Sodium nitroprusside produced a dose-dependent increase in extracellular levels of cGMP in the cerebellar cortex in vivo. This was independent of nitric oxide synthase activity. The metalloporphyrins zinc-protoporphyrin-IX, tin-protoporphyrin-IX and zinc-deuteroporphyrin-IX,2,4-bis glycol prevented the increase in cGMP in the cerebellar cortex produced by sodium nitroprusside. At high doses, tin-protoporphyrin-IX also decreased the basal extracellular levels of cGMP. These drugs had no effect on nitric oxide synthase activity. We conclude that the neuropharmacological effects of metalloporphyrins may result from their direct inhibition of soluble guanylyl cyclase, rather than from an effect on carbon monoxide synthesis.