Mechanism of phosphaturia elicited by administration of phosphonoformate in vivo.
We examined whether phosphonoformate (PFA) can cause phosphaturia through its direct action on brush-border membrane (BBM) in vivo. Infusion of PFA or of parathyroid hormone (PTH) to thyroparathyroidectomized rats caused a marked increase in fractional excretion of phosphate without changes in excretion of Na+ or of GFR. The PFA-induced phosphaturia was not accompanied by an increase in urinary adenosine-3',5'-cyclic monophosphate (cAMP); moreover, PFA added in vitro did not influence the PTH-sensitive adenylate cyclase and cAMP-phosphodiesterase in proximal convoluted tubules. In BBM vesicles (BBMV) from rats with PFA-elicited phosphaturia, neither the rate of Na+-Pi symport nor Na+-dependent binding of [14C]PFA on BBMV was changed, whereas in BBMV from PTH-infused rats the Vmax of Na+-Pi symport decreased. PFA is almost completely ultrafiltrable; no metabolic transformation of PFA was detected after [14C]PFA exposure to rat renal cortical slices, homogenate, or to blood. We conclude that PFA causes phosphaturia by direct inhibition of Na+-Pi symport across BBM in proximal tubules, acting from the luminal side. Thus PFA (foscarnet) has a unique direct mechanism of phosphaturic effect, via its action on Pi reabsorption in proximal tubules in vivo.
VanScoy
M
M
Department of Medicine, Mayo Clinic, Mayo Medical School, Rochester, Minnesota 55905.
Loghman-Adham
M
M
Onsgard
M
M
Szczepanska-Konkel
M
M
Homma
S
S
Knox
F G
FG
Dousa
T P
TP
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000378:metabolism; D000042:Absorption; D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D000242:Cyclic AMP / Q000652:urine; D017245:Foscarnet; D005919:Glomerular Filtration Rate / Q000187:drug effects; D007668:Kidney / Q000187:drug effects / Q000502:physiology* / Q000648:ultrastructure; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008871:Microvilli / Q000187:drug effects / Q000502:physiology; D009318:Natriuresis / Q000187:drug effects; D009943:Organophosphorus Compounds / Q000494:pharmacology*; D010281:Parathyroid Hormone / Q000494:pharmacology; D010710:Phosphates / Q000378:metabolism / Q000652:urine*; D010746:Phosphonoacetic Acid / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D012964:Sodium / Q000378:metabolism
D009943:Organophosphorus Compounds; D010281:Parathyroid Hormone; D010710:Phosphates; D017245:Foscarnet; D012964:Sodium; D000242:Cyclic AMP; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D000262:Adenylyl Cyclases; D010746:Phosphonoacetic Acid