thromboxane-b2 and Nephritis

The present study was conducted to investigate the antinephritic effects of berberine and coptisine, which are contained in Coptidis rhizoma, on original-type anti-GBM nephritis in rats. Berberine and coptisine at the doses of 0.5, 1.0 and 5.0 mg/kg/day, i.p. were effective in inhibiting urinary protein excretion, elevation of serum cholesterol and creatinine contents as well as glomerular histopathological changes. In addition, berberine at 20 mg/kg/day, p.o. also inhibited urinary protein excretion throughout the experimental periods. Berberine and coptisine inhibited platelet aggregation in both in vitro and in vivo assays, and berberine inhibited the decline of renal blood flow. Although berberine inhibited an increase in thromboxane B2 formation, it increased the formation of 6-keto-prostaglandin F1 alpha in platelets and isolated glomeruli. These results indicate that the antinephritic effects of berberine and coptisine may be partly due to antiplatelet action and improved renal hemodynamics via changing prostanoid synthesis.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Berberine; Cholesterol; Creatinine; Dipyridamole; Drug Evaluation, Preclinical; In Vitro Techniques; Male; Nephritis; Plant Extracts; Platelet Aggregation; Proteinuria; Rats; Rats, Sprague-Dawley; Renal Circulation; Thromboxane B2

1. To obtain direct evidence of abnormal eicosanoid biosynthesis in rats injected with anti-glomerular-basement-membrane antibodies (a-GBM), products derived from thromboxane A2 (TXA2) and prostacyclin (PGI2) were measured in 24 h urine collections before and after a-GBM. 2. Administration of a-GBM (9.5 mg) caused albuminuria, decreased creatinine clearance, increased numbers of intra-glomerular neutrophils and increased excretion of TXB2, 2,3-dinor-TXB2 (products of TXA2) and 6-oxo-PGF 1 alpha and 2,3-dinor-6-oxo-PGF 1 alpha (products of PGI2) at 24 h. 3. Interleukin-1 (IL-1 beta; 5 micrograms) alone caused an increase in PGI2 metabolite excretion but had no effect on TXA2 metabolites. It had no effect on creatinine clearance but increased numbers of glomerular neutrophils by approximately 4-5 fold compared to a-GBM. 4. Pretreatment of rats with IL-1 beta before a-GBM synergistically increased albumin excretion but only additively increased eicosanoid excretion. Numbers of intra-glomerular neutrophils and creatinine clearance were unchanged compared to IL-1 beta alone. 5. The cyclo-oxygenase inhibitor, ibuprofen (10 mgkg-1 i.p., twice daily for 4 days) inhibited both serum TXB2 production and urinary prostaglandin excretion. It also caused an almost complete attenuation of albumin excretion. Creatinine clearance and glomerular neutrophils remained unchanged after a-GBM/IL-1 beta. 6. We conclude that the 50% inhibition of thromboxane production induced by ibuprofen does not modify the fall in creatinine clearance of accumulation of neutrophils in the glomerulus caused by the a-GBM. This degree of inhibition of eicosanoid production was associated with a striking decrease in proteinuria, but this may reflect a haemodynamic rather than a disease modifying action.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Creatinine; Cyclooxygenase Inhibitors; Epoprostenol; Ibuprofen; In Vitro Techniques; Interleukin-1; Kidney Glomerulus; Male; Nephritis; Neutrophils; Rats; Rats, Inbred Strains; Thromboxane B2; Thromboxanes

We studied the effects of OKY-046 on types II, III and IV allergic reactions, as classified by Coombs and Gell. In Type II, OKY-046 at 30-100 mg/kg intraduodenally (i.d.) and at 1-30 mg/kg intravenously (i.v.) inhibited the bronchoconstriction in a dose-dependent manner after Forssman antigen injection. Aspirin (3 mg/kg, i.v.) also suppressed it. OKY-046 (30-100 mg/kg, i.d.) suppressed the increase of TXB2 level in the plasma in a dose-dependent manner. However, there was no effect of OKY-046 and aspirin on the decrease in complement activity (CH50), platelets and leukocytes. Additionally, OKY-046 (300 mg/kg, p.o.) prolonged the survival time following Forssman antigen injection. However, the immune hemolysis reaction was not prevented by OKY-046 (10(-6)-10(-3) M). FUT-175 protected against the Forssman shock at 1 mg/kg, i.v. and the in vitro immune hemolysis reaction at 10(-5) M. In Type III, OKY-046 (300 mg/kg, p.o.) significantly suppressed the direct passive Arthus reaction and immune complex nephritis in rats. There was no effect of OKY-046 on the delayed-type hypersensitive response to picryl chloride in mice. We think that OKY-046 should be a beneficial drug for the treatment of types II and III allergic reactions.

