Induction of intramembranous particle clusters in mice with nephrogenic diabetes insipidus.
In mice with hereditary nephrogenic diabetes insipidus (NDI), the inability of vasopressin to increase hydraulic water permeability is reflected in a lack of intramembranous particle (IMP) clusters in apical membranes of inner medullary collecting ducts. The lack arises from anomalously high activity of one or two isozymes of adenosine 3',5'-cyclic monophosphate-phosphodiesterase (cAMP-PDE). We asked whether inhibition of these isozymes with rolipram and cilostamide would raise not only the tissue content of cAMP but also and simultaneously restore IMP clusters. Inner medullary collecting ducts from NDI mice were incubated in vitro. Tissue content of cAMP (fmol of cAMP per bundle) and number of IMP clusters (per 100 microns 2 of principal cell apical membrane) were, respectively: control, 44.8 +/- 13.0 and 4.16 +/- 1.49; arginine vasopressin (AVP), 31.7 +/- 8.0 and 3.98 +/- 1.56; rolipram and cilostamide, 109.7 +/- 21.0 and 58.09 +/- 15.74; and AVP plus rolipram and cilostamide, 305.7 +/- 75 and 48.63 +/- 11.03 (with the last four values showing significant difference from control and AVP only, respectively). In addition, treating NDI mice with rolipram and cilostamide in vivo reduced their high fluid turnover. We conclude that failure by AVP to increase cAMP in cells of collecting ducts, which results from anomalously high activity of one or two specific isozymes of cAMP-PDE, is the major or sole cause for the excretion of hypotonic urine in NDI mice (DI +/+ Severe strain).
Coffey
A K
AK
Department of Physiology, Dartmouth Medical School, Hanover, New Hampshire 03756.
O'Sullivan
D J
DJ
Homma
S
S
Dousa
T P
TP
Valtin
H
H
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors; D000818:Animals; D002462:Cell Membrane / Q000378:metabolism / Q000648:ultrastructure; D000242:Cyclic AMP / Q000378:metabolism; D003919:Diabetes Insipidus / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D005614:Freeze Fracturing; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D007674:Kidney Diseases / Q000150:complications*; D051379:Mice; D008817:Mice, Mutant Strains; D008854:Microscopy, Electron; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D011760:Pyrrolidinones / Q000494:pharmacology; D015363:Quinolones / Q000494:pharmacology; D020889:Rolipram
D007527:Isoenzymes; D010726:Phosphodiesterase Inhibitors; D011760:Pyrrolidinones; D015363:Quinolones; C021294:cilostamide; D000242:Cyclic AMP; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D020889:Rolipram