ROLE OF CAMP-PHOSPHODIESTERASE ISOZYMES IN PATHOGENESIS OF MURINE NEPHROGENIC DIABETES-INSIPIDUS

To test the hypothesis that rapid adenosine 3',5'-cyclic monophosphate (cAMP) catabolism via cyclic 3',5'-nucleotide phosphodiesterase (PDE) is a cause of the unresponsiveness to vasopressin (VP) in mice with hereditary nephrogenic diabetes insipidus (NDI), we investigated properties of PDEs and other aspects of the VP-dependent cAMP-signaling system in segments of collecting ducts [inner medullary (IMCD), cortical (CCD), and outer medullary (OMCD) ducts] microdissected from control mice and mice with NDI. The activity of cAMP-PDE, but not of cGMP-PDE, was markedly higher in IMCD (+109%), and to a lesser degree in OMCD (+41%) and CCD (+27%), of NDI mice than in normal controls. The cAMP-PDE in IMCD of NDI mice was more sensitive to inhibition by the PDE isozyme-specific inhibitors rolipram and cilostamide, but not by 3-isobutyl-1-methylxanthine, than was the cAMP-PDE in controls. Levels of cAMP in intact IMCD and CCD from NDI mice completely failed to increase in response to 10(-6) M VP. Incubation with rolipram alone, but not with cilostamide alone, restored VP-dependent cAMP accumulation in IMCD of NDI mice to the levels found in control mice; addition of cilostamide further enhanced the effect of rolipram. Analogous (but quantitatively lesser) anomalies of the VP-dependent cAMP system, including the effects of PDE inhibitors, were observed also in CCD of NDI mice. However, the activity of VP-stimulated adenylate cyclase assayed in permeabilized IMCD did not differ in NDI and control mice. These results indicate that anomalously high activities of low-K(m) cAMP-PDE isozymes account for the failure of collecting ducts of NDI mice to increase cAMP levels in response in VP. We suggest that abnormally rapid breakdown of cAMP, solely or predominantly via isozyme PDE-IV, in collecting ducts of NDI mice is a major cause of resistance of these ducts to VP.