Topics: Acrylates; Animals; Antigens, Heterophile; Arthus Reaction; Bronchi; Depression, Chemical; Dose-Response Relationship, Drug; Forssman Antigen; Guinea Pigs; Male; Methacrylates; Mice; Muscle Contraction; Muscle, Smooth; Nephritis; Rats; Rats, Inbred Strains; Thromboxane B2; Thromboxane-A Synthase

Dietary fish oil intake improves glomerular pathology and proteinuria in murine models of autoimmune disease. We evaluated glomerular prostanoid formation, glomerular hemodynamics, and proteinuria in rats with nephrotoxic serum nephritis (NSN) to test whether this beneficial effect of marine lipids also applies to other animal models of glomerular immune injury. Rats were fed diets (8 weeks) containing either cod liver oil or sunflower oil. NSN was induced with a rabbit anti-rat glomerular basement membrane antiserum. Antibody injection significantly stimulated glomerular thromboxane B2 (TxB2) formation in animals fed cod liver oil and sunflower oil at 2 hours, 24 hours, and 7 days. TxB2 production in glomeruli of sunflower oil rats, however, was five to seven times higher when compared with that in rats fed cod liver oil. The dietary regimen led to a significant decrease of glomerular TxB2 and prostaglandin E2 formation in the animals receiving cod liver oil when compared with those fed sunflower oil. Induction of NSN resulted in a significant fall of inulin clearance (Cin) and paraaminohippurate clearance at 2 hours, 24 hours, and 7 days in both groups. The decrease in Cin at 2 hours was greater in rats fed cod liver oil when compared with animals receiving sunflower oil (p less than 0.02); it was not different, however, at 24 hours and 7 days. Animals with NSN developed proteinuria. There was no difference in protein excretion between rats fed cod liver oil or those fed sunflower oil (days 2 and 7).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Diet; Dinoprostone; Eicosanoids; Fish Oils; Glomerular Filtration Rate; Hemodynamics; Immune Sera; Insulin; Kidney Glomerulus; Leukotrienes; Metabolic Clearance Rate; Nephritis; p-Aminohippuric Acid; Proteinuria; Rabbits; Rats; Thromboxane B2

Fish oil diets preserve renal function in murine lupus, but we have found that these diets accelerate renal deterioration in renoprival nephropathy. In this study we examined the effects of dietary fish oil in accelerated nephrotoxic serum nephritis. For 1 month, 14 female rats were fed diets that differed only in fat composition, containing either menhaden (fish) oil or beef tallow (control). Rats were then preimmunized with rabbit IgG and, 5 days later, were injected with nephrotoxic serum. Glomerular filtration rate (GFR) was measured continuously in conscious animals by means of intraperitoneal 14C-labeled inulin minipumps. Fish oil-containing diets markedly attenuated the nephrotoxic serum-induced decline in GFR and the rise in proteinuria and significantly reduced glomerular prostaglandin E2 and thromboxane A2. The results of tests of renal histology showed no differences between the two groups. Five days after preimmunization, rats fed fish oil had more rabbit IgG remaining in their serum and had mounted less of an antibody response to the rabbit IgG. Fish oil diets also resulted in an attenuated disappearance of injected 14C-labeled rabbit IgG. In vitro, peritoneal macrophages from rats fed fish oil took up less rabbit IgG than macrophages from rats fed control diets. Thus the beneficial effects of a fish oil diet may result from defective immune surveillance and from alterations in eicosanoids.

Topics: Animals; Antibodies, Anti-Idiotypic; Basement Membrane; Dietary Fats, Unsaturated; Dinoprostone; Female; Fish Oils; Immunization, Passive; Immunoglobulin G; Kidney; Kidney Glomerulus; Macrophages; Nephritis; Peritoneal Cavity; Proteinuria; Rats; Rats, Inbred Strains; Thromboxane B2; Tissue Distribution

Measurement of serum thromboxane B2 (TXB2) and 6-keto-prostaglandins F1 alpha (6-keto-PGF1 alpha) was carried out in 62 patients of renal diseases. The results showed that decrease of TXB2 and 6-Keto-PGF1 alpha values and TXB2/6-Keto-PGF1 alpha ratio was correlated with the decrease of the renal function and was negatively correlated with the level of serum creatinine. The values of TXB2 and 6-Keto-PGF1 alpha were markedly elevated after hemodialysis in 19 patients. It was found that the difference between patients with and without renal hypertension was statistically significant (P less than 0.05). The results indicated that the inbalance of PG value was one of the causes of uremic hemorrhage, PG takes part in the development of renal hypertension.

