A high plasma prostaglandin to thromboxane ratio protects against renal ischemia.
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.
Kaufman
R P
RP
Department of Surgery, Brigham and Women's Hospital, Boston, Massachusetts 02115.
Anner
H
H
Kobzik
L
L
Valeri
C R
CR
Shepro
D
D
Hechtman
H B
HB
D015121:6-Ketoprostaglandin F1 alpha / Q000097:blood*; D000818:Animals; D001572:Benzofurans / Q000627:therapeutic use; D003404:Creatinine / Q000097:blood; D005069:Evaluation Studies as Topic; D007052:Ibuprofen / Q000627:therapeutic use; D007093:Imidazoles / Q000627:therapeutic use; D007511:Ischemia / Q000517:prevention & control*; D007668:Kidney / Q000098:blood supply*; D007683:Kidney Tubular Necrosis, Acute / Q000517:prevention & control; D008297:Male; D008689:Methacrylates / Q000627:therapeutic use; D011725:Pyridines / Q000627:therapeutic use; D051381:Rats; D013929:Thromboxane B2 / Q000097:blood*; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors
D001572:Benzofurans; D007093:Imidazoles; D008689:Methacrylates; D011725:Pyridines; C039242:dazmegrel; D013929:Thromboxane B2; D015121:6-Ketoprostaglandin F1 alpha; C037787:pirmagrel; D003404:Creatinine; D013930:Thromboxane-A Synthase; C039936:furegrelate; C034364:ozagrel; D007052:Ibuprofen