Significant Reduction In Urinary Excretion Research Articles

Organic diet intervention significantly reduces urinary pesticide levels in U.S. children and adults

BackgroundPrevious diet intervention studies indicate that an organic diet can reduce urinary pesticide metabolite excretion; however, they have largely focused on organophosphate (OP) pesticides. Knowledge gaps exist regarding the impact of an organic diet on exposure to other pesticides, including pyrethroids and neonicotinoids, which are increasing in use in the United States and globally. ObjectiveTo investigate the impact of an organic diet intervention on levels of insecticides, herbicides, and fungicides or their metabolites in urine collected from adults and children. MethodsWe collected urine samples from four racially and geographically diverse families in the United States before and after an organic diet intervention (n = 16 participants and a total of 158 urine samples). ResultsWe observed significant reductions in urinary levels of thirteen pesticide metabolites and parent compounds representing OP, neonicotinoid, and pyrethroid insecticides and the herbicide 2,4-D following the introduction of an organic diet. The greatest reductions were observed for clothianidin (− 82.7%; 95% confidence interval [95% CI]: − 86.6%, − 77.6%; p < 0.01), malathion dicarboxylic acid (MDA), a metabolite of malathion (− 95.0%; 95% CI: − 97.0%, − 91.8%; p < 0.01), and 3,5,6-trichlor-2-pyridinol (TCPy), a metabolite of chlorpyrifos (− 60.7%; 95% CI: − 69.6%, − 49.2%; p < 0.01). Metabolites or parent compounds of the fungicides boscalid, iprodione, and thiabendazole and the neonicotinoid insecticide imidacloprid were not detected among participants in our study. ConclusionAn organic diet was associated with significant reductions in urinary excretion of several pesticide metabolites and parent compounds. This study adds to a growing body of literature indicating that an organic diet may reduce exposure to a range of pesticides in children and adults. Additional research is needed to evaluate dietary exposure to neonicotinoids, which are now the most widely used class of insecticides in the world.

Gut micro flora in genesis of methilthyo metabolites of paracetamol

Gut micro flora represents a system of extensive metabolic capacity which is quite different when compared to other cells of body and organs. In recent times, there has been an evidence of very important role of gut cysteine conjugate beta-lyases in metabolism of cystein conjugates. A lot of studies are dedicated to exploration of the role of gut micro flora in formation of methylthio adducts from paracetamol in conventional mice and those treated with neomycin as our study. A highly significant reduction in urinary excretion of 3-methylthioparacetamol in group of neomycin-treated mice was confirmed as well its glucuronic acid and sulphate conjugates. Following the principal role of gut flora in the C-S cleavage of paracetamol l-3-cyctein it is clear that highest concentration of methylthio adducts from paracetamol are presented in pretreated mice.

Consumption of 5-hydroxymethylfurfural-rich dried fruits is associated with reduction in urinary excretion of 8-hydroxy-2′-deoxyguanosine: a randomized clinical trial

5-Hydroxymethylfurfural is widely presented in foods and produced through the degradation of hexoses and the Maillard reaction. This study aimed to investigate any association between 5-HMF content of consumed dried fruits and urinary excretion of 8-hydroxydeoxyguanosine (8-OHdG). The study consisted of 75 healthy volunteers. After an overnight fasting, two urine samples were collected before and 5 h after consumption of date, apricot, currant, plum and fruit bread, 100 g each. Twenty-five samples from frequently consumed types of dried fruits were analyzed for 5-HMF with HPLC. Urinary 5-hydroxymethyl-2-furoic acid (HMFA) and 8-OHdG were determined using HPLC and ELISA, respectively. The amount of 5-HMF in the tested samples varied from 314.8 ± 166.1 to 2496.3 ± 2301.2 mg/kg. The lowest and highest levels of 8-OHdG were 10.1 ± 1.5 µg/g creatinine for plum and 24.7 ± 6.6 µg/g creatinine for date. At the two time points, mean HMFA levels varied from 630.6 ± 114.5 to 2116.8 ± 600.3 and 286.7 ± 24.8 to 582.0 ± 119.2 (µg/g creatinine), respectively. There was a significant difference in HMFA amounts of the samples before and after consumption of apricot and plum (P 0.66, P < 0.01). It is concluded that consumption of 5-HMF-rich dried fruits is associated with a significant reduction in urinary excretion of 8-OHdG.

