine levels (> 1.30 mg/dl) was noted following surgery. A positive correlation was found between serum creatinine levels and excretion of the tubular enzyme beta NAG (r = 0.36; p < 0.05), but not between creatinine levels and alpha 1-MG or the glomerular markers. Furthermore, no correlation between urinary excretion of 11k-TXB2 and any of the urinary markers for renal injury could be detected. Our data do not strengthen the hypothesis that acute renal injury observed during CPB is related to exaggerated thromboxane biosynthesis in these patients. Monitoring of urinary markers for incipient renal damage, particularly excretion of beta NAG, might be of additional diagnostic value for detection of otherwise subclinical renal injury in patients undergoing CPB.

Topics: Acetylglucosaminidase; Acute Kidney Injury; Aged; Albuminuria; Alpha-Globulins; Biomarkers; Cardiopulmonary Bypass; Coronary Artery Bypass; Coronary Disease; Creatinine; Humans; Immunoglobulin G; Male; Middle Aged; Thromboxane B2; Transferrin

Wistar rats (4-week-old) were administered with streptozotocin (45 mg/kg) through tail veins. After 3 months, diabetic rats were divided into 2 groups. One group (EPA group, n = 16) was fed a lipid-free diet (90%, w/w) plus lard (8%) and 90% pure eicosapentaenoic acid ethyl ester (2%) for 6 months. The other group (control group, n = 16) was fed in the same way except that eicosapentaenoic acid ethyl ester was replaced by safflower oil. Twenty-four-hour urine was collected just before starting the experimental diets and during the 6-month experimental period at monthly intervals. There were no differences in food intake and body weight between the two groups throughout the experiment. The mean microalbuminuria of the EPA group became significantly lower than that of the control group after 4 months on the diets through the end of the study (6 months). The mean microalbuminuria levels at the end of the study were 1.38 mg/day in the EPA group (n = 9) and 5.19 mg/day in the control group (n = 6) (p < 0.01). Eicosapentaenoic acid administration might retard the progression of diabetic nephropathy by reducing microalbuminuria.

Topics: 6-Ketoprostaglandin F1 alpha; Albuminuria; Animals; Blood Glucose; Blood Pressure; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Eating; Eicosapentaenoic Acid; Fatty Acids; Kidney; Lipids; Male; Organ Size; Rats; Rats, Wistar; Thromboxane B2; Weight Gain

Previous studies have demonstrated that urinary thromboxane B2 (TXB2) excretion (UTXB2) and glomerular production of TXB2 are enhanced in experimental diabetes and that selective inhibitors of TX synthesis prevent or delay the development of albuminuria. The present study was conducted to examine the contribution of platelet TXB2 production to the enhancement of UTXB2 and glomerular TXB2 production and to the pathogenesis of albuminuria in the partially insulin-treated moderately hyperglycemic (blood glucose, 200 to 400 mg/dL) streptozotocin-diabetic rat (SDR). Treatment of control rats or of SDR with diabetes of 5 months' duration with antiplatelet serum for 4 consecutive days reduced circulating platelet counts and serum TXB2 generation, an index of platelet cyclooxygenase activity, by 80% or greater, but reduced UTXB2 excretion by only 30%. UTXB2 and glomerular production of TXB2 of thrombocytopenic SDR remained markedly elevated compared with corresponding values from age-matched thrombocytopenic or platelet-replete, nondiabetic controls. Similarly, treatment of rats for 180 days with a dose of aspirin (ASA), which selectively inhibited platelet versus renal cyclooxygenase activity, reduced UTXB2 of both SDR and controls by 25% to 35%. The absolute reductions in UTXB2 induced by either ASA or thrombocytopenia in SDR were significantly greater than the absolute decrements in corresponding controls, suggesting that increased platelet TXB2 production in SDR may contribute to the enhanced UTXB2. However, as in the thrombocytopenic SDR, UTXB2 and glomerular production of TXB2 of SDR treated with ASA remained clearly above corresponding control values. Moreover, chronic ASA treatment failed to prevent the development of albuminuria in SDR.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Albuminuria; Animals; Aspirin; Blood Platelets; Diabetes Mellitus, Experimental; Dinoprostone; Female; Glomerular Filtration Rate; Kidney Glomerulus; Rats; Rats, Inbred Strains; Thrombocytopenia; Thromboxane B2

Recently the beneficial effects of captopril (angiotensin-converting-enzyme inhibitor) on diabetic nephropathy, especially proteinuria, have been reported by some investigators. The mechanism whereby proteinuria is reduced, however, have not been clarified yet. The present study was undertaken to evaluate the effects of captopril on urinary albumin excretion in relation to urinary prostaglandins (PGs) excretion in patients with non-insulin-dependent diabetes mellitus (NIDDM). Captopril (37.5 mg/day) was orally administered to 13 diabetic patients for an eight-week period. A single administration of captopril (12.5 mg) was performed in the same patients. The spot urine samples were collected in the early morning and 2 hr after the single administration of captopril. The albumin index (mg/gram-creatinine) was markedly decreased in eight patients (Group A) within four weeks, but no decrease was found in five patients (Group B). Furthermore, in Group A, by the single administration of captopril urinary excretions of 6-keto-PCF1 alpha (a stable metabolite of PGI2) and PGE2 were significantly (p less than 0.05) increased while urinary TXB2 (a stable metabolite of TXA2) excretion did not change significantly. The urinary 6-keto-PGF1 alpha/TXB2 ratio, which is significantly (p less than 0.05) low in diabetic patients was significantly (p less than 0.01) increased up to the normal value in Group A. In Group B, however, there were no significant changes in urinary PGs excretion. These results suggest that captopril enhances the production of intrarenal vasodilatory PGs such as PGI2 and PGE2, which may be deeply involved in the reduction of intraglomerular capillary pressure and urinary protein excretion in diabetic patients.

