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Endothelin stimulates endothelial nitric oxide synthase expression in the thick ascending limb

Hypertension and Vascular Research Division, Henry Ford Hospital, Detroit, Michigan 48202-2689

Submitted 25 November 2003 ; accepted in final form 22 April 2004

Endothelin-1 (ET-1) acutely inhibits NaCl reabsorption by the thick ascending limb (THAL) by activating the ET_B receptor, stimulating endothelial nitric oxide synthase (eNOS), and releasing nitric oxide (NO). In nonrenal tissue, chronic exposure to ET-1 stimulates eNOS expression via the ET_B receptor and activation of phosphatidylinositol 3-kinase (PI3K). We hypothesized that ET-1 increases eNOS expression in the THAL by binding to ET_B receptors and stimulating PI3K. In primary cultures of medullary THALs treated for 24 h, eNOS expression increased by 36 ± 18% with 0.01 nM ET-1, 123 ± 30% with 0.1 nM (P < 0.05; n = 5), and 71 ± 30% with 1 nM, whereas 10 nM had no effect. BQ-788, a selective ET_B receptor antagonist, completely blocked stimulation of eNOS expression caused by 0.1 nM ET-1 (12 ± 25 vs. 120 ± 40% for ET-1 alone; P < 0.05; n = 5). BQ-123, a selective ET_A receptor antagonist, did not affect the increase in eNOS caused by 0.1 nM ET-1. Sarafotoxin c (S6c; 0.1 µM), a selective ET_B receptor agonist, increased eNOS expression by 77 ± 30% (P < 0.05; n = 6). Wortmannin (0.01 µM), a PI3K inhibitor, completely blocked the stimulatory effect of 0.1 µM S6c (77 ± 30 vs. –28 ± 9%; P < 0.05; n = 6). To test whether the increase in eNOS expression heightens activity, we measured NO release in response to simultaneous treatment with L-arginine, ionomycin, and clonidine using a NO-sensitive electrode. NO release by control cells was 337 ± 61 and 690 ± 126 pA in ET-1-treated cells (P < 0.05; n = 5). Taken together, these data suggest that ET-1 stimulates THAL eNOS, activating ET_B receptors and PI3K and thereby increasing NO production.

endothelial nitric oxide synthase; phosphatidylinositol 3-kinase

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