DIURETIC ACTION OF METOLAZONE IN DOGS

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Abstract
Metolazone, the sulfonamide diuretic, was investigated to determine the sites of action. A radioactive microsphere, clearance and stop-flow method was used in anesthetized dogs. Urine flow and urinary excretion of Na and K were increased at 5-60 min when metolazone was given i.v. at doses of 0.2-5.0 mg/kg, while total renal blood flow, distribution of cortical renal blood flow and GFR [glomerular filtration rate] did not change. The urinary excretion rate of Na to K (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[urinary to plasma Na ratio]/U/Pcreatinine [urinary to plasma creatinine ratio] was observed at the dip situated distally to the ascending limb of Henle. The diuretic action of metolazone may be due to the inhibition of Na reabsorption in the distal nephron segments, in addition to the absence of modification of the cortical regional blood flow.