The Effect of Immunization with Protein-sulphanilic Acid Conjugate on Sulphanilic Acid Disposition in the Rat

Rats were immunized with bovine gamma-globulin-sulphanilic acid conjugate and the plasma concentration of sulphanilic acid examined after an intravenous injection of this drug. There was a significant increase in plasma half-life and AUC and a significant decrease in clearance of sulphanilic acid in the immunized rats compared with the control. In the immunized rats, binding of sulphanilic acid to macromolecules in serum, determined by ultrafiltration, decreased with increase of sulphanilic acid concentration. At low concentrations, there was a significant increase in % binding of the drug in the serum of immunized rats compared with controls. There was also a significant reduction in urinary excretion of total drug in the immunized rats compared with controls. These findings suggest that sulphanilic acid-specific antibodies in the serum of immunized animals bind [14C]sulphanilic acid, giving rise to higher serum levels thereby making it unavailable for normal excretory processes.

Beneficial effect of pioglitazone in proteinuric IgA nephropathy with concomitant ACEI/ARB treatment.

Methods: Forty-one biopsy-proven IgAN patients with proteinuria (>0.5g/day) who were currently treated with renin angiotensin system inhibitors and had at least two out of four risk factors for progressive disease (male gender, blood pressure >150/90 mmHg, creatinine clearance of 20-80 mL/min/1.73m 2 , and chronicity index >1) were randomly assigned to receive either PGZ 30 mg/day (PGZ group; n=21) or placebo (control group, n=20) for 16 weeks. Results: Baseline characteristics of patients in both groups were comparable. Following 16-week treatment, proteinuria in the PGZ group was significantly lower than the control group, [1.2 vs. 2.1 g/day (p<0.05)]. Patients in the PGZ group also showed a significant reduction in urinary excretion of TGF-β (from 361.4 to 234.4 ng/gCr) and VEGF (from 1353.1 to 765.1 ng/gCr) after 16-week treatment (p<0.05, both). Conclusion: PGZ significantly reduced proteinuria, urinary TGF-β, and urinary VEGF in IgAN patients. These findings suggest that PGZ could have a role in the treatment of proteinuric IgAN. Further studies with larger cases and longer follow-up time are warranted.

Therapeutic Effect of Artemether in an Experimental Model of Nephrosis

This study was carried out to elucidate the therapeutic efficacy of a new antimalarial drug, artemether, in adriamycin-induced nephropathy. To induce experimental nephrosis, adriamycin was given once by a single intravenous injection through the tail vein. Six days after adriamycin injection, therapeutic protocol was developed by intramuscular (i.m.) administration of 5 mg/kg artemether (ART). The total of i.m. injections were 14, in which five injections were made every day and nine injections were carried out at regular 48-h intervals. The therapeutic protocol was terminated on day 28, and animals were sacrificed on day 49. Our results showed that treatment with ART caused a significant reduction in the level of proteinuria (118 ± 15 vs. 48 ± 21 mg/24 h), urine urea (723 ± 226 vs. 414 ± 185 mg/dL), and urine sodium (38 ± 8 vs. 28 ± 6 mEq/L) compared with nontreated controls. In addition, a decrease in serum cholesterol (250 ± 58 vs. 163 ± 58 mg/dL) and creatinine (1.4 ± 0.2 vs. 0.9 ± 0.2 mg/dL) and an increase in the level of serum albumin (3.3 ± 0.5 vs. 5.6 ± 0.5 g/dL) were significant in the group treated with ART compared with the patient group. Moreover, treatment with ART significantly reduced glomerular PMN and mononuclear cells infiltration, hypercellularity, karyorrhexis, wire loops and hydropic change in the capillary network within the renal cortex, as well as decreased hyalin casts. On the other hand, healthy controls receiving ART showed a significant decrease in amounts of serum triglyceride (174 ± 55 vs. 88 ± 27mg/dL), urine urea (720 ± 113 vs. 511 ± 211 mg/dL), urine sodium (45 ± 5 vs. 26 ± 6 mEq/L), and potassium (71 ± 14 vs. 53 ± 6 mEq/L) compared with the normal group, where significant reduction of urinary excretion of sodium and urea must be considered as a side effect of ART therapy. These data suggest that artemether therapy can ameliorate proteinuria and suppress the progression of glomerular lesions in an experimental model of nephrosis, and that it may be recommended as a lipid-lowering drug.

