The in vivo and in vitro effect of calmodulin antagonists on the renal actions of 25(OH) vitamin D3 in the rat.
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.
Friedlaender
M M
MM
Nephrology Services, Hadassah University Hospital, Jerusalem, Israel.
Darmon
D
D
Wald
H
H
Popovtzer
M M
MM
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*
D002147:Calmodulin; D010281:Parathyroid Hormone; D014268:Trifluoperazine; D010758:Phosphorus; D000242:Cyclic AMP; D000262:Adenylyl Cyclases; D002112:Calcifediol; D002118:Calcium