Endogenous prostaglandin E2 mediates inhibition of rat thick ascending limb Cl reabsorption in chronic hypercalcemia.
The hypothesis that endogenous PGE2 mediates defective thick ascending limb (TAL) Cl reabsorption (percent delivered load: FRCl%) in rats with vitamin D-induced chronic hypercalcemia (HC) was tested by measuring FRCl% in loop segments microperfused in vivo in HC and control rats treated acutely with indomethacin (Indo) or its vehicle, and obtaining the corresponding outer medullary [PGE2]. Microperfusion conditions were developed in which FRCl% was exclusively furosemide sensitive. To determine the cellular mechanism, tubules were perfused acutely with forskolin (FSK), cAMP, or the protein kinase C inhibitor staurosporine (SSP). Outer medullary [PGE2] in HC rats was 9 to 10 times greater than control and could be normalized by Indo. FRCl% was 20% lower in HC rats infused with vehicle, and Indo, FSK, and cAMP returned FRCl% to normal despite sustained HC. Indo or FSK had no effect on FRCl% in control rats and Indo did not prevent inhibition of FRCl% by luminal PGE2 (1 microM). Luminal SSP (10(-7), 10(-8) M) in HC did not return FRCl% to control values. We conclude that impaired TAL FRCl% in HC occurs at a pre-cAMP site and is due to endogenous PGE2 and not to HC.
Departments of Physiology and Paediatrics, University of Ottawa, Ontario, Canada.
L N
LN
Peterson
A J
AJ
McKay
J S
JS
Borzecki
D000470:Alkaloids / Q000494:pharmacology; D000818:Animals; D001693:Biological Transport, Active / Q000187:drug effects; D002712:Chlorides / Q000378:metabolism*; D002908:Chronic Disease; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000494:pharmacology; D004097:Dihydrotachysterol / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism*; D005665:Furosemide / Q000494:pharmacology; D006934:Hypercalcemia / Q000139:chemically induced / Q000503:physiopathology*; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D007679:Kidney Medulla / Q000503:physiopathology*; D007685:Kidney Tubules, Collecting / Q000503:physiopathology*; D008297:Male; D010477:Perfusion; D051381:Rats; D017207:Rats, Sprague-Dawley; D019311:Staurosporine
D000470:Alkaloids; D002712:Chlorides; D005576:Colforsin; D005665:Furosemide; D000242:Cyclic AMP; D019311:Staurosporine; D015232:Dinoprostone; D004097:Dihydrotachysterol; D007213:Indomethacin