Studies were performed to evaluate the effect of solute permeability and extracellular osmolality in protecting against ischemic acute renal failure. The functional protective effect of a 1-min intrarenal perfusion (prior to intrarenal norepinephrine 0.75 micrograms . kg-1 . min-1) of a hypertonic permeant solute (hypertonic saline, 1,400 mosmol/kg H2O) and an isotonic impermeant solute (isotonic mannitol, 280 mosmol/kg H2O or isotonic polyethylene glycol, IPEG, 300 mosmol/kg H2O) was evaluated. Three hours after ischemia, the glomerular filtration rate was significantly lower in hypertonic saline group vs. either the isotonic mannitol- or IPEG-treated animals (2.4 vs. 8.9 and 10.4 ml/min, respectively; both P less than 0.05). Mean renal blood flow was similar in all three groups. The effects of hypertonic saline and IPEG on glomerular filtration pressure and tubular obstruction were also evaluated. Stop-flow pressure, as an index of glomerular filtration pressure, was higher in the IPEG- vs. the hypertonic saline-treated animals (40 vs. 35 mmHg, P less than 0.001). Although proximal tubular pressure was increased in both groups, transglomerular hydrostatic pressure was higher in the IPEG vs. the hypertonic saline group (13 vs. 6 mmHg, P less than 0.01). Tubular microperfusion studies demonstrated increases in proximal tubular pressure in the hypertonic saline but not the IPEG studies. The present results indicate that isotonic, impermeant solutes provide functional protection against ischemic acute renal failure. The beneficial effect of impermeant solute is mediated, at least in part, by better maintenance of transglomerular hydrostatic pressure and prevention of secondary tubular obstruction.