thromboxane-b2 and Kidney-Diseases

In contrast to a variety of clinical conditions characterized by ineffective circulatory volume, chronic glomerular disease is not usually associated with increased circulating levels of vasoconstrictor hormones. However, a reduction in glomerular prostacyclin production can possibly account for the prostaglandin dependence of renal function in these patients by virtue of the enhanced constrictor effects of angiotensin II on glomerular arterioles and mesangium. The reduction of renal function induced by a nonselective cyclo-oxygenase inhibitor is inversely related to the basal prostacyclin production. Increased renal synthesis of vasoconstrictor thromboxane A2, as noted in patients with systemic lupus erythematosus, might contribute to the cyclo-oxygenase dependence of renal function. Aspirin as well as a variety of structurally unrelated nonsteroidal anti-inflammatory drugs reduce renal function in systemic lupus erythematosus patients. However, the functional consequences of renal cyclo-oxygenase inhibition are partially attenuated in patients with lupus nephritis vis-à-vis other forms of chronic glomerular disease because of concomitant suppression of enhanced glomerular thromboxane A2 production. Animal data consistent with a prevailing functional significance of vasodilator prostaglandins have also been reported. Short-term administration of sulindac at the recommended dosage is relatively safe in patients with chronic glomerular disease because of selective sparing of glomerular cyclo-oxygenase activity. The long-term consequences of selective versus nonselective cyclo-oxygenase inhibition remain to be established in humans. The beneficial effects of a combination of aspirin and dipyridamole in slowing the deterioration of renal function in patients with membranoproliferative glomerulonephritis does provide a rationale for exploring the effects of low-dose aspirin (i.e., 0.5 to 1.0 mg/kg per day), which most effectively suppresses platelet thromboxane A2 production without interfering with renal prostacyclin synthesis.

Topics: Animals; Anti-Inflammatory Agents; Blood Platelets; Chronic Disease; Cyclooxygenase Inhibitors; Humans; Kidney; Kidney Diseases; Kidney Glomerulus; Prostaglandins; Thromboxane B2

Topics: Antibodies; beta 2-Microglobulin; Biopsy; Creatinine; Dinitrochlorobenzene; Graft Rejection; Humans; Kidney; Kidney Diseases; Kidney Transplantation; Methods; Monitoring, Physiologic; T-Lymphocytes, Regulatory; Thromboxane B2; Time Factors

Nephrotoxicity is the main untoward effect of cyclosporine (CsA) treatment. Experimental and clinical data suggest that dietary supplementation with fish oil may lessen cyclosporine nephrotoxicity, possibly by lowering renal thromboxane (Tx) production. We have studied the renal effects of a daily supplementation for 2 months of 12 g fish oil (18% C20:5 n-3 eicosapentaenoic acid [EPA] and 12% C22:6 n-3 docosahexanoic acid [DHA]) in a placebo-controlled (12 g corn oil), prospective, randomized, double-blind study of stable CsA-treated liver transplant recipients. Thirteen patients ingested corn oil capsules and 13 fish oil. Compliance with dietary regimen was confirmed by fatty acid chromatography that showed increased plasma concentrations of EPA (from 0.4 +/- 0.02% to 4.6 +/- 0.5%, P < .0001) and DHA (from 1.8 +/- 0.2% to 3.9 +/- 0.1%, P < .0001) in the fish oil group and increased plasma concentration of linoleic acid (C18:2 n-6) in the corn oil group (from 25 +/- 2% to 28.4 +/- 2%, P < .001). At the end of the 2 months of the study, in the fish oil group the effective renal plasma flow increased by 22% (P = .012), the glomerular filtration rate increased by 33% (P = .057), the renal blood flow increased by 17% (P = .024), and the calculated total renal vascular resistances decreased by 20% (P = .034). In contrast, none of these parameters changed in the corn oil group. The renal functional reserve determined during L-arginine infusion, plasma renin activity (PRA), and plasma aldosterone (PA) remained unchanged during the study in either group.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adolescent; Adult; Cyclosporine; Dietary Fats, Unsaturated; Double-Blind Method; Fatty Acids; Female; Fish Oils; Glomerular Filtration Rate; Humans; Immunosuppressive Agents; Kidney Diseases; Liver Transplantation; Male; Middle Aged; Placebos; Prospective Studies; Renal Plasma Flow, Effective; Thromboxane B2; Urea

The objective of this prospective, randomized, placebo-controlled, single-blinded study in 28 heart-transplanted patients was to investigate whether the dehydropeptidase inhibitor cilastatin reduces cyclosporine-induced nephrotoxicity. Cilastatin is available only in combination with imipenem, a beta-lactam antibiotic to which it is added for reduction of nephrotoxic side-effects of the antimicrobial agent. Patients received either 100 ml placebo (n = 12) or 100 ml (500 mg) imipenem/cilastatin (n = 16) twice perioperatively, and 4 times daily for the first 7 postoperative days. Serum creatinine and urea, as well as urine concentrations of N-acetyl-beta-D-glucosaminidase, which is directly correlated with tubular cell damage, were used as markers for renal function. Thromboxane B2 and 6-keto-prostaglandin F1-alpha serum concentrations were determined to investigate whether there is an imbalance in synthesis of thromboxane A2 and prostacyclin as a possible mechanism for cyclosporine-induced nephrotoxicity. Two placebo patients and 6 patients receiving imipenem/cilastatin had to be excluded from further analysis. Three of 10 placebo patients required hemofiltration, and 2 of them even required hemodialysis, as compared with none in the imipenem/cilastatin group. Creatinine concentrations increased significantly from the second to the fourth postoperative day in the placebo group, but remained nearly normal in cilastatin patients (P < 0.05 for intergroup comparison on postoperative days 2-4). The same trend was observed in urea and N-acetyl-beta-D-glucosaminidase concentrations, without the difference reaching statistical significance. For thromboxane B2 and 6-keto-prostaglandin F1-alpha no differences between the groups could be found. These results suggest that imipenem/cilastatin can counteract acute cyclosporine-induced nephrotoxicity, which appears to be associated with alterations of tubular cell function. The combined use of cyclosporine and imipenem/cilastatin appears to be advantageous in patients following heart transplantation during the initial postoperative period.

Topics: 6-Ketoprostaglandin F1 alpha; Acetylglucosaminidase; Adolescent; Adult; Blood Urea Nitrogen; Cilastatin; Creatinine; Cyclosporine; Female; Heart Transplantation; Hemofiltration; Humans; Kidney Diseases; Male; Middle Aged; Single-Blind Method; Thromboxane B2

We have evaluated 45 elderly patients with both musculoskeletal problems and mild to moderate renal dysfunction. We treated these patients with a non-steroidal anti-inflammatory drug (NSAID) for 2 weeks. The serum creatinine, urinary creatinine clearance and blood pressure were monitored before and after therapy. In some patients serum levels of thromboxane B2 (TxB2) and the urinary prostaglandins E2 (PGE2) and I2 (prostacyclin) measured as 6-keto-PGF1 alpha were also monitored before and after therapy and correlated with the clinical measurements. This study has demonstrated that in the entire patient group, the trial drug was tolerated extremely well. There were no changes in the serum creatinine or in the urinary creatinine clearance after 2 weeks of therapy. There was also no change in the early morning diastolic blood pressure. In the 11 patients in whom the serum and urinary prostaglandins were measured, the serum thromboxane levels fell with therapy to a level of 1.5% of the initial value. The urinary levels of PGE2 also fell but not to the same degree. The urinary PGE2 levels fell to 28% of the baseline values. There was no significant change in the levels of urinary 6-keto-PGF1 alpha (prostacyclin). These observations suggest that prostacyclin may be the important prostaglandin in maintaining normal renal haemodynamics when patients are treated with NSAIDs.

