Role of prostaglandins in collecting duct-derived endothelin-1 regulation of blood pressure and water excretion.
Collecting duct (CD)-derived endothelin-1 (ET-1) exerts natriuretic, diuretic, and hypotensive effects. In vitro studies have implicated cyclooxygenase (COX) metabolites, and particularly PGE(2), as important mediators of CD ET-1 effects. However, it is unknown whether PGE(2) mediates CD-derived ET-1 actions in vivo. To test this, CD ET-1 knockout (KO) and control mice were studied. During normal salt and water intake, urinary PGE(2) excretion was unexpectedly increased in CD ET-1 KO mice compared with controls. Salt loading markedly increased urinary PGE(2) excretion in both groups of mice; however, the levels remained relatively higher in KO animals. Acutely isolated inner medullary collecting duct (IMCD) from KO mice also had increased PGE(2) production. The increased IMCD PGE(2) was COX-2 dependent, since NS-398 blocked all PGE(2) production. However, increased CD ET-1 KO COX-2 protein or mRNA could not be detected in inner medulla or IMCD, respectively. Inner medullary COX-1 mRNA and protein levels and IMCD COX-1 mRNA levels were unaffected by Na intake or CD ET-1 KO. KO mice on a normal or high-Na diet had elevated blood pressure compared with controls; this difference was not altered by indomethacin or NS-398 treatment. However, indomethacin or NS-398 did increase urine osmolality and reduce urine volume in KO, but not control, animals. In summary, IMCD COX-2-dependent PGE(2) production is increased in CD ET-1 KO mice, indicating that CD-derived ET-1 is not a primary regulator of IMCD PGE(2). Furthermore, the increased PGE(2) in CD ET-1 KO mice partly compensates for loss of ET-1 with respect to maintaining urinary water excretion, but not in blood pressure control.
Ge
Yuqiang
Y
Division of Nephrology, Univ. of Utah Health Sciences Center, 900 East 30 North, Salt Lake City, UT 84132, USA.
Strait
Kevin A
KA
Stricklett
Peter K
PK
Yang
Tianxin
T
Kohan
Donald E
DE
D000818:Animals; D001794:Blood Pressure / Q000502:physiology*; D015153:Blotting, Western; D000242:Cyclic AMP / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism; D019332:Endothelin-1 / Q000502:physiology*; D007213:Indomethacin / Q000494:pharmacology; D007679:Kidney Medulla / Q000378:metabolism; D007685:Kidney Tubules, Collecting / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009578:Nitrobenzenes / Q000494:pharmacology; D009994:Osmolar Concentration; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics / Q000378:metabolism; D011453:Prostaglandins / Q000502:physiology*; D012076:Renal Agents / Q000494:pharmacology; D012964:Sodium / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology; D013686:Telemetry; D014667:Vasopressins / Q000494:pharmacology; D014867:Water / Q000378:metabolism*
D016861:Cyclooxygenase Inhibitors; D019332:Endothelin-1; D009578:Nitrobenzenes; D011453:Prostaglandins; D012076:Renal Agents; D013449:Sulfonamides; D014867:Water; D014667:Vasopressins; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D012964:Sodium; D000242:Cyclic AMP; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone; D007213:Indomethacin