Mapping of a new candidate locus for uromodulin-associated kidney disease (UAKD) to chromosome 1q41

Autosomal-dominant juvenile hyperuricemia, gouty arthritis, medullary cysts, and progressive renal insufficiency are features associated with familial juvenile hyperuricemic nephropathy (FJHN), medullary cystic kidney disease type 1 (MCKD1) and type 2 (MCKD2). MCKD1 has been mapped to chromosome 1q21. FJHN and MCKD2 have been mapped to chromosome 16p11.2. FJHN and MCKD2 are allelic, result from uromodulin (UMOD) mutations and the term uromodulin-associated kidney disease (UAKD) has been proposed for them. Linkage studies also reveal families that do not show linkage to any of the identified loci. To identify additional UAKD loci, we analyzed one of these families, with features suggestive of FJHN. Clinical, biochemical, and immunohistochemical investigations were used for phenotype characterization. Genotyping, linkage and haplotype analyses were employed to identify the candidate disease region. Bioinformatics and sequencing were used for candidate gene selection and analyses. We identified a new candidate UAKD locus on chromosome 1q41, bounded by markers D1S3470 and D1S1644. We analyzed and found no linkage to this region in eight additional families, who did not map to the previously established loci. We noted that affected individuals showed, in addition to the characteristic urate hypoexcretion, significant reductions in urinary excretion of calcium and UMOD. Immunohistochemical analysis showed that low UMOD excretion resulted from its reduced expression, which is a different mechanism to intracellular UMOD accumulation observed in cases with UMOD mutations. We have mapped a new candidate UAKD locus and shown that UAKD may be a consequence of various defects affecting uromodulin biology.

Effect of Yogurt on a Urinary Marker of Bone Resorption in Postmenopausal Women

Adding three servings of yogurt to the daily diet of older women with habitually low calcium intakes resulted in a significant reduction in urinary excretion of N-telepeptide, a marker for bone resorption. Results were compared to the effects of three servings of a nutrition-poor snack and differences were apparent 7–10 days of starting the diet change. The satiety effect of the snacks resulted in a decrease in intake of other foods. The added nutrients of the yogurt improved overall diet quality substantially, while diet quality declined with the nutrient-poor snack. The results show that diets low in dairy intake are often marginal for several nutrients and that, so far as calcium is concerned, bone makes up for what the diet lacks. Moreover, bone resorption responds rapidly and sensitively to improvements in calcium intake that are readily achievable by an older female population. J Am Diet Assoc. 2002; 102:1672-1674.

Short-term effects of angiotensin II receptor blockade in patients with primary glomerulonephritis: Pilot study

Objective: There is evidence that angiotensin II, the main effector of renin-angiotensin system, plays a crucial role in the pathogenesis of chronic renal injury. Angiotensin II type 1 (AT-1) receptor blockers reduce renin-angiotensin system activity by blocking the receptor, the activation of which is responsible for the majority of deleterious angiotensin II effects. The aim of the present study was to investigate renal and metabolic effects of specific AT-1 receptor blocker-losartan in patients with primary glomerulonephritis. Design: Pilot clinical study. Setting: Department of Nephrology, Transplantology and Internal Medicine, Medical University of Gdańsk, Poland. Participants: Fifteen patients aged 43.3 ± 11.3 years with primary glomerulonephritis confirmed by renal biopsy were studied. Intervention: Creatinine clearance, urinary excretion of protein and uric acid, urinary activity of N-acetyl-beta-D-glucosaminidase, and serum concentrations of lipids, protein, and uric acid were evaluated before and after 3 months of losartan (Cozaar; Merck Sharp & Dohme, Harlow, Essex, United Kingdom) treatment at a dose of 25 mg daily. Results: We found a significant reduction of urinary excretion of protein (P <.008; average, 32%). Results also revealed a decrease of serum uric acid level (P <.01), probably as a consequence of elevated uric acid urinary excretion (P <.09). No significant changes in creatinine clearance, N-acetyl-beta-D-glucosaminidase activity, protein, or lipid levels were observed. Conclusion: We concluded that losartan treatment at a small dose of 25 mg daily produces antiproteinuric effect without adverse effects, notably with no decrease of glomerular filtration, and simultaneously induces beneficial changes in purine metabolism. © 2002 by the National Kidney Foundation, Inc.