Topics: Aged; Aging; Anti-Inflammatory Agents, Non-Steroidal; Blood Pressure; Creatine; Dinoprostone; Dose-Response Relationship, Drug; Epoprostenol; Hemodynamics; Humans; Kidney; Kidney Diseases; Middle Aged; Naproxen; Prostaglandins F; Thromboxane B2

Topics: Adult; Creatinine; Cyclosporins; Humans; Kidney Diseases; Kidney Transplantation; Phthalic Acids; Thromboxane B2

The effects of a 7 day-treatment with isoxicam (200 mg/24 h) on the urinary excretion of prostaglandins (PG) were compared to those of indomethacin (150 mg/24 h) in a double-blind randomized study conducted in 18 patients with degenerative arthritic disease and normal renal function. Indomethacin decreased the urinary excretion of PGF2 alpha by about 70% and 6-keto-PGF1 alpha and thromboxane (Tx)B2, the stable break-down products of prostacyclin and TxA2 respectively, by about 40%. Isoxicam effects on urinary PG did not significantly differ from those of indomethacin. During both treatments, urinary gamma-glutamyl transferase and N- acetyl-glucosaminidase remained stable and none of the changes in the urinary excretion of PGs could be related to either plasma or urinary drug concentrations. In conclusion, chronic administration of isoxicam inhibited the renal PG biosynthesis to a similar extent than indomethacin which suggests that non steroidal anti-inflammatory drugs of the oxicam group ought also be used cautiously in patients with renal impairment.

Topics: 6-Ketoprostaglandin F1 alpha; Anti-Inflammatory Agents, Non-Steroidal; Arthritis; Dinoprost; Double-Blind Method; Female; Humans; Indomethacin; Kidney Diseases; Male; Middle Aged; Piroxicam; Prostaglandins; Thromboxane B2

Oxidative stress and inflammation are involved in the pathogenesis of paracetamol-induced renal damage. This study examines the relationship between 8-iso-prostaglandin F2α (8-iso-PGF2α) and platelet activation as well as the relative contribution of the pro-inflammatory markers interleukin (IL)-1β and tumor necrosis factor-α (TNF-α) in enhanced 8-iso-PGF2α biosynthesis, as a complementary onset during analgesic nephropathy induced by chronic treatment with paracetamol. The protective effects of vitamin C on the aforementioned settings are also investigated.. Analgesic nephropathy was induced in Wistar rats. Renal function markers and the activity of antioxidant enzymes were determined spectrophotometrically. Immunoassays were used to measure the pro-inflammatory markers and the markers of lipid peroxidation and platelet activation.. The chronic treatment with paracetamol led to renal dysfunction, represented by the elevation of plasma urea and creatinine and the decline in the enzymatic antioxidant status, but did not cause a significant increase in TNF-α and IL-1β. The paracetamol-induced lipid peroxidation and enhanced production of 8-iso-PGF2α was not sufficient to cause changes in platelet activation represented by the level of 11-dehydro thromboxane B2.. Our results suggest that oxidative stress cannot circumvent the need of stimulation by circulatory cytokines in order to induce inflammatory response and changes in platelet activation during analgesic nephropathy. Vitamin C proved to be beneficial in restoring the renal function markers to normal, increasing the renal enzymatic antioxidant potential, inhibiting lipid peroxidation, and lowering cytokine production and 11-dehydro thromboxane B2 excretion. The observed effects of vitamin C offer support for its potential use as protective treatment in cases of chronic paracetamol overdose.

Topics: Acetaminophen; Analgesics; Animals; Antioxidants; Ascorbic Acid; Biomarkers; Cytokines; Dinoprost; Inflammation; Interleukin-1beta; Kidney Diseases; Lipid Peroxidation; Male; Oxidative Stress; Platelet Activation; Rats; Rats, Wistar; Thromboxane B2; Tumor Necrosis Factor-alpha

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

The study of early markers for glomerular and tubular dysfunction in dogs with renal diseases holds promise to gain new insights in the pathogenesis of canine nephropathies. However, the validation of such markers in canine urine is largely lacking. Therefore, immunoassays for the quantification of a set of four urinary markers, C-reactive protein (CRP), immunoglobulin G (IgG), thromboxane B(2) (TXB(2)) and retinol binding protein (RBP), were validated by determining their sensitivity, reproducibility, precision and accuracy in a large patient group. The results show that the immunoassays are appropriate for analysis of urinary CRP, IgG, TXB(2) and RBP in dogs. Furthermore, the significant differences in urinary concentrations of the selected glomerular and tubular markers between healthy (H) dogs and dogs with several types of nephropathies (R) support their future application in both clinical settings and research models.

Topics: Animals; Biomarkers; C-Reactive Protein; Case-Control Studies; Dog Diseases; Dogs; Enzyme-Linked Immunosorbent Assay; Immunoenzyme Techniques; Immunoglobulin G; Kidney; Kidney Diseases; Retinol-Binding Proteins; Thromboxane B2

In China, cantharidin has been reported to be active against various human cancers, but with severe side effects such as nephrotoxicity. In order to reduce this toxicity, its demethylated analogue nor-cantharidin has been synthesized and used in cancer therapy, but with only few data regarding safety assessment. The aim of this study was to compare the in vitro effects of cantharidin and nor-cantharidin on renal toxicity and on inflammatory events associated with tumoural process where protein phosphatases could be involved (energy status, prostanoid production, glutathione and nitrite contents) on RAW 264.7 and LLC-PK1 cells. In macrophages, both cantharidin and nor-cantharidin decreased cell viability, in a concentration- and time-dependent manner. However, IC50 was lower with cantharidin than with nor-cantharidin. These two drugs significantly decreased the ATP level after 24 hr incubation. However, ATP decreased much more with cantharidin (up to 4 times) than with nor-cantharidin. When control macrophages were activated with lipopolysaccharide+interferon-gamma for 24 hr a significant increase in nitrite content and in prostanoids were observed. Addition of either drug decreased nitrite generation and prostanoids, however these decreases were greater with cantharidin than with nor-cantharidin. In LLC-PK1 cells, incubated with either cantharidin or nor-cantharidin, our results show significant differences between the two drugs, similar to those observed in peritoneal macrophages, except for GSH content with opposite variations in both cells. We provide a better understanding of the various mechanisms of cantharidin side effects, allowing an easier comparison with nor-cantharidin which could be an attractive therapeutic potential in cancer chemotherapy in western countries.

Topics: Adenosine Triphosphate; Animals; Bridged Bicyclo Compounds, Heterocyclic; Cantharidin; Cell Line; Cell Separation; Cell Survival; Enzyme Inhibitors; Epoprostenol; Glutathione; Inflammation; Irritants; Kidney Diseases; Lipopolysaccharides; LLC-PK1 Cells; Macrophage Activation; Macrophages; Mice; Nitric Oxide; Phosphoprotein Phosphatases; Prostaglandins; Swine; Thromboxane B2

In this study we investigated the role of a mixture of n-6/n-3 essential fatty acids, in the cyclosporine model nephrotoxicity. Administration of cyclosporine in rats decreased creatinine clearance and provoked body weight loss, but it did not induce proteinuria and did not alter the urine volume. These changes were associated with decreased urinary ratios of prostaglandin E/thromboxane B and prostaglandin I/thromboxane B excretions. Light microscopic sections showed that 100% of the animals were affected by histological tubular lesions on their kidneys. Administration of cyclosporine to animals fed for 3 months on standard chow containing a mixture of n - 6/n - 3 essential fatty acids, restored creatinine clearance, augmented urine volume and prevented body weight loss. The improvement of renal function was accompanied by increased urinary ratios of prostaglandin E/thromboxane B and prostaglandin I/thromboxane B excretions. Light microscopic sections showed that only 40% of the animals demonstrated histological tubular lesions, of minor importance, to their kidneys. Our results suggest that the metabolites of arachidonic acid can play important role in the development of cyclosporine-nephrotoxicity because they increase the levels of thromboxane A and that the enchanced synthesis of prostaglandins (E) and (I) induced by a mixture of n - 6/n - 3 essential fatty acids, could play a beneficial role in the prevention of this renal dysfunction.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Cyclosporine; Dietary Fats, Unsaturated; Dinoprostone; Fatty Acids, Omega-3; Fatty Acids, Omega-6; Female; Kidney; Kidney Diseases; Prostaglandins I; Proteinuria; Rats; Rats, Wistar; Thromboxane B2; Weight Loss

