Acute kidney dysfunction, manifested by reductions in renal blood flow and glomerular filtration rate with increased renal vascular resistance, is a common finding in septic shock. In an attempt to halt the progressive renal dysfunction, the hemorheologic methylxanthines, pentoxifylline (1, 5, or 10 mg/kg of PTX) and 2 structurally-related analogues, 5 mg/kg of HWA-138 and 5 mg/kg of HWA-448, or saline wee given 7.5 hr after endotoxin infusion in the rat. Renal function, assessed by single-dose inulin clearances (CIN), was measured at 6 hr after the infusion of endotoxin and also 1 hr following the drug treatment. The mean CIN at 6 and 9 hr after endotoxin infusion were 2- and 3-fold decreased compared with control rats given either saline or 5 mg/kg of PTX. Although renal function declined in all rats throughout the study period, the reduction in renal function was markedly slowed in endotoxemic rats given 10 mg/kg of PTX or 5 mg/kg of HWA-448 compared with untreated controls (74 +/- 9% and 77 +/- 9 vs. 47 +/- 12% of 6 hr CIN at 9 hr, respectively; P less than 0.01). Similar results were found with single doses of 5 mg/kg of PTX or HWA-138; PTX 1 mg/kg had a modest beneficial effect on renal function. There was no evidence of vascular congestion in endotoxemic kidneys upon histologic examination. These data suggest the potential benefit of PTX and related methylxanthines in stopping progressive renal damage associated with septic shock.