6-ketoprostaglandin-f1-alpha and 3-methyl-2-(3-pyridyl)-1-indoleoctanoic-acid

Greyhounds (n = 38) were randomized to aspirin and dipyridamole (ASA + DPM), the thromboxane synthetase inhibitor (TSI) CGS12970 (CIBA-GEIGY) or placebo twice daily for 48 hours prior to bilateral implantation of femoral artery Dacron grafts. In-vivo 111In-platelet deposition on grafts was measured at 5 days and 2 months. Grafts were removed at 2 months when ex-vivo graft and arterial release of 6-ketoprostaglandin F1a (6-keto PGF1a) was measured by radioimmunoassay. Graft 6-keto-PGF1a was significantly increased by CGS12970 but ASA + DPM had no significant effect. ASA + DPM significantly reduced arterial 6-keto-PGF1a although this was marginally increased by CGS12970. Neither active treatment reduced in-vivo 111In-platelet deposition. Preservation of vascular or graft prostacyclin by thromboxane synthetase inhibitors may represent an alternative strategy in preventing prosthetic graft thrombosis.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Aspirin; Blood Vessel Prosthesis; Dipyridamole; Dogs; Drug Therapy, Combination; Female; Femoral Artery; Graft Occlusion, Vascular; Pyridines; Radiography; Random Allocation; Thromboxane-A Synthase

To determine the role of thromboxane A2 in the pathogenesis of experimentally induced immune complex glomerulonephritis, 12 concanavalin A-immunized Beagles were infused with 1 mg of concanavalin A via each renal artery and treated twice daily for 8 days with either 30 mg of CGS 12970/kg, PO, a specific thromboxane synthetase inhibitor, or placebo. The effect of treatment was assessed by measuring endogenous creatinine clearance and urine protein and eicosanoid excretion, and by evaluating changes in glomerular morphometric characteristics. On postinfusion day 8, urine protein, thromboxane B2, and 11-dehydro-thromboxane B2 excretion, glomerular epithelial crescent formation, and glomerular cell proliferation in the CGS 12970-treated dogs were significantly decreased when compared with values in the placebo-treated group. Differences were not observed in endogenous creatinine clearance, urine prostaglandin E2 and 6-keto-prostaglandin F1 alpha excretion, or glomerular polymorphonuclear leukocyte infiltration between groups in this study. These findings suggest thromboxane A2 has a role in the development of immune complex glomerulonephritis and that thromboxane synthetase inhibition may be beneficial in attenuating some of the functional and histological changes associated with immune complex glomerulonephritis.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Concanavalin A; Dinoprostone; Disease Models, Animal; Dogs; Glomerular Filtration Rate; Glomerulonephritis; Immune Complex Diseases; Kidney; Kidney Glomerulus; Male; Pyridines; Thromboxane A2; Thromboxane B2; Thromboxane-A Synthase

These data indicate that chronic administration of CGS-12970 to renal allograft recipients maintains renal allograft function. These effects are probably due to selective inhibition of local tissue TXA2 production. These data also suggest that elevations in renal allograft tissue prostacyclin production may be secondary to ischemia since improving renal blood flow and GFR with selective thromboxane synthesis inhibitors leads to normalization of renal prostacyclin synthesis. The possible utility of using CGS-12970 as an adjunct therapy in human renal allotransplantation should be strongly considered.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Dogs; Glomerular Filtration Rate; In Vitro Techniques; Kidney; Kidney Transplantation; Pyridines; Renal Circulation; Thromboxane B2; Thromboxane-A Synthase; Transplantation, Autologous; Transplantation, Homologous

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

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