In this study we investigated the role of a mixture of n-6/n-3 essential fatty acids, in the cyclosporine model nephrotoxicity. Administration of cyclosporine in rats decreased creatinine clearance and provoked body weight loss, but it did not induce proteinuria and did not alter the urine volume. These changes were associated with decreased urinary ratios of prostaglandin E/thromboxane B and prostaglandin I/thromboxane B excretions. Light microscopic sections showed that 100% of the animals were affected by histological tubular lesions on their kidneys. Administration of cyclosporine to animals fed for 3 months on standard chow containing a mixture of n - 6/n - 3 essential fatty acids, restored creatinine clearance, augmented urine volume and prevented body weight loss. The improvement of renal function was accompanied by increased urinary ratios of prostaglandin E/thromboxane B and prostaglandin I/thromboxane B excretions. Light microscopic sections showed that only 40% of the animals demonstrated histological tubular lesions, of minor importance, to their kidneys. Our results suggest that the metabolites of arachidonic acid can play important role in the development of cyclosporine-nephrotoxicity because they increase the levels of thromboxane A and that the enhanced synthesis of prostaglandins (E) and (I) induced by a mixture of n - 6/n - 3 essential fatty acids, could play a beneficial role in the prevention of this renal dysfunction.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arachidonic Acid; Creatinine; Cyclosporine; Dinoprostone; Fatty Acids, Omega-3; Fatty Acids, Omega-6; Female; Kidney; Kidney Diseases; Prostaglandins I; Rats; Rats, Wistar; Thromboxane B2; Urine; Weight Loss

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

The causes for the nephrotoxicity of cyclosporine A (CsA) have not been fully elucidated. Intrarenal vasoconstriction induced by several different mediators, both in humans and experimental animals, have been proposed.. We studied prostaglandin metabolites, endothelin and nitric oxide in kidney transplant patients receiving their first CsA dose. Prostaglandin metabolites in the urine and endothelin and nitric oxide (NO2/NO3 in urine and plasma were measured in 14 patients before and 3 and 6 h after oral ingestion of CsA (10 mg/kg b.w.). Clearances for inulin and p-aminohippuric acid (PAH) were measured before and in two separate 3-hour periods after CsA. Blood pressure, heart rate, and CsA blood levels were also determined.. Clearances of inulin and PAH decreased progressively after CsA dosage while renal vascular resistance increased. Nitric oxide plasma levels decreased in nearly all patients from 21.0 +/- 2.8 to 19.1 +/- 2.6 (p = 0.003) and then rose slightly to 19.5 +/- 2.5 micromol/l (p = 0.1) 3 and 6 h after CsA ingestion, respectively. Urinary excretion of NO2/NO3 decreased nonsignificantly from 269 +/- 38.8 to 259 +/- 27.7 and 254 +/- 41.6 micromol/min (p = 0.5 and 0.5). At the same time, urinary prostaglandin E2 and 6-keto-prostaglandin F(1 alpha) excretion rate declined significantly [from 1,187 +/- 254 to 1,186 +/- 351 and 730 +/- 148 pg/min (p = 0.27 and 0.02) and from 697 +/- 115 to 645 +/- 134 and 508 +/- 58.2 pg/min (p = 0.34 and 0.05)]. Urinary thromboxane B2 and plasma and urinary endothelin first increased and then decreased nonsignificantly. Mean arterial pressure rose from 107 +/- 2.5 to 110 +/- 2.6 and 114 +/- 3.4 mm Hg (p = 0.1 and 0.05).. The pathophysiology of CsA-induced acute renal vasoconstriction involves several different mechanisms including a decrease of the vasodilating prostaglandins E2 and 6-keto-prostaglandin F(1 alpha) and possibly nitric oxide.

Topics: 6-Ketoprostaglandin F1 alpha; Administration, Oral; Adult; Blood Pressure; Cyclosporine; Dinoprostone; Endothelins; Female; Heart Rate; Humans; Immunosuppressive Agents; Inulin; Kidney Diseases; Kidney Transplantation; Male; Metabolic Clearance Rate; Nitrates; Nitric Oxide; Nitrites; p-Aminohippuric Acid; Prostaglandins; Renal Artery; Renal Circulation; Thromboxane B2; Vascular Resistance; Vasoconstrictor Agents

The main adverse effect of cyclosporine A (CyA) is nephrotoxicity. CyA increases urinary concentrations of thromboxane A2 (TXA2), a potent vasoconstrictor that can be involved in kidney failure induced by CyA. Furthermore, it has been postulated that a relationship exists between oxygen free radicals and the synthesis of arachidonate metabolites in experimental models of CyA nephrotoxicity. We studied the effect of vitamin E (VitE), an oxygen free radical scavenger, on renal function, on glomerular synthesis of thromboxane B2 (TXB2), and on free radicals in rats treated with CyA. Four groups of male Wistar rats were studied: (1) a control group; (2) a group given VitE at 0.05 mg/dl in drinking water for 25 days; (3) a group given CyA at 50 mg/kg body weight/day orally for 10 days; and (3) a group given Vit E + CyA, in which rats were provided with drinking water containing VitE for 15 days and afterwards were treated with VitE and CyA for 10 days. Renal function parameters and glomerular synthesis of TXB2, superoxide anion (02.-), malondialdehyde (MDA), and hydrogen peroxide (H202) were evaluated. CyA decreased body weight, caused deterioration of kidney function and increased glomerular synthesis of TXB2, O2.-, MDA, and H202. Pretreatment with VitE prevented the effects of CyA on kidney function and decreased glomerular synthesis of these mediators. In conclusion, CyA induced glomerular synthesis of reactive oxygen species (ROS) and TxB2. Pretreatment with VitE inhibited acute renal failure induced by CyA, probably by scavenging free radicals and by inhibiting the synthesis of TXB2.

Topics: Animals; Body Weight; Cyclosporine; Free Radical Scavengers; Hydrogen Peroxide; Kidney Diseases; Kidney Glomerulus; Lipid Peroxides; Male; Rats; Rats, Wistar; Reactive Oxygen Species; Superoxides; Thromboxane A2; Thromboxane B2; Vitamin E

To evaluate the protective effects of dietary n-3 fatty acid supplementation versus treatment with a thromboxane synthetase inhibitor (TXSI) in dogs given high-dose gentamicin.. Clinicopathologic and renal histopathologic changes induced by gentamicin (10 mg/kg of body weight, IM, q 8 h, for 8 days) were compared in dogs fed an n-3 fatty acid-supplemented diet containing a fatty acid ratio of 5.7:1 (n-6:n-3), dogs treated with CGS 12970 (a specific TXSI given at 30 mg/kg, PO, q 8 h, beginning 2 days prior to gentamicin administration), and control dogs. The TXSI-treated and control dogs were fed a diet with a fatty acid ratio of 51.5:1 (n-6:n-3). Both diets were fed beginning 42 days prior to and during the 8-day course of gentamicin administration.. Eighteen 6-month-old male Beagles, 6 in each group.. After 8 days of gentamicin administration, differences existed among groups. Compared with n-3-supplemented and control dogs. TXSI-treated dogs had higher creatinine clearance. Both TXSI-treated and n-3-supplemented dogs had higher urinary prostaglandin E2 and E3 (PGE2/3) and 6-keto prostaglandin F1a (PGF1a) excretion, compared with control dogs. Urinary thromboxane B2 (TXB2) excretion was higher in n-3-supplemented and control dogs, compared with TXSI-treated dogs. Urine PGE2/3-to-TXB2 and PGF(in)-to-TXB2, ratios were increased in TXSI-treated dogs, compared with n-3-supplemented and control dogs, and these ratios were increased in n-3-supplemented dogs, compared with control dogs. In addition, TXSI-treated and n-3-supplemented dogs had lower urinary protein excretion, compared with control dogs. Proximal tubular necrosis was less severe in TXSI-treated dogs, compared with control dogs.. Treatment with CGS 12970 prior to and during gentamicin administration prevented increases in urinary TXB2 excretion and reduced nephrotoxicosis.. Increased renal production/excretion of thromboxane is important in the pathogenesis of gentamicin-induced nephrotoxicosis.

