title: The in vivo and in vitro effect of calmodulin antagonists on the renal actions of 25(OH) vitamin D3 in the rat.
abstract: Previous work from this laboratory has demonstrated that 25(OH) vitamin D3 [25(OH)D3] acutely suppresses the phosphaturic action of parathyroid hormone (PTH) and interferes with the PTH-induced activation of adenylate cyclase (AC). Calmodulin inhibitors block vitamin D-induced Ca2+ transport in the gut and phosphorus uptake in renal BBMV's. We have examined whether calmodulin antagonists affect the renal action of 25(OH)D3. Acute clearance experiments were performed in PTH-infused parathyroidectomized rats receiving 25(OH)D3 after pretreatment with trifluoperazine (TFP) or promethazine (P). In vitro PTH-induced activation of renal AC was also studied in membrane preparations from pretreated rats in the presence of 25(OH)D3. 25(OH)D3 reduced the PTH-stimulated increase in fractional excretion of phosphorus (CP/CIn) from 0.292 +/- 0.024 to 0.195 +/- 0.018 (p less than 0.005) and urinary cAMP from 149.3 +/- 20.3 to 78.1 +/- 10.4 pmol/min (p less than 0.01) and also blunted AC activation in vitro. TFP but not P abolished the effects of 25(OH)D3 both in vivo and in vitro. R 24571 also abolished the in vitro effect of 25(OH)D3. Thus, (1) TFP abolishes both the antiphosphaturic and the AC/cAMP-related actions of 25(OH)D3, (2) P does not have these effects, and (3) R 24571 abolishes the in vitro effect of 25(OH)D3. These results suggest that the antiphosphaturic effect of 25(OH)D3 acting via the AC/cAMP system may be calmodulin dependent.
authors.affiliation: Nephrology Services, Hadassah University Hospital, Jerusalem, Israel.
authors.forename: M M
authors.initials: MM
authors.lastname: Friedlaender
authors.forename: D
authors.initials: D
authors.lastname: Darmon
authors.forename: H
authors.initials: H
authors.lastname: Wald
authors.forename: M M
authors.initials: MM
authors.lastname: Popovtzer
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D002112:Calcifediol / Q000378:metabolism / Q000494:pharmacology*; D002118:Calcium / Q000097:blood; D002147:Calmodulin / Q000037:antagonists & inhibitors*; D000242:Cyclic AMP / Q000652:urine; D005919:Glomerular Filtration Rate / Q000187:drug effects; D007668:Kidney / Q000378:metabolism*; D007672:Kidney Cortex / Q000187:drug effects / Q000201:enzymology; D008297:Male; D010280:Parathyroid Glands / Q000601:surgery; D010281:Parathyroid Hormone / Q000494:pharmacology; D010758:Phosphorus / Q000097:blood / Q000652:urine; D051381:Rats; D014268:Trifluoperazine / Q000494:pharmacology*
chemical_list: D002147:Calmodulin; D010281:Parathyroid Hormone; D014268:Trifluoperazine; D010758:Phosphorus; D000242:Cyclic AMP; D000262:Adenylyl Cyclases; D002112:Calcifediol; D002118:Calcium