The ability of adenosine 5'-triphosphate (ATP) to suppress the contractile response of guinea pig urinary bladder to nonadrenergic, noncholinergic nerve stimulation was investigated. Strips of guinea pig urinary bladder were incubated for 1 h at 37 degrees C in a modified Krebs solution containing atropine (2 X 10(-7) M), guanethidine (1 X 10(-6) M), and indomethacin (5.5 X 10(-6) M). Four successive administrations of ATP, guanosine, 5'-triphosphate (GTP), and cytidine 5'-triphosphate (CTP), each at 5 X 10(-4) M, in the absence of washout resulted in complete desensitization of the tissue to the contractile effect of the nucleotide. Strips desensitized to GTP or CTP were also nonresponsive to ATP. The response of the strips to electrical stimulation (100 V, 0.1-ms pulse, 5-s train at 3 Hz) was markedly reduced following desensitization with ATP but only slightly with GTP or CTP. Under similar conditions, adenosine 5'-monophosphatase (AMP) or diphosphate (ADP) or adenosine (A) also reduced the response of the strips to intramural nerve stimulation, but guanosine 5'-monophosphate (GMP) or diphosphate (GDP), guanosine (G), cytidine 5'-monophosphate (CMP) or diphosphate (CDP), or cytidine (C) did not. The present data suggest that desensitization of smooth muscle to exogenous ATP may be predominantly the result of its conversion to metabolic products rather than inactivation of "purinergic" receptor per se.