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The role of intracellular guanosine 3′,5′-cyclic monophosphate concentration ([cGMP]_i) in nitric oxide (NO)-mediated relaxations in the uterus has become controversial. We found the NO donorS-nitroso-l-cysteine (CysNO) to potently (IC₅₀ = 30 nM) inhibit spontaneous contractions in the nonpregnant human myometrium. CysNO treatment increased [cGMP]_i significantly (P < 0.001), and this increase was blocked by the guanylyl cyclase inhibitors methylene blue (10 μM) or LY-83583 (1 μM); however, pretreatment with these guanylyl cyclase inhibitors failed to block CysNO-mediated relaxations. Intracellular cAMP concentrations were not altered by treatment of tissues with 10 μM CysNO. Incubation with the cGMP analogs 8-bromo-cGMP or β-phenyl-1,N ²-etheno-cGMP did not significantly affect spontaneous contractility. Pretreatment of tissues with charybdotoxin [a calcium-dependent potassium channel (BK …