I.v. dose-response data obtained from renal clearance studies in anesthetized dogs indicated that bumetanide was approximately 30-fold more potent than furosemide in enhancing Na excretion. After the administration of 0.01 mg/kg of bumetanide or 1.0 mg/kg of furosemide, the relationship between i.v. diuretic activity and tissue distribution was evaluated. In dog renal clearance experiments, bumetanide and furosemide significantly enhanced urine flow, Na and K excretion. Inulin clearance as an estimate of glomerular filtration rate was not altered by either drug, but Na reabsorption was decreased with bumetanide (13%) and furosemide (12%). At these diuretic doses, both compounds were bound to dog plasma protein to about the same extent (86-91%), although total plasma levels were 100-fold higher for furosemide. Within 1/2 h after the i.v. administration of 14C-bumetanide or 14C-furosemide, 86-99% of the 14C in urine, plasma, kidney and liver appeared as unchanged drug. One min after maximal diuresis bumetanide had a higher affinity (3-fold) for kidney compared to furosemide. A possible explanation for the i.v. diuretic potency difference between these 2 compounds is offered. The lack of significant difference in plasma protein binding and the absence of urinary metabolites of either drug suggest that other factors may also contribute to the marked differences in diuretic activity between bumetanide and furosemide.