thromboxane-a2 and Glomerulonephritis--Membranoproliferative

In glomerulonephritis there is co-activation of the arachidonic acid cyclooxygenase pathway toward synthesis of prostaglandins (PG) and thromboxane (Tx) and of lipoxypenase pathways toward synthesis of hydroxyeicosatetraenoic acids (HETEs) and leukotrienes (LTs). Cyclooxygenase inhibition with non-steroidal anti-inflammatory drugs results in enhanced glomerular LT synthesis with potentially adverse effects on the severity of the inflammation. The effect of Tx inhibition or antagonism on LT synthesis is unknown. Because TxA2 is the most abundant eicosanoid synthesized in nephritic glomeruli, and because TxA2 synthase inhibitors and receptor antagonists are now available for the treatment of glomerulonephritis, it becomes important to address this question. In this study we assessed the effect of a TxA2 synthase inhibitor, Dazmegrel, and a TxA2 receptor antagonist, SQ-29 548, on glomerular PGE2, LTB4, and 12-HETE synthesis in a model of mesangial nephritis induced in the rat by the administration of a monoclonal antibody against the Thy 1.1 antigen of rat mesangial cells. Dazmegrel, in doses sufficient to effectively block glomerular TxA2 synthesis, significantly increased 12-HETE and PGE2 synthesis without an effect on the synthesis of LTB4. SQ-29 548 had no effect on glomerular PGE2, LTB4, or 12-HETE production. Because PGE2 preserves kidney function in glomerulonephritis, and because 12-HETE inhibits 5-lipoxygenase, the enhanced PGE2 and 12-HETE production within nephritic glomeruli after TxA2 synthase inhibition may be a superior anti-inflammatory strategy when compared with TxA2 receptor antagonism.

Topics: 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; Animals; Antilymphocyte Serum; Bridged Bicyclo Compounds, Heterocyclic; Dinoprostone; Disease Models, Animal; Fatty Acids, Unsaturated; Glomerulonephritis, Membranoproliferative; Hydrazines; Kidney Glomerulus; Leukotriene B4; Macrophages; Rats; Rats, Wistar; Thromboxane A2; Thromboxane-A Synthase; Thy-1 Antigens

Fourteen patients with chronic proliferative glomerulonephritis were given for the period of one year 400 mg acetylsalicylic acid and 225 mg dipyridamole per day. During this treatment the thrombocyte aggregation became normal, however, the mean reduction of antiheparin plasma activity was not statistically significant. Normal synthesis of renal prostacyclin declined significantly as a result of treatment, while the renal thromboxane A2 synthesis remained normal even during treatment. Treatment did not influence proteinuria. The mean annual decline of glomerular filtration was greater during the investigation period than the mean annual decline in previous years, the difference was, however, only at the borderline of statistical significance. The authors did not prove a favourable effect of this treatment in patients with chronic proliferative glomerulonephritis.

Topics: Adult; Aspirin; Chronic Disease; Dipyridamole; Drug Therapy, Combination; Epoprostenol; Female; Glomerulonephritis, Membranoproliferative; Humans; Male; Platelet Aggregation; Thromboxane A2

In 14 patients with chronic proliferative glomerulonephritis, corrected arterial hypertension and normal or marginal glomerular filtration the authors assessed plasmatic and urinary metabolites of PGI2 and TXA2. They found that the production of both PGI2 and TXA2 was raised in the organism and they assume that in the stimulated synthesis hypertension and its treatment participated. The production of both prostaglandins in the kidneys was, however, normal.

Topics: 6-Ketoprostaglandin F1 alpha; Chronic Disease; Epoprostenol; Female; Glomerulonephritis, Membranoproliferative; Humans; Male; Prostaglandins; Thromboxane A2; Thromboxane B2