Topics: Animals; Body Weight; Creatinine; Diet; Dog Diseases; Dogs; Dose-Response Relationship, Drug; Eating; Enzyme Inhibitors; Fatty Acids, Omega-3; Food, Fortified; Gentamicins; Glomerular Filtration Rate; Kidney Cortex; Kidney Diseases; Male; Potassium; Prostaglandins; Protein Synthesis Inhibitors; Pyridines; Random Allocation; Sodium; Thromboxane B2; Thromboxane-A Synthase

Abnormalities of prostanoid metabolism, which may affect renal function, were studied in lupus nephritis. The subjects were 31 patients with lupus nephritis, ten with non-renal SLE, and four with renal, non-SLE collagen disease. Urinary levels of various prostanoids, thromboxane B2(TXB2), 11-dehydro-TXB2, 6-keto-PGF1 alpha,2,3-dinor-6-keto-PGF1 alpha and PGE2, and plasma level of 11-dehydro-TXB2, were determined. The effects of four days' dosing of a selective thromboxane A2 (TXA2) synthetase inhibitor, DP-1904 (DP), on prostanoid metabolism, were also studied. Urinary excretion of TXB2, which reflects the renal production of TXA2, was significantly increased in patients with lupus nephritis as compared with non-renal SLE (p < 0.05). The urinary TXB2/6-keto-PGF1 alpha ratio was also increased in lupus nephritis as compared with non-renal SLE or healthy controls (p < 0.01), indicating a prostanoid imbalance, which may lead to impaired renal function and subsequent pathology. The urinary TXB2/6-keto-PGF1 alpha ratio in these lupus nephritis patients showed negative correlations with Ccr and positive correlations with anti-DNA antibody titer (p < 0.001). DP was administered orally (400 mg/day, given in two divided doses) for four days to eight lupus nephritis patients. The urinary excretion of TXB2 and urinary TXB2/6-keto-PGF1 alpha ratio were decreased after one to two days of treatment in all patients. An increase in creatinine clearance used as a measure of renal function was observed in four of eight patients. Furthermore, no side effects were elicited during the four days of treatment. The conclusion reached were that the abnormal prostanoid metabolism observed in lupus nephritis could aggravate renal function through hemodynamic mediation, and that the deviated metabolism was reversible and, at least partially, corrected by a TXA2 synthetase inhibitor.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Enzyme Inhibitors; Female; Humans; Imidazoles; Kidney Diseases; Lupus Erythematosus, Systemic; Lupus Nephritis; Male; Middle Aged; Prostaglandins; Reference Values; Regression Analysis; Tetrahydronaphthalenes; Thromboxane B2; Thromboxane-A Synthase

The involvement of arachidonic acid metabolism in cyclosporin (CsA) nephrotoxicity depending on CsA vehicle has been explored in this study. For this purpose creatinine clearance, urinary excretion and renal levels of eicosanoids were measured in the following rat experimental groups: group I, control; group II, CsA was administered in olive oil by gavage at 15 mg/kg/d for 7 d; group III, same as group II but 30 mg/kg/d; group IV, CsA was administered in fish oil by gavage at 15 mg/kg/d for 7 d; group V, same as group IV but 30 mg/kg/d; group VI, CsA was administered in olive oil at 15 mg/kg/d with prednisolone (1 mg/kg/d). The results indicate that (1) CsA nephrotoxicity and prostanoid alterations seem to be greatly improved when fish results indicate that (1) CsA nephrotoxicity and prostanoid alterations seem to be greatly improved when fish oil substitutes olive oil as a vehicle for CsA administration and (2) a correlation was found between eicosanoids measured and renal function, except in group II in which creatinine clearance remains unmodified but eicosanoids were altered, thus suggesting that other factors play a role in mediating nephrotoxicity due to cyclosporin.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arachidonic Acid; Creatinine; Cyclosporine; Eicosanoids; Kidney; Kidney Diseases; Male; Olive Oil; Plant Oils; Prednisolone; Rats; Rats, Inbred Lew; Thromboxane B2

This investigation was carried out to assess the amelioration by two antithrombotic drugs of radiation nephropathy in mice. Mouse kidneys were given split-dose irradiation to total doses between 17 and 22 Gy. A first group of animals was given acetylsalicylic acid (ASA) in drinking water, a second received daltroban, a thromboxane A2/prostaglandin H2 receptor antagonist, and a third received normal tap water, serving as a control. Both antithrombotic drugs were started 1 week prior to the irradiation and were given throughout the whole follow-up period. Renal function was assessed every 4 weeks from 18 weeks after the start of irradiation onwards by measuring the [51Cr] EDTA retention and haematocrit. The dose of ASA (600 mg/kg/day) caused an inhibition of thromboxane A2 and prostacyclin biosynthesis to 19 +/- 10 (mean +/- SEM) and 85 +/- 22%, respectively, as assessed by the excretion of their urinary metabolites. A significant sparing effect on the renal function after irradiation was observed in the ASA-treated animals. Using the latency time to reach 4% residual plasma activity of [51Cr] EDTA, a dose-modifying factor of 1.19 was calculated. No effect was seen with daltroban (10 mg/kg/day). Histopathological analysis of the kidneys at 12 months after irradiation demonstrated a substantially lower level of damage in the ASA-treated mice compared with daltroban-treated and radiation-only animals. These data indicate that long-term treatment with ASA is effective in reducing renal functional impairment after irradiation.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Aspirin; Female; Kidney Diseases; Kidney Function Tests; Mice; Mice, Inbred C3H; Radiation Injuries, Experimental; Rats; Thromboxane B2; X-Rays

In rats with incipient adriamycin nephropathy, pregnancy increases urine protein excretion and mean arterial pressure, with no changes in the glomerular filtration rate. Renal histology is normal and the glomerular TxB2/PGE2 ratio is increased.. In the present study we evaluated the influence of repeated pregnancies on the evolution of adriamycin nephropathy. Two weeks after a first delivery, rats were mated again and were followed till 35 days after the second delivery.. In pregnant rats with adriamycin nephropathy, urine protein excretion and mean arterial pressure returned to values identical to those found in age-sex-matched virgin rats with adriamycin nephropathy. At the end of the second pregnancy, mean arterial pressure and urine protein excretion were again elevated, compared with virgin rats with adriamycin nephropathy. Thirty-five days after the second delivery, urine protein excretion and mean arterial pressure remained elevated, 296 +/- 50 mg/day vs 115 +/- 26 and 121 +/- 4 vs 110 +/- 1 mmHg respectively, P < 0.05. Glomerular filtration rate remained unchanged 0.84 +/- 0.09 vs 0.79 +/- 0.09 ml/min in virgin rats with adriamycin nephropathy. The glomerular TxB2/PGE2 ratio was decreased, contrasting with the first pregnancy. At the end of the second pregnancy, histological examination of the kidneys in rats with adriamycin nephropathy revealed a significant increase in mesangial expansion. It was even more marked 35 days later, at the last follow-up, with a semiquantitative score of 162 +/- 29 vs 81 +/- 20 in virgin adriamycin nephropathy rats, P < 0.05.. In rats with adriamycin nephropathy, repetitive pregnancies seem to aggravate the natural course of the disease in an irreversible fashion. The earlier changes in glomerular prostanoid synthesis, particularly on thromboxane, may play a pathogenic role by activating mesangial cell matrix synthesis.

