Single nephron microperfusion experiments were conducted to evaluate the influence of changes in perfusate osmolality on feedback-mediated responses in stop-flow pressure. Both nonelectrolyte- and sodium chloride-containing solutions with varying osmolalities perfused toward the distal nephron from a late proximal segment at perfusion rates (PR) ranging from 16 to 68 nl/min. A wax block was placed in an intermediate segment and stop-flow pressure (SFP) was measured from an early proximal tubule segment. Perfusion with hypertonic NaCl solutions (1,000 mosmol/kg; n = 18) resulted in decreases in stop-flow pressure such that maximum responses occurred at lower PR than in tubules perfused with isotonic electrolyte solutions, while hypotonic NaCl solutions (100 mosmol/kg; n = 15) failed to elicit feedback responses even at maximum perfusion rates. During perfusion with a 300 mosmol/kg mannitol solution (n = 33) SFP was significantly lower than in nonperfused tubules (35±2 vs. 51±1 mmHg) and was not altered greatly with increases in PR. During perfusion with hypotonic mannitol solutions (150 and 75 mosmol/kg; n = 39), urea solutions, and glucose solutions (300 mosmol/kg) decreases in SFP of about 15-25 mmHg occurred. Perfusion with more dilute mannitol solutions failed to elicit decreases in SFP. The addition of furosemide (10-3 M) to the mannitol solutions led to complete inhibition of the SFP response to increases in PR. These results demonstrate that in the dog significant feedback-mediated decreases in SFP can occur with nonelectrolyte, as well as electrolyte perfusion solutions.