Direct effect of metolazone on sodium-dependent transport across the renal brush border membrane.

Studies with clearance and micropuncture techniques indicate that metolazone inhibits transport of sodium and phosphate in the proximal tubule. The present study is focused on transport across the luminal BBM of the proximal tubule to determine whether metolazone has any direct effect on this initial step in transtubular reabsorption. Addition of metolazone (0.01 to 1.00 mM) to isolated renal BBM vesicles caused dose-dependent inhibition (30% to 70%) of the initial uphill phase of Na+ gradient-dependent phosphate transport but did not inhibit the uptake at equilibrium. There were no significant changes in Na+-independent phosphate transport and phosphate transport under nongradient conditions when metolazone was present at 1.0 mM. The initial Na+ gradient-dependent BBM transport of both D-glucose and L-proline was markedly inhibited by 1.0 mM metolazone, indicating the nonspecific inhibitory action of the drug. Metolazone also inhibited efflux of D-glucose and L-proline from vesicles. Neither acetazolamide nor chlorothiazide at 0.1 to 1.0 mM inhibited BBM transport of phosphate, D-glucose, or L-proline. Metolazone did not change significantly BBM transport of Na+, suggesting that inhibition of Na+-dependent transport was not due to major changes in Na+ flux. These in vitro data indicate that metolazone inhibition of phosphate reabsorption in vivo may be due, in part, to a direct effect of metolazone on transport across the BBM of the proximal tubule.