Renal hemodynamic effects of therapeutic plasma levels of sulindac sulfide during hemorrhage

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 μg/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.