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This Article Full Text Full Text (PDF) All Versions of this Article: 288/1/F58    most recent 00209.2004v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via ISI Web of Science (23) Citing Articles via Google Scholar Google Scholar Articles by Herrera, M. Articles by Garvin, J. L. Search for Related Content PubMed PubMed Citation Articles by Herrera, M. Articles by Garvin, J. L.

A high-salt diet stimulates thick ascending limb eNOS expression by raising medullary osmolality and increasing release of endothelin-1

Hypertension and Vascular Research Division, Henry Ford Hospital, Detroit, Michigan

Submitted 4 June 2004 ; accepted in final form 1 September 2004

A high-salt diet increases renal endothelin (ET) production and thick ascending limb (THAL) endothelial nitric oxide synthase (eNOS) expression. ET stimulates THAL eNOS expression via ET_B receptors. The tonicity of the renal medulla is highly variable, and hyperosmolality stimulates ET-1 synthesis by endothelial cells. We hypothesized that a high-salt diet raises medullary osmolality, increases ET release by the THAL, and thus enhances eNOS expression. Seven days of high salt (1% NaCl in drinking water) increased eNOS expression in THALs by 125 ± 31%. High salt increased outer medullary osmolality from 362 ± 13 to 423 ± 6 mosmol/kgH₂O (P < 0.05). Bosentan, a dual-ET receptor antagonist, blocked the increase in THAL eNOS expression caused by high salt (2.66 ± 0.44 absorbance units with bosentan vs. 5.15 ± 0.67 for vehicle; P < 0.05). Conscious systolic blood pressure did not differ between the two groups. In primary cultures of medullary THALs, raising osmolality from 300 to 350 and 400 mosmol/kgH₂O using NaCl increased eNOS expression by 39 ± 11% (P < 0.05) and 71 ± 16%, respectively (P < 0.05). In primary cultures of THALs, raising osmolality from 300 to 400 mosmol/kgH₂O for 1 h increased ET-1 release from 62 ± 7 to 113 ± 2 pg/mg protein (P < 0.05). BQ-788, an ET_B receptor antagonist (1 µM), blocked the stimulatory effect of 400 mosmol/kgH₂O on eNOS expression (70 ± 13% vs. –5 ± 10%; paired difference, 74 ± 15%; P < 0.05). BQ-788 alone had no significant effect. We concluded that high salt stimulates THAL eNOS expression by increasing outer medullary osmolality, ET-1 release by the THAL and ET_B receptor activation. This may be an important regulatory mechanism of THAL NaCl absorption when dietary salt intake is increased.

nitric oxide; kidney; outer medulla; Henle's loop