Topics: 6-Ketoprostaglandin F1 alpha; Adolescent; Adult; Aged; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Nephritis; Renal Dialysis; Thromboxane B2

Recent studies have suggested a role for thromboxane in the progression of renal disease. The current study evaluated the role of this arachidonic acid metabolite in a model of renal disease which bears many biologic similarities to that in the kidneys of patients with chronic progressive renal failure. The model is that induced by ferritin-anti-ferritin immune complex nephritis in Dahl-salt sensitive rats rendered hypertensive by a high salt intake. Rats with this model of renal disease were chronically given a thromboxane synthetase antagonist OKY-046 or a placebo treatment from 16 to 29 weeks of age. Sequential observations of serum creatinine and 24-hour urinary protein excretion showed an ameliorating effect of OKY-046 on these renal parameters. Histologic examination of the kidneys also showed significantly less glomerular sclerosis in OKY-046 treated animals. The efficacy of OKY-046 was monitored by measurements of serum TXB2 levels and of glomerular production of TXB2 (and other prostaglandins); amounts of TXB2 were significantly reduced in the OKY-046 group. It is concluded that blockade of thromboxane generation has been successful in ameliorating the functional and structural lesions in this model of renal disease, providing further support to the thesis that thromboxane is an important mediator in events leading to eventual chronic renal failure and sclerosis.

Topics: Acrylates; Animals; Creatinine; Fatty Acids, Unsaturated; Immune Complex Diseases; In Vitro Techniques; Kidney Glomerulus; Male; Methacrylates; Nephritis; Proteinuria; Rats; Thromboxane B2; Thromboxane-A Synthase; Thromboxanes

Topics: Animals; Antigen-Antibody Complex; Creatinine; Hydralazine; Hypertension, Renal; In Vitro Techniques; Kidney Glomerulus; Male; Nephritis; Prostaglandins; Rats; Rats, Inbred Strains; Thromboxane B2

One hundred NZB/W F1 female mice were studied to compare the effects of a thromboxane synthase inhibitor (TSI), a stable prostacyclin analog (iloprost) and prostaglandin E1 (PGE1) in the evolution of the nephritis. At 10 weeks of age mice were randomly assigned to cohorts of 20 to receive either no treatment, vehicle control, PGE1, iloprost or TSI. Proteinuria, mortality, systemic blood pressure, renal immune complex deposition, urinary TX B2 and 6 keto PGF1 alpha levels were measured. Mice receiving PGE1 and iloprost had a significant delay in the onset of proteinuria and reduction in mortality at 40 weeks. The TSI treatment had no apparent effect on proteinuria or mortality. The amelioration of the nephritis was not associated with an alteration in immune complex deposition in survivors at 40 weeks. Although PGE1 and iloprost lessened the age related increase in urinary TX B2, increased the urinary 6 keto PGF1 alpha levels and the ratio of 6 keto PGF1 alpha to TX B2; so did the TSI. The PGE1 treated mice did experience a marked and persistent reduction in blood pressure but this was not observed in the iloprost- or the TSI-treated mice. All drugs tested reduced the age-related increase in thromboxane B2 but only the PGE1 and iloprost had a significant effect on the evolution of the nephritis.

Topics: 6-Ketoprostaglandin F1 alpha; Age Factors; Alprostadil; Animals; Benzofurans; Blood Pressure; Disease Models, Animal; Epoprostenol; Female; Iloprost; Lupus Nephritis; Mice; Mice, Inbred NZB; Mice, Inbred Strains; Nephritis; Proteinuria; Thromboxane B2; Vasodilator Agents

