We investigated, using rat brain cortex supernatant as a source of guanylate cyclase (GC), whether sodium nitroprusside (SNP) can not only activate but also inhibit GC. SNP (I and 10 microM) activated the rat brain GC; however, at higher concentrations GC activation was reduced, resulting in a bell-shaped concentration-activation curve. Preincubation of GC with 10 microM SNP attenuated GC activation by SNP, S-nitroso-N-acetylpenicillamine (SNAP) or 3-morpholinosydnonimine-N-ethyl-carbamine (SIN). Such inhibitory effects of SNP were partially supressed by a nitric oxide (NO) scavenger oxyhemoglobin. The preincubation of GC with K4Fe(CN)6 (a carrier molecule for SNP but devoid of NO) had no inhibitory effects on GC activation. These results indicate that SNP, probably through NO, has dual effects on GC activity, stimulation and inhibition.