Topics: Animals; Blood Pressure; Dinoprostone; Doxorubicin; Female; Glomerular Filtration Rate; Kidney Diseases; Kidney Glomerulus; Pregnancy; Pregnancy Complications; Proteinuria; Rats; Rats, Wistar; Recurrence; Thromboxane B2

To clarify the profile of the tacrolimus (FK506)-induced nephrotoxicity and its mechanism, 1, 2 and 4 mg/kg/day of tacrolimus was administered intramuscularly (i.m.) to spontaneous hypertensive rats (SHR) for 2 weeks, and biochemical and pathological parameters were studied in the animals. The acute nephrotoxicity of tacrolimus was characterized as increase of blood urea nitrogen (BUN) and plasma creatinine (P-Cr) levels in the groups of 1 mg/kg/day and more, decrease of creatinine clearance (CCr) value in the groups of 2 mg/kg/day and more, and histopathologically luminal narrowing of the arteriole adjacent the glomerulus in the groups of 1 mg/kg/day and more. These changes were associated with an increase of plasma renin activity (PRA) and urinary thromboxane B2 content and decrease of 6-keto-prostagrandinF1 alpha (6-keto-PGF1 alpha) content. Nilvadipine, which is one of the Ca2+ antagonist and is known to have renal vasodilating activity, prevented both biochemical and histopathological changes due to tacrolimus. The results indicated that the acute nephrotoxicity of tacrolimus was derived from impairment of glomerular function associated with the constriction of the renal arteriole brought about by the drug. All of these renal disorders induced by tacrolimus recovered completely or partially when the drug was withdrawn for 2 or 4 weeks. Consequently, the acute nephrotoxicity of tacrolimus in SHR was considered to be reversible.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arterioles; Blood Urea Nitrogen; Creatinine; Hypertension; Kidney; Kidney Diseases; Male; Nifedipine; Rats; Rats, Inbred SHR; Renal Artery; Renin; Tacrolimus; Thromboxane B2; Vasoconstriction

The regional production of prostaglandin E2 and thromboxane B2 was investigated in the kidney with unilateral or bilateral ureteral obstruction for 24 hours in rats. The production of these eicosanoids was highest in the inner medulla both with or without ureteral obstruction, although the production rate by the tubules was relatively low in the obstructed kidney compared to the sham-operated control. A greater production of these vasoactive compounds was noted by glomeruli from the kidneys with unilateral or bilateral obstruction and the contralateral kidney with unilateral obstruction. Glomeruli obtained from the kidney with unilateral obstruction produced more thromboxane B2 than the kidney with bilateral obstruction, and the resultant TxB2/PGE2 ratio was higher in the unilaterally obstructed kidney. This difference in the glomerular thromboxane B2 production may be responsible for the haemodynamic changes between unilateral and bilateral ureteral obstructions. An increased prostaglandin E2 production by glomeruli from the contralateral kidney with unilateral obstruction may contribute to a compensatory response.

Topics: Animals; Constriction, Pathologic; Dinoprostone; Female; Kidney; Kidney Diseases; Rats; Rats, Sprague-Dawley; Thromboxane B2; Ureteral Obstruction

The ability of thromboxane synthetase inhibition to reverse acute cyclosporin A (CsA)-induced nephrotoxicity in the rat was investigated. CsA administration (50 mg/kg/day p.o. for 14 days) to male Sprague-Dawley rats caused a significant 50% decline in creatinine clearance rates, an increase in N-acetyl-beta-D-glucosaminidase (NAG) enzymuria and renal tubulointerstitial damage by day 14. These changes were associated with a 5-6-fold increase in urinary thromboxane B2 excretion (from pretreatment values of 28.1 +/- 7.9 to 122.6 +/- 38.9 and 165.8 +/- 39.0 eta g/24 hr body weight on days 7 and 14, respectively). Excretion rates of 6-keto-prostaglandin F1 alpha and prostaglandin E2 were, however, unaffected by CsA administration. Co-treatment with a thromboxane synthetase inhibitor (CGS 12970; 8-[3-methyl-2-(3-pyridyl)-1-indolyl]-octanoic acid) from day 7 (10 mg/kg/day) normalized thromboxane B2 excretion, resulted in creatine clearance rates which were similar to pretreatment values on days 10 and 14, reduced NAG enzymuria on day 10 and prevented acute proximal tubular vacuolation. However, the severity of chronic CsA nephrotoxicity, namely chronic tubular damage and microcalcification at the corticomedullary junction, was not diminished by the thromboxane synthetase inhibition. These results demonstrate that (i) elevated thromboxane synthesis plays an important role in the development of acute CsA nephrotoxicity and (ii) that different and/or additional mechanisms are involved in the pathogenesis of chronic nephrotoxicity.

Topics: Animals; Body Weight; Cyclosporine; Enzyme Inhibitors; Kidney Diseases; Male; Prostaglandins; Pyridines; Rats; Rats, Sprague-Dawley; Thromboxane B2; Thromboxane-A Synthase

The urinary excretion of selected markers for renal injury and thromboxane metabolites was studied in 16 patients undergoing cardiopulmonary bypass (CPB). Excretion of both tubular and glomerular markers sharply increased on day 1 after CPB and remained elevated throughout the observation period (five days). Immunoreactive thromboxane B2 (i-TXB2, mainly reflecting 2,3-dinor-TXB2) and immunoreactive 11-keto-thromboxane B2 (i-11-keto-TXB2) were measured by direct enzyme immunoassays. TXB2, 2,3-dinor-TXB2 and 11-keto-TXB2 were also measured in selected samples by GC-MS. Urinary excretion rates of both i-TXB2 and i-11-keto-TXB2 markedly increased on day 1 after surgery and decreased thereafter. Following CPB, excretion rates of 2,3-dinor-TXB2 and TXB2 displayed parallel changes, suggesting that in these patients most urinary TXB2 derives from blood platelets rather than the kidney. Taken together, our observations do not support the hypothesis that acute renal injury observed after CPB is caused by exaggerated thromboxane biosynthesis in the kidney.

Topics: Adult; Aged; Biomarkers; Cardiopulmonary Bypass; Gas Chromatography-Mass Spectrometry; Humans; Immunoenzyme Techniques; Kidney Diseases; Kidney Glomerulus; Kidney Tubules; Male; Middle Aged; Thromboxane B2

Topics: Animals; Calcium Channel Blockers; Cyclosporine; Diltiazem; Glomerular Filtration Rate; Kidney; Kidney Diseases; Male; Rats; Rats, Sprague-Dawley; Renal Circulation; Thromboxane B2