Induction of Oxidative Stress by Glutathione Depletion Causes Severe Hypertension in Normal Rats

59 Several recent studies have shown that certain forms of genetic and acquired hypertension (HTN) are associated with oxidative stress and respond favorably to antioxidant therapy. We hypothesize that oxidative stress, per se, may cause HTN via (among other mechanisms) enhanced oxidation and inactivation of nitric oxide (NO). To test this hypothesis, Sprague-Dawley rats were subjected to oxidative stress by glutathione (GSH) depletion using GSH synthase inhibitor, buthionine sulfoximine (BSO, 30 mmol/L in drinking water), for two weeks. The control group was given drug-free drinking water. In parallel experiments, subgroups of animals were provided vitamin E-fortified chow and vitamin C-supplemented drinking water. Arterial blood pressure, urinary excretion of NO metabolites (NO 2 +NO 3 , NOx), and liver tissue GSH were measured. In addition, plasma, kidney, heart, liver and aorta were tested by Western blot analysis for nitrotyrosine, which is the footprint of NO inactivation by reactive oxygen species (ROS). The BSO-treated group showed a three-fold fall in hepatic tissue GSH content (0.99±0.3 vs 3.4±0.3 μmol/g wet tissue, P&lt;0.001), a marked elevation in blood pressure (203±3 vs 120±2 mmHg, P&lt;0.001) and a significant reduction in urinary excretion of NO metabolites, nitrate + nitrite (316±23 vs 595±29 μmol/g creatinine, P&lt;0.01), suggesting depressed NO availability. This was associated with a significant accumulation in all tested tissues of nitrotyrosine (P&lt;0.05 for all comparisons). Administration of vitamins E+C ameliorated HTN (156±4 mmHg, P&lt;0.01), improved urinary NOx excretion (392±28 μmol/g creatinine, P&lt;0.05) and mitigated nitrotyrosine accumulation (despite persistent GSH depletion) in the BSO-treated animals. However, vitamins E+C treatment had no effect on any of the above parameters in the control group (data not shown). In conclusion, GSH depletion resulted in perturbation of the NO system and severe HTN in normal animals. The effects of BSO were mitigated by concomitant antioxidant therapy despite GSH depletion, supporting the notion that oxidative stress was involved in the pathogenesis of HTN in this model.

Increased oxidative stress in rats with chronic nitric oxide depletion:measurement of urinary 8-hydroxy-2′-deoxyguanosine excretion

Urinary 8-hydroxy-2′-deoxyguanosine (8-OHdG) has been reported to serve as a sensitive biomarker of oxidative stress. We examined the effect of chronic blockade of nitric oxide (NO) on urinary excretion of 8-OHdG in rats. Two types of NO synthase inhibitor were used: NG-nitro-L-arginine methyl ester (L-NAME) as a non-selective inhibitor and aminoguanidine (AG) as a selective inhibitor of the inducible isoform. Oral administration of L-NAME (20, 50 and 80 mg/dl of drinking water), but not AG (400 mg/dl), for 4 weeks induced systemic hypertension and a significant reduction in urinary excretion of NO2-/NO3-. Rats treated with L-NAME also showed a significant increase in urinary 8-OHdG excretion compared with the control animals. The effects of L-NAME (50 mg/dl) on blood pressure and urinary excretion of NO2-/NO3- and 8-OHdG were restored by a large dose of L-arginine (2.0 g/dl). Chronic AG administration did not significantly alter urinary 8-OHdG excretion. On combining all the data, there was a significant negative correlation between urinary NO2-/NO3- and 8-OHdG. These observations suggest the importance of constitutive NO synthase activity in the maintenance of oxidant buffering capacity in rats. Oral administration of L-NAME may serve as a model of hypertension due to chronic NO deficiency with increased oxidative stress.

