부산대학교 도서관

Collecting duct (CD)-derived endothelin-1 (ET-1) exerts natriuretic, diuretic, and hypotensive effects. In vitro studies have implicated cyclooxygenase (COX) metabolites, and particularly POE2, as important mediators of CD ET- I effects. However, it is unknown whether POE2 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 POE2 excretion was unexpectedly increased in CD ET-1 KO mice compared with controls. Salt loading markedly increased urinary POE2 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 POE2 production. The increased IMCD PGE2 was COX-2 dependent, since NS-398 blocked all POE2 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 POE2 production is increased in CD ET-1 KO mice, indicating that CD- derived ET-1 is not a primary regulator of IMCD POE2. Furthermore, the increased POE2 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. [ABSTRACT FROM AUTHOR]