Interleukin-2 (IL-2), an agent known to activate neutrophils (PMN) with thromboxane (Tx)B2 release, produces pulmonary edema within 6 hours of intravenous infusion. This study tests the role of PMN in mediating the edema. Anesthetized rats received 10(6)U recombinant human IL-2 (n = 15) or vehicle (n = 14) as a constant intravenous infusion during a period of 1 hour. At this time there was leukopenia 3.63 +/- 0.43 (x10(3)/mm3) relative to vehicle-infused control rats 6.12 +/- 0.86 and a decline in PMN, 2.19 +/- 0.14 relative to control value of 3.33 +/- 0.05 (both p less than 0.05). After 6 hours edema, as measured by increase in the wet to dry weight (W/d) ratio, was present in the lungs (4.93 +/- 0.20 relative to control 4.06 +/- 0.10), heart (4.09 +/- 0.11 versus 3.76 +/- 0.08), liver (3.50 +/- 0.10 versus 3.18 +/- 0.10), and kidney (4.25 +/- 0.07 versus 4.00 +/- 0.07) (all p less than 0.05). There was increased lung permeability demonstrated by bronchoalveolar lavage fluid protein concentration of 1970 +/- 210 micrograms/mL relative to control 460 +/- 90 micrograms/mL (p less than 0.05). Interleukin-2 resulted in lung PMN sequestration of 53 +/- 7 PMN/10 high-power fields (HPF) relative to 23 +/- 2 PMN/10 HPF in controls (p less than 0.05) and increased plasma TxB2 levels to 1290 +/- 245 pg/mL relative to control 481 +/- 93 pg/mL (p less than 0.05). Pretreatment of other rats (n = 8) with selective anti-rat neutrophil antiserum 18 hours before the experiment led to a peripheral PMN count 10% of baseline and prevented edema in the lungs (W/d ratio 4.20 +/- 0.16) and heart (3.67 +/- 0.07) (both p less than 0.05) but not liver or kidney. Protein in lung lavage was reduced to 760 +/- 220 micrograms/mL (p less than 0.05). The protection afforded by leukopenia was associated with lack of PMN sequestration and prevention of the increase in plasma Tx levels (484 +/- 120 pg/mL, p less than 0.05). These data indicate that the rapid induction of lung and heart edema with a 1-hour infusion of IL-2 in the rat is mediated, in large part, by activated PMNs.

Topics: Animals; Bronchoalveolar Lavage Fluid; Bronchopulmonary Sequestration; Chemical and Drug Induced Liver Injury; Edema; Interleukin-2; Kidney Diseases; Leukocyte Count; Leukopenia; Liver Diseases; Male; Neutrophils; Platelet Count; Pulmonary Edema; Rats; Rats, Inbred Strains; Recombinant Proteins; Thromboxane B2

Interleukin 2 (IL-2) is a potent cytokine with diverse effects, including the ability to stimulate lymphocyte differentiation into cells capable of lysing tumor. Its therapeutic efficacy is limited because of side effects such as breakdown of the microvascular barrier and edema. Control of the microvascular barrier is in part regulated by endothelial cell cytoskeletal contractile proteins. This study tests whether the cyclopeptides that maintain actin filament organization and distribution and reduce macromolecular flux across the endothelial cell junction in vitro would similarly maintain barrier tightness and prevent early edema produced by IL-2 in vivo. Anesthetized rats were treated at 30-min periods with intravenous saline (0.5 ml, n = 41), phalloidin (20 micrograms in 0.5 ml, n = 21), or antamanide, (20 micrograms in 0.5 ml, n = 21), starting 30 min before the 1-h infusion of 10(6) U of recombinant human IL-2 or saline. Six hours after the start of IL-2, there was edema in the saline/IL-2 group, as measured by increased wet-to-dry ratios (W/D) in the lungs, heart, and kidney. With saline/IL-2, bronchoalveolar lavage (BAL) fluid contained an elevated protein concentration and higher plasma thromboxane levels compared with controls. The number of neutrophils sequestered in the lungs was more than twice that of saline controls. Phalloidin significantly attenuated edema in lung and reduced BAL protein leak. Antamanide treatment was as effective in limiting lung and heart edema, but, in contrast to phalloidin, antamanide prevented kidney edema and did not lead to an alteration in the liver W/D. Antamanide also prevented BAL fluid protein leak.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Capillary Permeability; Chemical and Drug Induced Liver Injury; Edema; Edema, Cardiac; Interleukin-2; Kidney Diseases; Liver Diseases; Male; Peptides, Cyclic; Phalloidine; Pulmonary Edema; Rats; Rats, Inbred Strains; Thromboxane B2

Previous studies have demonstrated that inhibition of thromboxane A2-dependent platelet aggregation by the thromboxane A2 synthase inhibitor, OKY 1581, ameliorated the progressive kidney disease of rats with subtotal renal ablation. OKY 1581 also decreased the excessive renal thromboxane A2 synthesis and lowered systemic blood pressure. In the same model, a low dose aspirin and a specific thromboxane A2 receptor antagonist failed to influence proteinuria, glomerulosclerosis, and hypertension, thus excluding a role for either platelet or renal thromboxane A2 in renal disease progression. The aims of this study were to establish (1) whether a thromboxane A2 synthase inhibitor different from OKY 1581 could retard the progression of glomerular disease in rats with remnant kidney and (2) whether this effect was associated with an increase in renal synthesis of the vasodilatory prostacyclin. Treatment of rats with renal mass ablation with FCE 22178 (100 mg/kg by gavage and 200 mg/kg in the drinking water) for 35 days starting 10 days after surgical ablation was associated with an improvement in renal function in comparison with rats receiving the vehicle alone. Proteinuria was significantly lower, and rats were partially protected from the development of glomerulosclerosis. Systolic blood pressure was significantly lower than in animals given the vehicle. Urinary thromboxane B2 excretion was significantly decreased, and urinary 6-keto-prostaglandin F1 alpha increased in respect to vehicle-treated rats. We conclude that FCE 22178 limits glomerular injury in rats with remnant kidney.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Bleeding Time; Blood Pressure; Epoprostenol; Imidazoles; Kidney; Kidney Diseases; Male; Naphthalenes; Platelet Aggregation; Proteinuria; Rats; Rats, Inbred Strains; Thromboxane B2; Thromboxane-A Synthase; Thromboxanes

The administration of the aminonucleoside of puromycin (PAN) to rats causes the nephrotic syndrome that is associated with an acute decline in renal function, and an interstitial infiltrate. We examined whether essential fatty acid deficiency (EFAD), which inhibits macrophage infiltration in glomerulonephritis, affects PAN-induced renal dysfunction. Both control and EFAD rats developed proteinuria that resolved over 28 d. After PAN administration, there was a prominent infiltration of macrophages in rats fed a normal diet. The infiltrate was prevented by the EFAD diet. The absence of a macrophage interstitial infiltrate was associated with a significantly higher Cin in the EFAD rats than in controls at 7 d (5.21 +/- 1.19 versus 0.39 +/- 0.08, P less than 0.002 ml/min/kg BW). In addition, CPAH fell to less than 10 ml/min/kg BW by day 7 in controls, but remained the same as normal in the EFAD. After administration of PAN to control rats, there was no increase in urinary thromboxane excretion or an increase in glomerular thromboxane production. Furthermore, the effect of EFAD could not be mimicked by the administration of a thromboxane synthase inhibitor. Irradiation-induced leukopenia in rats on a normal diet markedly improved glomerular filtration and renal blood flow in acutely nephrotic rats. EFAD prevents the interstitial cellular infiltrate and the renal ischemia associated with experimental nephrosis. The recruitment of mononuclear cells into the kidney following PAN directly contributes to the decline in renal function.