Accelerated anti-glomerular basement membrane nephritis was induced in rabbits, and the immunological, clinical and histological evolution studied in relation to urinary immunoreactive thromboxane B2 (i-TXB2) and immunoreactive prostaglandin E2 (i-PGE2) excretion. In control nephritic animals, urinary i-TXB2 increased 5-fold on day +1, but was normal again by day +5. The urinary i-TXB2 showed a positive correlation with creatinine clearance (CCr), proteinuria and anti-sheep immunoglobulin antibody. Urinary i-PGE2 excretion increased by 50% on day +1, but was indistinguishable later from controls. The effects of the specific thromboxane synthetase inhibitor OKY-046 on this model was studied. In non-nephritic control animals, OKY-046 did not affect the CCr, the urinary protein excretion or the number of monocytes in glomeruli but reduced the excretion of i-TXB2. Although OKY-046 markedly inhibited the i-TXB2 excretion throughout the experiment in nephritic animals, the creatinine clearances were significantly worse, the proteinuria greater, and the number of infiltrating monocytes greater at day +5; by day +10 there was no difference from controls. There was no evidence that TXB2 is involved in the induction of proteinuria, and increased PGE2 synthesis did not protect against later proteinuria and fall in creatinine clearance. Inhibition of thromboxane synthetase appears to make this model of nephritis worse, rather than better.

Topics: Acrylates; Animals; Basement Membrane; Creatinine; Depression, Chemical; Dinoprostone; Disease Models, Animal; Female; Immunoenzyme Techniques; Immunoglobulin G; Kidney Glomerulus; Methacrylates; Nephritis; Prostaglandins E; Rabbits; Thromboxane B2; Thromboxane-A Synthase

The platelet-derived growth factor (PDGF) antagonist, trapidil, which also blocks the thromboxane and/or PG-endoperoxide receptor and is an inhibitor of thromboxane synthetase, was administered during rabbit accelerated nephrotoxic nephritis; the clinical and histological evolution was studied as well as urinary immunoreactive thromboxane (i-TXB2) and immunoreactive prostaglandin E2 (i-PGE2) excretion. Although the dose we used has been shown to be effective in vivo, and it inhibited the urinary i-TXB2 excretion on days 5 and 10, it neither inhibited the enhanced production of i-TXB2 on day 1, nor prevented the glomerular influx of monocytes on days 5 and 10. All clinical and histological data tend to be worse rather than better in trapidil-treated animals on days 5 and 10.

Topics: Animals; Dinoprostone; Female; Kidney Glomerulus; Monocytes; Nephritis; Platelet-Derived Growth Factor; Prostaglandins E; Pyrimidines; Rabbits; Thromboxane B2; Trapidil

The process of renal inflammation was examined using the partial renal vein constricted rabbit kidney ( RVC ) as a model. Forty eight hours of partial renal vein constriction in the rabbit was associated with an increase in prostaglandin (PG) and thromboxane (Tx) production. The ex vivo perfused RVC kidney showed an enhanced time-dependent increase in PG and Tx production in response to bradykinin stimulation when compared with the unaltered contralateral ( CLK ) or normal kidney. At 6 hrs of perfusion bradykinin stimulation released 2950 +/- 350 ng PGE2, 61 +/- 15 ng TxB2 from the RVC , and 225 +/- 85 ng PGE2 and undetectable TxB2 from the CLK . Histological examination of the RVC cortex showed an increase in fibroblast-like cells, a modest increase in the interstitial space and an appearance of macrophages and lymphocytes not seen in the normal or CLK . Endotoxin has been reported to stimulate macrophages in culture to produce PGE2 and TxB2. Endotoxin (100 ng) stimulation of the perfused RVC kidney caused an immediate, followed by a chronically increasing, release of PGs and Tx. Two hours after endotoxin injection 50 ml of effluent from the RVC contained 1450 +/- 107 ng PGE2 and 15.0 +/- 4.5 ng TxB2. Other animals of renal inflammation (e.g., the hydronephrotic kidney, chronic glomerulonephritis) also show the histological appearance of macrophages. In addition, hydronephrotic kidneys undergo fibroblast proliferation and changes in arachidonic acid metabolism similar to that we observed in the RVC . This work suggests that the inflammatory process (mononuclear cell infiltration, fibroblast-like cell proliferation, and accompanying changes in arachidonate metabolism is common among different forms of renal injury.

Topics: Animals; Arachidonic Acid; Arachidonic Acids; Bradykinin; Constriction; Dinoprostone; Disease Models, Animal; Endotoxins; Kidney; Microscopy, Electron; Nephritis; Prostaglandins E; Rabbits; Renal Veins; Thromboxane B2