We have investigated the relationship between cAMP and sodium,potassium-ATPase (Na+,K(+)-ATPase) activity in the sciatic nerves of rats treated with cilostazol, a potent phosphodiesterase inhibitor; iloprost, a stable prostacyclin analog; or (Bu)2cAMP, a cAMP analog, which increase cAMP content by different mechanisms. In in vivo studies, administration of cilostazol (20 mg/kg BW.day), iloprost (4 micrograms/kg BW.day), or (Bu)2cAMP (4 mg/kg BW.day) for 4 weeks restored decreased cAMP content and Na+,K(+)-ATPase activity in the sciatic nerves of diabetic rats and further improved motor nerve conduction velocities without alteration of myo-inositol contents. There was a positive correlation between cAMP contents and Na+,K(+)-ATPase activities in the sciatic nerves. In in vitro experiments, cAMP accumulation and Na+,K(+)-ATPase activity in the desheathed sciatic nerve blocks obtained from both normal and diabetic rats were significantly increased by incubation with cilostazol, iloprost, or (Bu)2cAMP. In addition, cAMP accumulation and Na+,K(+)-ATPase activities in endoneurial preparations incubated in both normal and high glucose buffer were also significantly increased by cilostazol, iloprost, and (Bu)2cAMP. These results strongly suggest that there is a close relationship between cAMP content and Na+,K(+)-ATPase activity in rat sciatic nerves. Therefore, cAMP content may play an important role in the development of diabetic neuropathy by modulating Na+,K(+)-ATPase activity in the peripheral nerves.