Topics: Acute Disease; Animals; Fatty Acids, Essential; Female; Kidney; Kidney Diseases; Leukopenia; Macrophages; Methacrylates; Nephrotic Syndrome; Puromycin Aminonucleoside; Rats; Rats, Inbred Lew; Thromboxane B2

Interleukin-2 (IL-2) produces toxicity characterized by generalized edema within 24 hours. This study tests whether the rate of IL-2 administration modulates the onset of edema and examines thromboxane (Tx) and neutrophils as possible mediators of this event. Recombinant human IL-2, 10(5) U (n = 7), 10(6) U (n = 9), or vehicle (n = 8) were given to anesthetized rats intravenously during a period of 1 hour. At 6 hours edema, as measured by increase in wet to dry weight (w/d) ratio, was present in the heart, liver, and kidney, with 10(5) U IL-2 and in the lung, heart, liver and kidney, with 10(6) U IL-2, relative to values with vehicle-infused controls (all p less than 0.05). With a 1-hour infusion of 10(6) U IL-2, there was an increase in plasma thromboxane (Tx)B2 level to 1290 +/- 245 pg/mL, higher than 481 +/- 93 pg/mL in control rats (p less than 0.05); lung polymorphonuclear leukocyte (PMN) sequestration of 53 +/- 7 PMN/10 higher-power fields (HPF) relative to 23 +/- 2 PMN/10 HPF in controls (p less than 0.05); and increased bronchoalveolar lavage (BAL) fluid protein concentration of 1970 +/- 210 micrograms/mL relative to 460 micrograms/mL in controls (p less than 0.05). When 10(6) U IL-2 was given as a 1-minute intravenous bolus (n = 9), edema was not demonstrated, plasma TxB2 levels were similar to controls, there was no leukosequestration, and BAL protein levels were normal. These data indicate that a constant infusion but not the rapid bolus administration of IL-2 produces in rats multiple-system organ edema, increased plasma TxB2, sequestration of PMNs, and microvascular permeability. These findings may explain the early toxicity seen in patients given high-dose IL-2 in cancer treatment.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Bronchoalveolar Lavage Fluid; Edema; Heart Diseases; Infusions, Intravenous; Injections, Intravenous; Interleukin-2; Kidney Diseases; Liver Diseases; Male; Neutrophils; Pulmonary Edema; Rats; Rats, Inbred Strains; Recombinant Proteins; Thromboxane A2; Thromboxane B2

Rats with extensive renal mass reduction develop hypertension, proteinuria and progressive glomerulosclerosis. Previous studies have demonstrated that these changes are associated with an increased urinary excretion of thromboxane compared with normal rats and that the administration of a thromboxane synthetase inhibitor prevents glomerulosclerosis and progressive renal function deterioration. On this basis it has been speculated that the thromboxane synthetase inhibitor, by inhibiting platelet thromboxane, reduces platelet aggregation and prevents the generation of substances that can influence glomerular functional properties. Because the thromboxane synthetase inhibitor also inhibits thromboxane synthesis by resident glomerular cells and lowers blood pressure in these animals, the question of whether platelet thromboxane is indeed the factor implicated in the development of renal disease after renal ablation remains unanswered. To address this issue the authors administered at different time intervals from the surgical procedure a low-dose of oral aspirin (ASA) to rats with remnant kidney. This approach resulted in selective inhibition of platelet cyclooxygenase leading to an almost complete prevention of platelet thromboxane generation. Low-dose ASA spared renal cyclooxygenase as documented by a lack of significant inhibition of glomerular and urinary 6-keto-PGF1 alpha and did not lower blood pressure. Renal function studies showed that low-dose ASA, despite inhibiting platelet aggregation, had no effect on proteinuria and progressive renal insufficiency irrespectively if administered late (ie, 80 days after surgery) and given daily for all the observation period (ie, 20 days) or earlier in the course of the disease (ie, 40 and 10 days after surgery). Histologic data showed that the degree of glomerulosclerosis and tubulo-interstitial damage was not significantly different in rats with reduction of renal mass alone compared with rats with remnant kidney given low-dose ASA. In conclusion, the present findings indicate that inhibition of platelet aggregation and thromboxane formation does not prevent the progressive glomerulosclerosis that develops in rats with surgical reduction of renal mass. It is suggested that the beneficial results obtained previously in the same model by the use of a thromboxane synthesis inhibitor must be attributed either to an effect on resident glomerular cell thromboxane synthesis or to lowering systemic blood pressure.

Topics: Animals; Aspirin; Blood Platelets; Kidney; Kidney Diseases; Kidney Glomerulus; Male; Platelet Aggregation Inhibitors; Prostaglandin-Endoperoxide Synthases; Proteinuria; Rats; Rats, Inbred Strains; Thromboxane B2

Several [(1H-imidazol-1-yl)methyl]- and [(3-pyridinyl)methyl] pyrroles were prepared and evaluated in vitro as thromboxane synthetase inhibitors in human platelet aggregation studies. A number of structures, e.g. 10b,f,g,i (respective IC50 values: 1 microM, 50 nM, 42 nM, 44 nM) showed superior in vitro inhibition of TXA2 synthetase when compared to the standard dazoxiben (1). However, it was found that in vitro potency did not translate into nor correlate with in vivo activity when these compounds were evaluated in mice in a collagen-epinephrine-induced pulmonary thromboembolism model. (E)-1-Methyl-2-[(1H-imidazol-1-yl)methyl]-5-(2-carboxyprop-1-enyl) pyrrole (10b) was found to offer protection against collagen-epinephrine-induced mortality in mice, thereby demonstrating that oral administration is an effective route for absorption of this drug. Additional evidence for the oral effectiveness of 10b in lowering serum TXB2 levels was obtained by performing ex vivo radioimmunoassay experiments with rats. A 13-week study of 10b in rats with reduced renal mass was conducted in order to evaluate the role of TXA2 production in hypertension and renal dysfunction. Although serum and urinary TXB2 levels in rats were found to be lowered during this study by 10b, the levels of urinary protein excretion remained comparable to that of the control group.

Topics: Animals; Aorta; Biological Availability; Blood Platelets; Chemical Phenomena; Chemistry; Humans; Imidazoles; Inflammation; Kidney Diseases; Male; Mice; Microsomes; Platelet Aggregation Inhibitors; Prostaglandin Endoperoxides, Synthetic; Prostaglandin H2; Prostaglandins H; Pyridines; Pyrroles; Rats; Structure-Activity Relationship; Swine; Thromboxane A2; Thromboxane B2; Thromboxane-A Synthase

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Creatinine; Cyclosporins; Dinoprostone; Kidney Diseases; Male; Prostaglandins E; Pyridines; Rats; Thromboxane B2; Thromboxane-A Synthase

Cyclosporin A (CsA) administration to rats is associated with a selective increase in urinary excretion of immunoreactive thromboxane B2 (i-TxB2), the stable breakdown product of TxA2. The exaggerated synthesis of TxA2 may play a role in the reduction of glomerular filtration rate (GFR) observed both in animals and humans undergoing CsA treatment. The present study was designed to get further insight into the origin of the abnormal i-TxB2 urinary excretion. Rats given orally CsA (50 mg/kg/day) for 30 days had a significant increase in the urinary excretion of both 2,3-dinor-TxB2 and TxB2 measured by technique of capillary column gas chromatography-negative ion chemical ionization mass spectrometry (HRGC-NICIMS). Urinary TxB2 is more likely to reflect the renal synthesis of the parent compound, whereas 2,3-dinor-TxB2 is considered to reflect the amount of TxB2 formed in the circulation. Experiments in isolated perfused kidney (IPK) taken from animals given CsA for 30 days showed a lower percentage increase in urinary TxB2 over vehicle treated animals. Moreover in IPK the ratio 2,3-dinor-TxB2/TxB2 was lower than in vivo. The amount of i-TxB2 detectable in serum of animals given CsA was not different from that of control animals. In contrast, isolated glomeruli taken from rats given CsA had an increase in their TxA2 synthesis measured as i-TxB2 in the supernatants. Ultrastructural studies on kidney specimens from animals given CsA showed a focal glomerular endothelial damage together with a marked infiltration of blood borne cells of monocyte-macrophage type in the glomerular tuft. In contrast, kidney specimens taken from IPK preparations were devoid of inflammatory cells. In vitro CsA did not interfere with platelet arachidonic acid (AA) metabolism as shown by a normal i-TxB2 generation in vitro by rat platelet-rich plasma (PRP) exposed to CsA and then challenged with AA or ADP. Similarly isolated glomeruli and isolated proximal tubules from normal rats when challenged with CsA in vitro converted AA into TxA2 normally. It is suggested that the cause of the increased urinary excretion of 2,3-dinor-TxB2 is the consequence of intrarenal platelet and macrophage activation, probably triggered by the endothelial damage. The parallel increase in the urinary excretion of unmetabolized TxB2 is likely to reflect a concomitant activation of resident renal cell AA metabolism induced by CsA.

