Human bronchial rings were contracted with histamine (3 microM), and inhibitory responses were obtained with electrical field stimulation (EFS) in the presence of propranolol (1 microM), atropine (1 microM), and indomethacin (3 microM). These nonadrenergic noncholinergic (NANC) relaxations were frequency-dependent (1 to 32 Hz) and inhibited by either tetrodotoxin or Nw-nitro-L-arginine (L-NNA, 100 microM). The selective cAMP-specific phosphodiesterase (PDE) type IV inhibitors rolipram (3 microM) and Ro 20-1724 (3 microM) significantly potentiated NANC relaxations at each frequency of stimulation. The selective cGMP-specific PDE type V inhibitor zaprinast (3 microM) failed to significantly alter the maximal NANC response, but it caused a slight potentiation of the response at lower frequencies. The adenylyl cyclase stimulant forskolin, the nitric oxide donor compound 3-morpholinosydnonimine (SIN-1), and the guanylyl cyclase stimulant sodium nitroprusside caused concentration-dependent relaxation of histamine-contracted airway smooth muscle. Rolipram significantly potentiated the relaxation elicited by forskolin. Rolipram also potentiated responses to SIN-1 and sodium nitroprusside. Considered together these data support the hypothesis that cAMP plays a facilitory role in NANC relaxation of the human bronchi.