Neonatal lead exposure produces selective rod degeneration and functional deficits in adult hooded rats. Similar alterations occur following retinal exposure to ouabain. This study determined whether there were long-term effects of neonatal lead exposure on rat retinal or renal Na+,K(+)-ATPase (Na,K-ATPase) activity and employed in vitro studies to examine the mechanism of ionic lead (Pb2+)-induced inhibition of retinal Na,K-ATPase. Pups, exposed to lead only via the milk of dams consuming 0, 0.02, or 0.2% lead solutions, had mean blood lead concentrations of 1.2, 18.8, and 59.4 micrograms/dl at weaning, respectively, and 5-7 micrograms/dl as adults. Prior lead exposure produced significant dose-dependent decreases in isolated retinal Na,K-ATPase activity (-11%; -26%) whereas activity in the kidney was unchanged. In contrast, Na,K-ATPase from both isolated control tissues was inhibited by Pb2+. The half-maximal inhibitory dose (I50) of Pb2+ for retinal and renal Na,K-ATPase was 5.21 x 10(-7) and 1.25 x 10(-5) M, respectively. The Hill coefficient of the retina was 0.42 whereas it was 0.88 in the kidney. With MgATP as a substrate, the Pb(2+)-induced inhibition of retinal Na,K-ATPase was competitive and reversible with a Ki of 2.1 x 10(-7) M. Retinal and renal Na,K-ATPase were 20-fold and 1.1-fold more sensitive to inhibition by Pb2+ than by Ca2+, respectively. The Pb(2+)-induced inhibition of retinal Na,K-ATPase was antagonized by Na+, potentiated by Mg2+, not altered by K+ or Ca2+, and prevented by ATP. Kinetic and competition studies with the retinal Na,K-ATPase establish that the Pb(2+)-induced inhibition is complex. The increased sensitivity of retinal, compared to renal, Na,K-ATPase to inhibition following in vivo or in vitro lead exposure may relate to their different alpha subunit composition. This is speculated to play a fundamental role in the target organ toxicity of lead.