1. This study was designed to test the hypothesis that acid-base status affects the response to a loop diuretic in human subjects. The renal responses to bumetanide (1 mg intravenously) were studied in eight normal subjects consuming a constant diet supplemented for 3 days on three separate occasions with equivalent quantities of NaCl, NaHCO3 (metabolic alkalosis) or NH4Cl (metabolic acidosis). 2. A significant (P < 0.025) reduction in bumetanide-induced diuresis (-40%), natriuresis (-21%), and chloruresis (-25%) was observed during NaHCO3 compared with NaCl. The renal response was unaltered during NH4Cl. 3. The creatinine and para-aminohippurate clearances were unchanged during NaHCO3, as were the blood pressure and plasma levels of renin activity, aldosterone and noradrenaline, and the plasma volume. 4. Bumetanide excretion was increased during NaHCO3 compared with NaCl (2.13 +/- 0.18 versus 1.76 +/- 0.17 micrograms/min, P < 0.025) but was not changed during NH4Cl (1.68 +/- 0.26 micrograms/min; not significant). 5. Plasma aldosterone concentration was increased 3-fold during acidosis and the kaliuretic response to bumetanide was enhanced significantly. 6. In conclusion, compared with NaCl, NaHCO3 reduces the diuretic, natriuretic and chloruretic response to bumetanide without significant changes in renal haemodynamics, plasma volume, the renin-angiotensin-aldosterone axis or the sympathetic nervous system, and despite increasing renal bumetanide excretion. NH4Cl enhances aldosterone secretion and diuretic-induced kaliuresis.