6-ketoprostaglandin-f1-alpha and sulindac-sulfide

There is continued debate over any renal sparing effects of sulindac (S): such a property would be of benefit and be unique among nonsteroidal anti-inflammatory drugs (NSAIDS). S undergoes a distinct metabolism whereby the active drug (sulindac sulfide (SS)) does not appear in the urine. Accordingly, we tested the effect of a plasma concentration of SS in the therapeutic range on renal blood flow (RBF), glomerular filtration rate (GFR), and renal prostaglandin (PG) concentrations during sudden renal ischemic stress. The ischemic stress was produced by a 15 to 20% reduction in arterial pressure by arterial hemorrhage (H) in four separate groups of anesthetized dogs: control, SS (0.4 mg/kg i.v. bolus followed by 0.03 mg/kg/min constant infusion), indomethacin (I, 10 mg/kg), and benoxaprofen (B, 75 mg/kg). A plasma concentration of 3.69 micrograms/ml of SS was achieved by the infusion, and no SS appeared in the urine. H reduced GFR (by 46%) and RBF (by 38%) in control dogs; in SS-treated dogs, a 60% decline in GFR and a 73% decrease in RGF occurred. These decreases in renal hemodynamics in the SS group during H were significantly greater than in the control group. Further, these decrements in GFR and RBF were similar to those observed in the I- and B-treated dogs. Finally, SS reduced baseline arterial and renal PG concentrations, and prevented any increase in renal PG release during H. Thus, we conclude that a concentration of SS in the therapeutic range, which does not appear in the urine, is capable of enhancing the decline in GFR and RBF during a sudden ischemic stress such as H.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Anti-Inflammatory Agents; Disease Models, Animal; Dogs; Glomerular Filtration Rate; Hemodynamics; Hemorrhage; Indenes; Indomethacin; Ischemia; Kidney; Kidney Diseases; Propionates; Renal Circulation; Sulindac

Previous reports have suggested that sulindac is a unique non-steroidal anti-inflammatory (NSAID) agent, because it does not inhibit renal prostaglandin synthesis in doses that inhibit platelet thromboxane B2 synthesis when tested ex vivo. NSAIDS are of potential therapeutic benefit in the treatment of septic or endotoxic shock. Therefore, this study was designed to investigate the proposed unique action of sulindac in experimental endotoxemia. In the current study, the effect of sulindac on aortic, portal and renal venous immunoreactive (i) 6-keto-PGF1 alpha levels, the stable metabolite of prostacyclin, was investigated during endotoxemia in the rat. In doses sufficient to reduce the elevation in aortic and portal venous plasma i6-keto-PGF1 alpha levels, sulindac also significantly (p less than 0.05) attenuated the elevated renal venous plasma 6-keto-PGF1 alpha levels, compared to the vehicle group. Using lower doses, sulindac failed to reduce the endotoxin associated increase in either aortic or renal venous plasma i6-keto- PGF1 alpha levels. Thus, sulindac failed to demonstrate any selective sparing effect on renal prostacyclin generation during endotoxemia.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Epoprostenol; Indenes; Kidney; Male; Rats; Shock, Septic; Sulindac