Adenovirus-mediated kallikrein gene delivery attenuates hypertension and protects against renal injury in deoxycorticosterone-salt rats

To demonstrate potential therapeutic effects of kallikrein gene delivery in salt-induced hypertension and renal diseases, we delivered adenovirus carrying the human tissue kallikrein gene (Ad.CMV-cHK) into deoxycorticosterone acetate (DOCA)-salt hypertensive rats. A single intravenous injection of Ad.CMV-cHK caused a delay in the rise of blood pressure that began 2 days post gene delivery and lasted for more than 23 days. A maximal blood pressure reduction of 50 mm Hg was observed in rats receiving kallikrein gene delivery, as compared to rats receiving adenovirus containing the luciferase gene (Ad.CMV-Luc) (172±5 vs. 222±13 mm Hg, n=6, P<0.01). Throughout the experimental period, a blood pressure reduction of at least 32 mm Hg was observed in the DOCA-salt rats injected with Ad.CMV-cHK as compared to DOCA-salt rats receiving control adenovirus. Immunoreactive human tissue kallikrein levels were detected in rat serum and urine post gene delivery. Adenovirus-mediated kallikrein gene delivery caused a significant reduction in urinary excretion, urinary protein levels and body weight. Morphological examination of the kidney showed that kallikrein gene transfer significantly reduced DOCA-salt-induced glomerular sclerotic lesions, brush border disruption of proximal tubules, tubular dilatation and protein cast accumulation. These findings showed that the expression of human tissue kallikrein via gene delivery has protective effects against hypertension and renal injury in DOCA-salt hypertensive rats.

Downregulation of nitric oxide synthase in chronic renal insufficiency: role of excess PTH.

The available data on the effect of chronic renal failure (CRF) on nitric oxide (NO) metabolism are limited and contradictory. We studied rats with CRF 6 wk after a five-sixths nephrectomy and compared the results with those in the sham-operated controls, felodipine-treated CRF, and parathyroidectomized (CRF-PTX) animals. CRF was produced by surgical resection of the upper and lower thirds of the left kidney, followed by contralateral nephrectomy. We chose this model, as opposed to that produced by renal artery branch ligation, because the latter causes exuberant hypertension (HTN), which independently affects NO metabolism. The CRF group exhibited a mild HTN coupled with elevated basal platelet cytosolic Ca2+ concentration ([Ca2+]i), blunted hypotensive response to L-arginine, decreased hypertensive response to NO synthase (NOS) inhibitor, NG-monomethyl-L-arginine, and normal hypotensive response to NO donor, sodium nitroprusside. This was associated with a significant reduction in urinary excretion of stable NO metabolites (NOX) and depressed NOS activity, as well as endothelial and inducible NO synthase (eNOS and iNOS, respectively) protein contents of thoracic aorta and the remnant kidney in the CRF animals. Calcium channel blockade and PTX lowered blood pressure, increased urinary NOX, and enhanced vascular NOS activity, as well as eNOS and iNOS protein expressions in the tested tissues. Thus CRF animals exhibited significant reductions in vascular NOS activity and eNOS and iNOS expressions. These abnormalities were reversed by calcium channel blockade and PTX, suggesting the possible causal role of CRF-induced dysregulation of [Ca2+]i.

Diets Containing Soluble Oat Extracts Reduce Urinary Malondialdehyde in Moderately Hypercholesterolemic Men and Women

