Cellular mechanism of lithium-induced nephrogenic diabetes insipidus in rats.
One of the mechanisms by which Li evokes polyuria is thought to be impairment of arginine vasopressin (AVP)-sensitive adenylate cyclase (AdC) in cells of the renal collecting duct. To investigate how AdC is influenced by chronic administration of Li, we created nephrogenic diabetes insipidus (NDI) in rats and microdissected the medullary collecting tubule from both control and NDI rats. In the NDI group, the 10(-6) M AVP-stimulated cAMP contents failed to increase completely, and the levels were significantly lower than that of the control group (10.4 +/- 1.4 vs. 48.4 +/- 4.7 fmol/mm, P less than 0.001). Pretreatment with pertussis toxin (PT), an inhibitor of inhibitory G protein (Gi), did not affect the basal cAMP levels in both groups, although it increased AVP-stimulated cAMP production in the NDI group in a dose- and time-dependent manner. AVP-stimulated cAMP production with over 100 ng/ml PT in the NDI group reached the levels observed in the control group. Incubation with cholera toxin, an agonist of stimulatory G protein (Gs), increased the cAMP content in the two groups to almost equal levels. To exclude the possibility that prostaglandin E2 (PGE2) is involved in the cellular mechanism of Li-induced NDI, the effect of indomethacin (Indo) on PT action was examined. However, Indo (10(-5) M) did not influence either the basal or AVP-dependent cAMP contents. From these results it is suggested that Li impairs AVP-sensitive AdC not through inhibition of Gs but through activation of Gi and that PGE2 may not be involved in the cellular pathogenesis of NDI at least in the rat at the step of cAMP formation.
Yamaki
M
M
Department of Medicine, Jichi Medical School, Tochigi, Japan.
Kusano
E
E
Tetsuka
T
T
Takeda
S
S
Homma
S
S
Murayama
N
N
Asano
Y
Y
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D037361:Adenylate Cyclase Toxin; D000818:Animals; D001127:Arginine Vasopressin / Q000494:pharmacology*; D002712:Chlorides / Q000633:toxicity*; D002772:Cholera Toxin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D003919:Diabetes Insipidus / Q000139:chemically induced / Q000378:metabolism*; D019204:GTP-Binding Proteins / Q000378:metabolism; D007213:Indomethacin / Q000494:pharmacology; D007684:Kidney Tubules / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D007700:Kinetics; D008094:Lithium / Q000633:toxicity*; D018021:Lithium Chloride; D008297:Male; D037342:Pertussis Toxin; D011141:Polyuria / Q000139:chemically induced / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D012016:Reference Values; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D037361:Adenylate Cyclase Toxin; D002712:Chlorides; D010566:Virulence Factors, Bordetella; D001127:Arginine Vasopressin; D002772:Cholera Toxin; D008094:Lithium; D000242:Cyclic AMP; D037342:Pertussis Toxin; D019204:GTP-Binding Proteins; D018021:Lithium Chloride; D015056:1-Methyl-3-isobutylxanthine; D007213:Indomethacin