Topics: 6-Ketoprostaglandin F1 alpha; Albuminuria; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Diabetic Retinopathy; Female; Humans; Male; Middle Aged; Prostaglandins; Thromboxane B2

Thromboxane contributes to the regulation of glomerular hemodynamics in experimental models of diabetes and has been implicated as mediator in some models of glomerular injury. In the present study we examined urinary albumin, protein, and thromboxane B2 (TXB2) excretion during the 170 days after induction of diabetes by injection of streptozotocin in insulin-treated moderately hyperglycemic (200 to 400 mg/dl glucose) rats (SDRs). The effects of a thromboxane synthesis inhibitor, 4'-(imidazol-1-yl)acetophenone (TXI) (100 mg/kg/day) on these parameters were also assessed. Urinary TXB2 and albumin excretion in SDRs was not different from that in normal rats between 7 and 90 days but were three times higher than normal in SDRs at 125 and 170 days after induction of diabetes. In SDRs, urinary protein excretion was higher than in controls at 170 days but not at earlier time points. Inulin clearance (CIn) of SDRs was significantly higher than control values at 7 and 90 days and was not influenced by TXI during this period. At 170 days CIn was not significantly different in SDRs and normal rats. By contrast, albumin clearance (CAIb) and fractional CAIb were elevated in SDRs when compared with those values in normal rats. Treatment of SDRs with TXI for 170 days completely prevented the rise in urinary TXB2, albumin, and protein excretion, as well as the rise in fractional CAIb, but did not alter prostaglandin E2 (PGE2) excretion. TXI also increased CIn in SDRs to levels that were significantly higher than normal at 170 days. TXI had no significant effect on urinary PGE2, TXB2, albumin, or protein excretion or on CIn in normal rats and did not influence blood pressure or blood glucose in normal rats or SDRs. The results suggest a role for thromboxane in the mediation of albuminuria in the SDR.

Topics: Albuminuria; Animals; Blood Glucose; Diabetes Mellitus, Experimental; Dinoprostone; Female; Glomerular Filtration Rate; Imidazoles; Proteinuria; Rats; Rats, Inbred Strains; Reference Values; Serum Albumin; Thromboxane B2; Thromboxanes

Triflusal (2-acetoxy-4-trifluormethylbenzoic acid) is a platelet-antiaggregant drug that selectively inhibits thromboxane synthesis with little effect on prostacyclin production. In this study, we evaluated the effect of 5-day administration of 900 mg/day triflusal on glomerular filtration rate (GFR), renal plasma flow (RPF), urinary albumin excretion (UAE), thromboxane B2 (TXB2), 6-ketoprostaglandin F1 alpha (PGF1 alpha), and PGE2 in nine normotensive insulin-dependent diabetic patients with UAE between 30 and 103 micrograms/min. Plasma TXB2 and plasma renin activity (PRA) were also determined. After administration of triflusal, we observed a reduction in microalbuminuria (59 +/- 25 vs. 33 +/- 22 micrograms/min, P less than 0.01), an increase in RPF (648 +/- 119 vs. 722 +/- 134 ml.min-1 x 1.73 m-2, P less than 0.01), and a reduction in filtration fraction (0.24 +/- 0.04 vs. 0.20 +/- 0.03, P less than 0.01). Triflusal produced a significant reduction in both plasma TXB2 (130 +/- 39 vs. 52 +/- 32 pg/ml, P less than 0.02) and urine TXB2 (523 +/- 249 vs. 312 +/- 11 pg/min, P less than 0.02), without changes in PRA and UAE of 6-keto-PGF1 alpha and PGE2. Metabolic control and arterial blood pressure did not change during the study. These results suggest that platelet-antiaggregant therapy can reduce microalbuminuria in diabetic patients. This effect could be mediated by a reduction in the transglomerular hydraulic pressure through a vasodilation of efferent arterioles secondary to renal thromboxane synthesis inhibition.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Albuminuria; Blood Glucose; Diabetes Mellitus, Type 1; Dinoprostone; Female; Glomerular Filtration Rate; Humans; Male; Platelet Aggregation Inhibitors; Renal Circulation; Renin; Salicylates; Thromboxane B2

The efficacy of dietary intervention with either 6% protein restriction, fish oil or safflower oil was assessed in the remnant nephron model. Female Munich Wistar rats were prefed for one week prior to 5/6 nephrectomy and followed for the ensuing 28 days. Fish oil, safflower oil and protein restriction prevented the gammaglobulinuria but only fish oil lessened the albuminuria in this model. The remnant nephrons of the fish oil treated rats contained less arachidonic acid and greater quantities of eicosapentaenoic and docosahexaenoic acid than the safflower oil or lab chow fed control rats. The fish oil, and to a lesser extent the safflower oil, treated animals had a higher ratio of 6 keto PGF1 alpha to TX B2 metabolites in their urine. We suggest these changes may be responsible for the lessening in urine protein excretion. Fish oil feeding was more effective than severe protein restriction or safflower oil dietary supplementation in lessening both the gammaglobulinuria and albuminuria of the remnant nephron model.

Topics: 6-Ketoprostaglandin F1 alpha; Albuminuria; Animals; Arachidonic Acids; Dietary Fats; Dietary Proteins; Fatty Acids, Unsaturated; Female; Fish Oils; Immunoglobulin G; Nephrectomy; Nephrons; Proteinuria; Rats; Safflower Oil; Thromboxane B2