Soluble oat extracts have been used successfully in a number of diet studies to lower plasma blood lipids. One of the mechanisms proposed for this reduction in lipids is the production of short-chain fatty acids in the large intestine, which, in turn, may inhibit low-density lipoprotein cholesterol synthesis, thereby limiting oxidation. Urinary excretion of malondialdehyde (MDA) is proportional to endogenous lipid peroxidation. The purpose of this report is to examine the effects of consuming oat extracts with low (1%) or high (10%) levels of soluble β-glucans on lipid peroxidation as measured by urinary malondialdehyde excretion. Twenty-four subjects with moderately elevated cholesterol levels (6.0 mmol/L) were selected for the study. A 1-week equilibration period was followed by two 5-week experimental periods during which defined diets contained the 1% or 10% oat extracts in a crossover design. Seventy-two-hr urine samples (3 × 24-hr) were collected at the end of each period. Urinary levels of MDA excreted were 10–18% of dietary MDA consumed. Consumption of either of the oat extracts resulted in highly significant reductions in urinary excretion of malondialdehyde ( P < 0.0001). These data would support the hypothesis that oat extracts inhibit endogenous lipid peroxidation by reduction of MDA (a marker for fatty acid oxidation); however, because no significant differences were found in MDA excretion after subjects consumed the two levels of β-glucans, this is apparently not the responsible component. Further examination of this mechanism in the control of lipid metabolism is warranted.

Assessment of different markers of bone resorption in postmenopausal osteoporotic women treated with pamidronate

The aim of this study was to evaluate the different bone resorption markers, total pyridinoline (Pyr) and total deoxypyridinoline (Dpyr), assessed by a HPLC method, free Dpyr, assessed by a new immunoassay, and urinary excretion of hydroxyproline (OH-proline), in postmenopausal osteoporotic women during long-term treatment with pamidronate.A total of 60 postmenopausal women with previous distal forearm fracture were included in this 12-month placebo-controlled and double-blind study, where intermittent oral pamidronate, 75 or 150 mg, or placebo were given daily for 4 weeks, every 16 weeks. After 1 week a significant reduction in urinary excretion of total Dpyr was observed in the group treated with 150 mg pamidronate compared to the placebo (p<0.01) and to the 75-mg group (p<0.001). A maximal 50.4% decrease in total Dpyr, (p<0.0001 compared to the placebo group, p<<0.01 compared to the 75-mg group), was observed after 3 weeks of treatment with 150 mg pamidronate, and this decrease persisted to week 52. After 4 weeks of treatment with 150 mg pamidronate the maximal decrease in free Dpyr was only 26.5%, which persisted during 12 months of treatment. Decreases in urinary excretion of total Pyr and OH-proline were less than the decreases in total DpyrThe correlation between total Dpyr (HPLC method) and free Dpyr (Pyrilinks-D assay) at baseline was r=0.91. Total Dpyr assessed by the HPLC method reflects the pamidronate-induced decrease in bone resorption, and the changes in this resorption marker were more pronounced than changes in free Dpyr, total Pyr and OH-proline. In this study free Dpyr analysis was less suitable for reflecting bone resorption during bisphosphonate therapy.

Renal functional measurements in young rats with chronic inhibition of nitric oxide synthase.

The purpose of the present study was to examine renal functional changes caused by chronic blockade of nitric oxide (NO) synthesis in young rats. Two types of NO synthase inhibitor were used: NG-nitro-L-arginine methyl ester (L-NAME) as a non-selective inhibitor and aminoguanidine (AG) as a selective inhibitor of the inducible isoform. Oral administration of L-NAME (20-80 mg/dL of drinking water), not AG (400 mg/dL), for 4 weeks induced systemic hypertension in the treated rats. Both inhibitors caused a significant reduction in urinary excretion of NO2-/NO3-. Rats treated with L-NAME developed proteinuria and tubular enzymuria (high excretion of N-acetyl-beta-D-glucosaminidase) in a dose-dependent fashion, with normal serum levels of creatinine, albumin and cholesterol. Chronic AG administration did not alter the urinary levels of protein and N-acetyl-beta-D-glucosaminidase or serum laboratory values. Overall, these observations highlight the importance of the continuous generation of NO by the constitutive isoform in the control of vascular tone and the maintenance of renal glomerular and tubular function. Oral administration of L-NAME may serve as a model of chronic NO-deficient hypertension with renal injury in young rats.

Amelioration of proteinuria with pravastatin in hypercholesterolemic patients with diabetes mellitus.

