Some Effects of Metolazone on Electrolyte Transport

Abstract

Metolazone action was studied 1) in vitro on isolated operculum of Fundulus heteroclitus (active chloride transport) using an Ussinq chamber (metolazone cone 500 öM) and in vivo 2) Using the modified Sperber technique in the hen (metolazone infusion rate 0. 75–1.2 ög/kg/min) and 3) in healthy volunteers using clearance techniques (metolazone infusion rate 10 mg/h). 1) Metolazone reduced (p>0.05) short circuit current and potential differences with 20% from average control values (p<0.05), while direct current resistance was unchanged. This is comparable to thiazide but much lower than loop diuretic effects. 2) True tubular excretion fraction of metolazone before and after novobiocin (2.7 μmol/kg/min coinfusion averaged 14.1 and 4.5 %, resp. (n<0.01; n=8). Thus metolazone is partly eliminated by renal tubular secretion. However, the diuretic effect (sodium, chloride and potassium excretion) - and clearances of Cr⁵¹ -EDTA and I¹²⁵ -Na-o-iodohippurate - were symmetrical, i. e. independent of metolazone urinary excretion rate, as previously shown for thiziades. 3) Renal clearance of metolazone in healthy volunteers. (HPLC-method) averaged 173±20 ml/min (n=8). Probenecid (1 g iv.) significantly reduced the renal clearance of metolazone to 33±7 ml/min and potassium excretion with maximum 30%, while diuretic and saluretic effects were significantly increased with maximum 30%. Thus, also in humans the diuretic effect of metolazone is not coupled to the urinary excretion rate of the drug, but suggests that its diuretic effect is elicited primarily from the peritubular side of the nephron. Probenecid apparently dissociates sodium from potassium excretion effects of metolazone. This implies a luminal, sodium-independent kaliuretic effect of the drug.