The kinetics of removal of Ni2(+) from the airways of the rat lung was studied in vivo and ex vivo. The uptake of Ni2(+) from the vasculature was investigated ex vivo. For ex vivo studies, the isolated, ventilated, and perfused lung (IVPL) was prepared using negative pressure ventilation and was perfused with Krebs-Henseleit buffer solution at 37C. Rates of removal of Ni2(+) from the airways were determined following intratracheal instillation of 1, 10, or 127 nmol 63NiCl2 in 100 microliters of isotonic sucrose. The Ni2(+) remaining in the lung was calculated from the 63Ni2(+) activity which appeared in the perfusate. Ex vivo studies revealed a concentration dependent alteration in lung permeability which was not observed in vivo. Also the rate of removal of Ni2(+) from the airways was inhibited by the presence of Ca2(+) and Mg2(+) in the perfusate. Uptake of Ni2(+) from the vasculature was studied in the IVPL supplied with NiCl2 at 0.01, 0.1, 1.0, and 10 micromole/min. The net rate of Ni2(+) varied with the supply rate and did not appear to be saturable. A two-compartment model described the efflux of Ni2(+) from the vasculature. These studies suggest that the airways of the mammalian lung are largely impermeable to inhaled Ni2(+) in the presence of physiologic concentrations of divalent cations, while uptake from the vasculature is relatively rapid.