Pravastatin, a novel inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, was administered to nine hypercholesterolemic patients with diabetes mellitus to examine its effects on diabetic nephropathy. Pravastatin treatment resulted in lowering serum total cholesterol by 22.1% on the average (p less than 0.001), and led to a significant reduction in urinary excretion of albumin and beta 2-microglobulin in patients with an elevated urinary protein excretion rate at the baseline period. But glycemic control, blood pressure, urinary excretion of creatinine and that of N-acetyl-beta-D-glucosaminidase showed no significant change during the study. These results suggest that reduction of atherogenic lipids and lipoproteins with pravastatin could alleviate diabetic glomerular injury.

The role of eicosanoids in cyclosporine nephrotoxicity in the rat

Nephrotoxicity is the most troublesome complication of cyclosporine (CSA) therapy. The present study was designed to investigate the effects of chronic treatment with CSA on the 24-hr urinary excretion of prostanoids (PGs) and thromboxane (Tx) and on the renal function in the absence or presence of indomethacin. CSA administration to Wistar rats (20 mg/kg/day, i.p.) for 14 days caused a significant increase in plasma creatinine, blood urea nitrogen (BUN), urine osmolality, fractional excretion of sodium and potassium and a reduction in creatinine clearance (CCr) and urine volume. These changes were associated with a significant reduction in urinary excretion of PGE2 (21.1 ± 3.3 vs 33.0 ± 2.5 ng/24hr) and PGF2α- (13.4 ± 1.4 vs 27.9 ± 3.8 ng/24hr) and an increase in TxB2 (12.1 ± 3.0 vs 4.6 ± 0.5 ng/24hr), and 6-keto PGFIα (56.2 ± 7.7 vs 27.7 ± 1.9 ng/24 hr). However, the synthesis of TxB2 and 6-keto PGFIα- by renal medullary and cortical slices prepared from CSA treated rats was not different from values obtained for vehicle treatment. In contrast, PGE2 synthesis by cortical slices prepared from the CSA group was increased. A single injection of indomethacin (10 mg/kg) to vehicle and CSA treated rats resulted in a significant reduction in PGs and TxB2 excretion. This, was associated with a further reduction in CCr (0.81 ± 0.06 vs 1.03 ± 0.04 ml/min) and an increase in BUN (38.5 ± 5.2 vs 28.2 ±1.4 mg%) only in the CSA group. We suggest that the vasodilating PGs attenuate the renal toxic effects induced by CSA.

Further metabolism of 4-acetylaminoantipyrine, the major metabolite of aminopyrine, in rats.

A significant reduction of urinary excretion of 4-acetylaminoantipyrine (AcAA) after administration of aminopyrine was observed in rats treated with phenobarbital or with 3-methylcholanthrene. Urinary excretion data and results obtained in the isolated rat hepatocyte system clearly demonstrated that both an alternative route of metabolism of 4-aminoantipyrine, an AcAA precursor, and further metabolism of AcAA itself accounted for the considerable reduction of AcAA recovery. The further metabolism of AcAA, which had been regarded as one of the final metabolic products of aminopyrine, was especially enhanced by 3-methylcholanthrene pretreatment.

Functional significance of exaggerated renal thromboxane A2 synthesis induced by cyclosporin A

Animals and humans undergoing a chronic treatment with cyclosporin A (CyA) show a reduction in glomerular filtration rate (GFR). The cause of this abnormality has not been established. Since CyA interferes with arachidonic acid (AA) metabolism in various cells, we wished to determine whether alterations in renal AA metabolites contribute to deteriorating renal function in rats on CyA. We show that chronic CyA treatment induces a progressive increase in the renal synthesis of thromboxane (TX) A2. This is a selective abnormality in that CyA does not influence the renal synthesis of prostaglandin E2 (PGE2) and prostacyclin (PGI2). A significant negative correlation has been found between TXB2 urinary excretion rate and inulin clearance. No correlation has been observed between TXB2 excretion and p-aminohippuric acid clearance. The withdrawal of CyA is followed by a normalization of both TXB2 urinary excretion rate and GFR. The administration of a selective TXA2 inhibitor, UK-38,485, resulted in a significant reduction in urinary excretion of TXB2 accompanied by a significant increase in GFR. We conclude that chronic treatment with CyA in rats is associated with a selective increase in renal TXA2 synthesis and suggest that this abnormality may play a role in the reduction of GFR.