The contribution of the loop segments to lithium reabsorption in sodium-replete, anesthetized Sprague-Dawley rats was examined by perfusing superficial loops of Henle between late proximal convolutions and early distal tubules. Preliminary experiments in which lithium was initially present only inside or outside the perfused loop confirmed substantial permeability of one or more of the loop segments to lithium. In subsequent experiments, in which lithium was infused intravenously and included in the perfusate so that the perfusate-to-plasma lithium concentration ratio was close to that found in late proximal tubules during lithium clearance studies, lithium reabsorption was inversely related to the perfusion rate: values for fractional lithium reabsorption (FRLi) at perfusion rates of 10, 20, and 30 nl/min were 58 +/- 3, 17 +/- 2, and 2 +/- 2%, respectively. Bumetanide (10(-6) M) markedly inhibited FRLi but also reduced water reabsorption, suggesting an effect on the pars recta at this dose; 10(-7) M bumetanide, which was without effect on water reabsorption, had only a small effect on FRLi at a perfusion rate of 10 nl/min but reduced FRLi by approximately 70% at 20 nl/min. We argue that the remarkable flow dependency of lithium reabsorption, together with its bumetanide sensitivity, provides evidence for significant voltage-driven lithium reabsorption in the thick ascending limb of Henle.