2-methyl-3-(4-(3-pyridinylmethyl)phenyl)-2-propenoic-acid and Glomerulonephritis

Administration of heparin to rats with 1 3/4 nephrectomy prevents the development of glomerulosclerosis, hypertension and retards the decrease in renal function seen in these rats. To further define the role of hypertension and/or coagulation in the pathogenesis of the glomerulopathy seen in this model we studied several groups of rats with 1 3/4 nephrectomy: (1) a control group; (2) a group receiving a 'high dose' of acetylsalicylic acid (50 mg/kg) plus dipyridamole (10 mg/kg); (3) a group receiving a 'low' dose (5 mg/kg body weight) of acetylsalicylic acid alone; (4) a group receiving OKY 1581, an inhibitor of thromboxane synthesis; (5) a group treated with antihypertensive medications; (6) a group receiving heparin subcutaneously twice daily, and (7) a group given oral Coumadin. Drugs in all groups were administered daily for 4 weeks. All treated groups had a decrease in blood pressure (BP), in the ratio of heart weight to body weight, in BUN levels and had fewer abnormal glomeruli. The effects of acetylsalicylic acid alone, of acetylsalicylic acid plus dipyridamole, and OKY 1581 may be due to inhibition of platelet aggregation and intraglomerular thrombosis, with the fall in BP being the consequence of improved renal function. On the other hand, the decrease in BP may be related to a primary effect of these drugs. The lower BP in turn may play a role in slowing the progression of renal disease and improving the renal histology in the treated groups.

Topics: Animals; Anticoagulants; Antihypertensive Agents; Blood Urea Nitrogen; Female; Glomerulonephritis; Glomerulosclerosis, Focal Segmental; Hypertension, Renal; Methacrylates; Nephrectomy; Platelet Aggregation Inhibitors; Rats; Rats, Inbred Strains; Thromboxane-A Synthase

Eicosanoid metabolites may play a role in the pathophysiology of nephrotoxic serum nephritis (NSN), a model of immune renal disease. Our purpose was to determine the relative importance of vasoconstrictor [thromboxane A2 (TX)A2] and vasodilator [prostaglandin E2 (PG)E2] eicosanoids as mediators of hemodynamic and renal functional changes. Glomerular filtration rate (GFR; inulin clearance), and renal plasma flow (RPF; para-aminohippurate clearance/extraction) were measured in rats on day 1 and day 14 of NSN. Specific inhibitors of TXA2 synthesis and receptor binding, and cyclooxygenase inhibitors were used to determine the relative roles of TXA2 and PGE2. In vitro glomerular production of radioimmunoassayable PGE2 and TXB2 were measured after clearances. At 1 day GFR is decreased compared to control, 1.9 +/- 0.2 vs. 2.6 +/- 0.2 ml/min. RPF is numerically increased, 10.0 +/- 1.0 vs. 7.0 +/- 0.6 ml/min. By 14 days GFR is normal, 2.2 +/- 0.2 ml/min, as a consequence of significantly increased RPF, 11.7 +/- 1.0 ml/min. Glomerular production of PGE2 and TXB2 was increased 11- and 15-fold respectively at both 1 and 14 days. Pretreatment with OKY-1581, or acute treatment with UK-38,485, both inhibitors of TXA2 synthesis, had no effect on GFR or RPF in NSN rats. Addition of EP 092, a TXA2 receptor antagonist was similarly without effect. In contrast, acute treatment with the cyclooxygenase inhibitors meclofenamate or indomethacin resulted in a 50% decrease in both RPF and GFR; these inhibitors had no effect in control rats. We conclude that PGE2 (vasodilator) is of greater relative significance than TXA2 (vasoconstrictor) with respect to renal function in the NSN rat at 1 and 14 days.

Topics: Animals; Dinoprostone; Glomerular Filtration Rate; Glomerulonephritis; Hemodynamics; Imidazoles; Kidney; Male; Methacrylates; Prostaglandins E; Rabbits; Rats; Rats, Inbred Strains; Renal Circulation; Thromboxane A2; Thromboxanes

Glomerular arachidonate cyclooxygenation by isolated rat glomeruli was assessed in vitro in antiglomerular basement membrane (anti-GBM) antibody-induced glomerulonephritis by radioimmunoassay for prostaglandins (PG) and thromboxane. After a single intravenous injection of rabbit anti-rat GBM serum, we observed enhancement of glomerular thromboxane B2 (TxB2) synthesis as early as 2 to 3 h with smaller increments in PGF2 alpha, PGE2 and 6-keto-PGF1 alpha synthetic rates. On day 2 of the disease, the glomerular synthesis of TxB2 and, to a lesser extent, PGF2 alpha and PGE2 remained enhanced, whereas on days 8, 11, and 14, TxB2 was the only prostanoid synthesized at increased rates. Glomerular TxB2 synthesis correlated with the presacrifice 24-h protein excretion. 60 min after intravenous infusion of anti-GMB serum, glomerular filtration rate (GFR) decreased (0.66 +/- 0.04 to 0.44 +/- 0.03 ml/min per 100 g, P less than 0.05), without a significant change in renal plasma flow (RPF): 1.97 +/- 0.23 to 1.80 +/- 0.23 ml/min per 100 g) and without a change in glomerular PG synthetic rates. At 2 h, GFR and RPF reached a nadir (0.25 +/- 0.04 and 1.3 +/- 0.1 ml/min per 100 g, respectively) coinciding with a fivefold increment in glomerular TxB2. By 3 h GFR and RPF partially recovered to 0.43 +/- 0.07 and 1.77 +/- 0.20 ml/min per 100 g, respectively, P less than 0.05, despite further increments in TxB2 synthesis. This recovery of GFR and RPF coincided with increments in vasodilatory PG, (PGE2 and PGI2). The thromboxane synthetase inhibitor OKY-1581 markedly inhibited platelet and glomerular TxB2 synthesis and preserved GFR at 1, 2, and 3 h. Another thromboxane synthetase inhibitor, UK-38485, also completely inhibited platelet and glomerular TxB2 synthesis and prevented decrements of GFR at 2 and 3 h. A cyclooxygenase inhibitor, ibuprofen, inhibited platelet TxB2 and PGE2 synthesis and significantly reduced glomerular PGE2 but not TxB2 synthesis. In the ibuprofen-treated rats, the partial recoveries of GFR and RPF at 3 h were attenuated. The in vitro glomerular TxB2 synthesis correlated inversely with the presacrifice GFR and filtration fraction. These observations indicate that in anti-GBM nephritis there is enhanced synthesis of TxA2 and PG in the glomerulus that mediate changes in renal hemodynamics.

Topics: Animals; Blood Physiological Phenomena; Glomerular Filtration Rate; Glomerulonephritis; Ibuprofen; Kidney Glomerulus; Male; Methacrylates; Nephrotic Syndrome; Prostaglandin Antagonists; Prostaglandins; Rabbits; Rats; Rats, Inbred Strains; Renal Circulation; Thromboxane B2; Thromboxane-A Synthase; Thromboxanes