Topics: Animals; Blood Platelets; Cyclosporins; Endothelium, Vascular; Glomerular Filtration Rate; Kidney Diseases; Kidney Glomerulus; Kidney Tubules, Proximal; Macrophages; Male; Rats; Rats, Inbred Strains; Renal Circulation; Thromboxane B2

Topics: Biopsy, Needle; Graft Rejection; Humans; Inflammation; Kidney Diseases; Kidney Transplantation; Macrophages; Monocytes; Thromboxane A2; Thromboxane B2

1. The kinetics of a single oral dose (300 mg) of cicletanine a new antihypertensive drug with diuretic properties, and its effects on the urinary excretion of electrolytes and of the major stable metabolites of prostacyclin and thromboxane A2 were studied in patients with normal renal function (n = 6), mild (n = 9) and severe (n = 10) renal insufficiency. 2. In normotensive subjects with normal renal function, cicletanine was rapidly and regularly absorbed, its apparent elimination half-life established around 7 h, and both its renal clearance (0.4 ml min-1) and its cumulative renal excretion (0.85% of the administered dose), were low. Mild renal insufficiency did not significantly alter these parameters, while severe renal impairment reduced the renal clearance and the cumulative urinary excretion of cicletanine and increased its apparent elimination half-life (31 h). However the area under the plasma curve was not changed due to reduced plasma concentrations in these patients. 3. Cicletanine induced a rapid and marked (four fold as a mean) increase in the urinary excretion of water, sodium and potassium which lasted for 6 to 10 h, in subjects with normal renal function. Renal insufficiency did not alter the slope of the calculated plasma concentration-effects curves but reduced the maximum effect observed for water, sodium and potassium. 4. A single oral dose of cicletanine did not change the urinary excretion of 6-keto-prostaglandin F1 alpha and thromboxane B2 in the three groups of patients studied, the basal values of which being found to be closely related to the creatinine clearance.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Aged; Creatinine; Diuretics; Electrolytes; Female; Glomerular Filtration Rate; Humans; Kidney Diseases; Male; Middle Aged; Prostaglandins; Pyridines; Thromboxane B2

Topics: beta 2-Microglobulin; Biopsy, Needle; Chromatography, High Pressure Liquid; Creatine; Graft Rejection; Humans; Immunologic Techniques; Kidney Diseases; Kidney Transplantation; Thromboxane B2

Topics: 6-Ketoprostaglandin F1 alpha; Female; Glomerulonephritis; Humans; Hypertension; Kidney Diseases; Liver Cirrhosis; Male; Nephrotic Syndrome; Radioimmunoassay; Thromboxane B2; Uremia

In view of the possible role of prostaglandins (PG) and thromboxane (TX) in the disturbances of renal function and blood flow after the injection of diatrizoate into the renal artery, we have determined the levels of PGE2, 6-keto-PGF1 alpha (a stable metabolite of prostacyclin) and TXB2 in the renal venous blood before, during and after renal arteriography in 12 patients. Radioimmunologically assayed PGE2 was the most abundant prostaglandin in renal venous blood. Lower basal levels of PGs were associated with renal adenocarcinomas or other tumours than non-tumour kidneys. The concentrations of 6-keto-PGF1 alpha and PGF2 alpha rapidly increased after diatrizoate injection and returned to the basal levels within 5 minutes. Slower elevation was noticed in the PGF2 level of 5 tumour kidneys. Renal plasma concentration of TXB2 remained unchanged throughout the study. The rapid elevation of renal venous prostacyclin and PGF2 alpha concentration after the contrast injection may reflect the enhanced intrarenal prostaglandin synthesis or may be secondary to hemodynamic changes in the kidney caused by hypertonic diatrizoate.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Aged; Angiography; Diatrizoate; Diatrizoate Meglumine; Dinoprost; Dinoprostone; Humans; Kidney Diseases; Kidney Neoplasms; Middle Aged; Prostaglandins; Prostaglandins E; Prostaglandins F; Renal Artery; Renal Veins; Thromboxane B2

Topics: Adolescent; Adult; Age Factors; Aged; Female; Humans; Kidney Diseases; Male; Middle Aged; Sex Factors; Thromboxane B2

Ablation of greater than 70% of renal mass in the rat results in hypertension, proteinuria, and glomerular sclerosis of the remnant kidney. Rats with a remnant kidney have increased excretion of thromboxane in the urine when compared with normal rats. Chronic oral administration of OKY 1581, an inhibitor of thromboxane synthesis, in rats with a remnant kidney increases renal blood flow and glomerular filtration rate (GFR), decreases protein and thromboxane excretion in the urine, lowers blood pressure and cardiac index, and improves renal histology. The degree of hypertrophy of the remnant kidney was unaffected by administration of OKY 1581. Calculated values for single nephron plasma flow and GFR were significantly greater in rats with remnant kidneys given OKY 1581 than in rats given saline. Acute i.v. administration of OKY 1581 increased renal plasma flow and GFR in rats with a remnant kidney but not in normal rats or rats with a remnant kidney previously treated with acetylsalicyclic acid. OKY 1581 markedly inhibited platelet aggregation. We suggest that in this model of renal disease platelet aggregation and intraglomerular thrombosis play a key role in the development of glomerulosclerosis. Inhibition of platelet aggregation prevents development of glomerulosclerosis, hypertension, and cardiac hypertrophy. We suggest that hyperperfusion and hyperfiltration per se occurring in remnant glomeruli are not directly responsible for the development of glomerulosclerosis.

Topics: Acrylates; Animals; Blood Pressure; Disease Models, Animal; Female; Glomerular Filtration Rate; Glomerulosclerosis, Focal Segmental; Heart; Kidney; Kidney Diseases; Methacrylates; Nephrectomy; Oxidoreductases; Platelet Aggregation; Rats; Thromboxane B2; Thromboxane-A Synthase

Topics: Dinoprostone; Humans; Kidney Diseases; Kidney Failure, Chronic; Liver Diseases; Prostaglandins E; Syndrome; Thromboxane B2; Thromboxanes

Vasodilatory prostaglandins function to maintain renal perfusion in patients with cirrhosis and ascites. To evaluate the potential contribution of the vasodilator prostaglandin E2 and the vasoconstrictor metabolite thromboxane B2 to the development of the hepatorenal syndrome, we measured urinary excretion of these products in 14 patients with hepatorenal syndrome and in control populations with acute or chronic liver or kidney failure. Radioimmunoassay measurements were confirmed by bioassay and by mass spectrometry. Prostaglandin E2 was decreased compared with healthy controls (2.2 +/- 0.3 vs. 6.3 +/- 0.8 ng/h, p less than 0.01) and compared with acute renal failure (9.6 +/- 2.1 ng/h) and with alcoholic hepatitis (9.2 +/- 3.3 ng/h). Thromboxane B2 concentration was normal in patients with alcoholic hepatitis (0.12 +/- 0.02 vs. 0.15 +/- 0.03 ng/ml) and minimally increased in acute renal failure (0.18 +/- 0.15 ng/ml), but markedly elevated in hepatorenal syndrome (0.69 +/- 0.15 ng/ml, p less than 0.001). Urinary thromboxane B2 concentration fell with improved renal function in 3 patients who survived. These data suggest an imbalance of vasodilator and vasoconstrictor metabolites of arachidonic acid in patients with the hepatorenal syndrome.

Topics: Acute Disease; Acute Kidney Injury; Adolescent; Adult; Biological Assay; Chronic Disease; Dinoprostone; Female; Humans; Kidney Diseases; Kidney Failure, Chronic; Liver Diseases; Male; Mass Spectrometry; Middle Aged; Prostaglandins E; Radioimmunoassay; Syndrome; Thromboxane B2; Thromboxanes