The present study was undertaken to investigate the cyclic AMP system in the isolated inner medullary collecting tubule (IMCT) of hypokalemic (HK) rats. In situ incubation of IMCT with 10(-7) M arginine vasopressin (AVP) at 300 mOsm/kg H2O in control normokalemic rats increased cyclic AMP content (fmoles/mm) from 5.68 +/- 1.41 to 30.3 +/- 5.31 (P less than 0.001). In HK rats the increase in cyclic AMP was blunted from 7.18 +/- 2.0 to 14.78 +/- 3.14 fmoles/mm (P less than 0.05 compared to controls). No such blunting was observed in the outer medullary collecting duct of hypokalemic rats, but was seen in the IMCT when studied at 800 (P less than 0.05), 1200 (P less than 0.01), and 2000 mOsm/kg H2O (P less than 0.05). The increase in cyclic AMP was also blunted in IMCT of HK rats not allowed to become polyuric or polydipsic by pair-watering studied at 300, 800, and 1200 mOsm/kg H2O. To define the process responsible for the failure to normally increase cyclic AMP in HK, adenylate cyclase activity (AC) was determined at 800 mOsm/kg H2O. While basal AC was not different, the response to all concentrations of AVP between 10(-10) and 10(-6) M was markedly depressed in tubules from HK rats. In contrast AC response to 10(-2) M NaF was not different in IMCT of normokalemic and HK rats. While the abnormal cyclic AMP content with AVP could be explained by abnormal generation, a contribution of increased metabolism was also sought.(ABSTRACT TRUNCATED AT 250 WORDS)