Lead inhibits Ca(2+)-stimulated nitric oxide synthase activity from rat cerebellum

Pb2+ is reported to cause cognitive dysfunctions in children and to inhibit long-term potentiation (LTP), a model form of synaptic plasticity that involves nitric oxide (NO). Since Pb2+ interacts with Ca(2+)-calmodulin, and brain nitric oxide synthase (NOS) is Ca(2+)-calmodulin regulated, we examined the effects of Pb2+ on NOS activity prepared from rat cerebellum. NOS required NADPH and was inhibited by monomethylarginine. Full NOS activity required 0.6 microM free Ca2+ and was inhibited 50% by 17 nM and 100% by 80 nM free Pb2+. NOS inhibition by Pb2+ was reversible by increasing free Ca2+ concentrations. Evaluation of other divalent cations resulted in the following ranked order of potencies: Cu2+ > Pb2+ >> Zn2+; Fe2+, Ba2+, Mg2+, Mn2+, and Sr2+ were ineffective. These results suggest that Pb2+ inhibition of brain NOS activity may account for some of the effects of Pb2+ on the CNS.