Metolazone, the sulfonamide diuretic was investigated to determine the sites of action. We used a radioactive microsphere, clearance and stop-flow method in anesthetized dogs. Urine flow and urinary excretion of sodium and potassium were increased at 5--60 min when metolazone was given intravenously at doses of 0.2--5.0 mg/kg, while total renal blood flow, distribution of cortical renal blood flow and GFR did not change. The urinary excretion rate of sodium to potassium (Na/K) increased from 5.69 +/- 0.82 to 8.07 +/- 0.76 in a dose of 1.0 mg/kg, i.v. Osmolar clearance and free water reabsorption increased almost proportionally, indicating that metolazone has little effect on the medullary portion of the ascending limb of Henle and may have a proximal site of action. In stop-flow experiments, a significantly raised U/PNa/U/Pcreatinine was observed at the dip situated distally to the ascending limb of Henle. These findings indicate that the diuretic action of metolazone may be due to the inhibition of sodium reabsorption in the distal nephron segments, in addition to the absence of modification of the cortical regional blood flow.