Four potent metalloporphyrin inhibitors of heme oxygenase were used to assess whether carbon monoxide production was required for induction of LTP in the CA1 region of the hippocampus. Although the metalloporphyrins produced a similar and substantial inhibition of heme oxygenase activity in hippocampal slices, only two compounds reduced the amount of LTP elicited by tetanic stimulation (chromium mesoporphyrin IX and zinc protoporphyrin IX). Both chromium mesoporphyrin IX and zinc protoporphyrin IX inhibited nitric oxide synthase in the hippocampus; tin mesoporphyrin IX and zinc deuteroporphyrin IX bis glycol neither reduced LTP induction nor inhibited NOS activity, although they did inhibit heme oxygenase. None of these metalloporphyrins reversed established LTP. Thus, together these data do not support carbon monoxide as a mediator in either LTP induction or expression/maintenance and emphasize further the nonselectivity of some metalloporphyrins.