benzofurans and Kidney-Tubular-Necrosis--Acute

Experimental preservation time for pulsatile perfused dog kidneys was extended from three to five days by phospholipase A2 inhibition suggesting a pathomechanical role of products of phospholipolysis like thromboxane and leukotrienes in the development of acute graft failure after renal transplantation. We therefore investigated the effects of thromboxane- and leukotriene synthase inhibitors on postoperative renal transplant function in a model of pulsatile perfusion preservation as well as a cold storage preservation of dog kidneys. Addition of a thromboxane-synthase-inhibitor to the perfusion medium in pulsatile perfused kidneys and the combined application of a thromboxane-synthase-inhibitor and a leukotriene-synthase-inhibitor to the recipient of a cold storage preserved graft, improved graft function and reduced the incidence of delayed graft function as well as histopathological features of acute tubular necrosis.

Topics: Adenosine; Allopurinol; Animals; Arachidonic Acid; Aspirin; Benzofurans; Dogs; Enzyme Inhibitors; Female; Glutathione; Ibuprofen; Imidazoles; Insulin; Kidney Transplantation; Kidney Tubular Necrosis, Acute; Kidney Tubules; Leukotriene Antagonists; Leukotrienes; Organ Preservation; Organ Preservation Solutions; Pyridines; Raffinose; Thromboxane-A Synthase

Topics: Animals; Arachidonic Acids; Benzofurans; Dogs; Female; Imidazoles; Kidney Transplantation; Kidney Tubular Necrosis, Acute; Organ Preservation; Pyridines; Thromboxane-A Synthase

Pretreatment with the thromboxane synthase inhibitor OKY-046 but not the cyclo-oxygenase inhibitor ibuprofen protects against ischemia-induced acute tubular necrosis. However, ibuprofen together with the vasodilating agent prostaglandin E1 is protective. This suggests that a high prostaglandin to thromboxane ratio is the major factor operative in preventing tubular necrosis, the subject of this study. Rats that had unilateral nephrectomy (n = 60) with the exception of rats that had sham operations (n = 8) underwent 45 minutes of left renal pedicle clamping. Thirty minutes before the operation, the rats received either a saline solution or a thromboxane synthase inhibitor that was given intravenously. The inhibitors OKY-046 (2 milligrams per kilogram, n = 10), UK38485 (1 milligram per kilogram, n = 9) and U63357A (10 milligrams per kilogram, n = 10) were given as a single bolus while the inhibitor CGS13080 (0.1 milligram per kilogram, n = 9, and 1.0 milligram per kilogram, n = 7) was given by constant infusion and continued for 60 minutes after reperfusion. With saline solution therapy, five minutes after reperfusion, thromboxane B2 increased from 154 to 2,537 picograms per milliliter (p less than 0.00001) and 6-keto-prostaglandin F1 alpha increased from 51 to 266 picograms per milliliter (p less than 0.004). At 24 hours, the creatinine level increased from 0.5 to 2.8 milligrams per deciliter (p less than 0.00001). Only OKY-046 yielded a creatinine level at 24 hours of 1.2 milligrams per deciliter, a value lower than that for those in the saline solution control group (p less than 0.002). Furthermore, OKY-046 led to the highest prostaglandin to thromboxane ratio (p less than 0.035). The five other ratios which occurred after drug therapy were inversely related to the decrease in the creatinine value (r = -0.93, p less than 0.02). Histologically, OKY-046 was the only thromboxane synthase inhibitor to prevent acute tubular necrosis (p less than 0.05). Results show that a high prostaglandin to thromboxane ratio protects against acute tubular necrosis.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Benzofurans; Creatinine; Evaluation Studies as Topic; Ibuprofen; Imidazoles; Ischemia; Kidney; Kidney Tubular Necrosis, Acute; Male; Methacrylates; Pyridines; Rats; Thromboxane B2; Thromboxane-A Synthase