Mechanisms of the synergistic combination of metolazone and bumetanide.

We assessed the effects of metolazone and of bumetanide alone and in combination in normal volunteers when both sodium replete and when sodium deprived. In both conditions a supra-additive natriuretic (P less than .025) and chloruretic (P less than .05) effect of the combination was observed, the magnitude of which was somewhat greater in the sodium-deprived state. Neither phosphate excretion nor an index of delivery to the diluting segment was supra-additive, indicating that the synergistic effect most likely did not emanate from the proximal tubule. In contrast, in the sodium-deprived subjects, free water clearance relative to the delivery term was diminished 72 +/- 2% with the combination compared to 64 +/- 2% for the two diuretics individually (P = .003). These data indicate that the supra-additive response is due to a synergistic effect of the combination at the diluting segment.