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Effects of isoprostane on tubuloglomerular feedback: roles of TP receptors, NOS, and salt intake

Division of Nephrology and Hypertension, Georgetown University Medical Center, Washington, District of Columbia

Submitted 21 July 2004 ; accepted in final form 17 December 2004

A thromboxane prostanoid receptor (TP-R) agonist U-46,619 enhances tubuloglomerular feedback (TGF). Glomerular expression of TP-R and enhancement of TGF by U-46,619 increase with salt intake. We investigated the hypothesis that 8-isoprostaglandin F₂ (8-Iso) activates TGF via TP-R. The maximal TGF response in rats was assessed from the fall in proximal stop flow pressure (PSF; an index of glomerular capillary pressure) during loop of Henle (LH) microperfusion of artificial tubular fluid (ATF) at 40 nl/min. Microperfusion of 8-Iso (10^–4 M) into the efferent arteriole (EA) enhanced TGF responses by 20 ± 3% (P < 0.01). TGF response to 8-Iso was independent of dietary salt [TGF%, low salt (LS): 21 ± 5%; normal salt (NS): 17 ± 4%; high salt (HS): 29 ± 8%, not significant (ns)], unlike the salt-dependent effect of U-46,619 (TGF%, LS: 41 ± 5%; NS: 52 ± 4%; HS: 112 ± 21%). Ifetroban, the TP-R antagonist, abolished TGF responses to 8-Iso and U-46,619 at all levels of salt intake. During luminal perfusion of N-monomethyl-L-arginine (L-NMA), the effect of 8-Iso on TGF was enhanced in NS and HS but not in LS (LS: 22 ± 6 vs. LS + L-NMA: 28 ± 6%, ns; NS: 18 ± 4 vs. NS + L-NMA: 40 ± 4, P < 0.01; HS: 27 ± 3 vs. HS + L-NMA: 65 ± 6, P < 0.01). However, U-46,619 did not further increase TGF after L-NMA in all salt groups (LS: 43 ± 7 vs. LS + L-NMA: 51 ± 6, ns; NS: 52 ± 7 vs. NS + L-NMA: 48 ± 8, ns; HS: 114 ± 21 vs. HS + L-NMA: 74 ± 22, ns). In conclusion, activation of TP receptors by U-46,619 and 8-Iso-PGF₂ enhances TGF. In addition, the effect of U-46,619 was salt dependent, whereas the effect of 8-Iso-PGF₂ was salt independent. However, stimulation of NO by 8-isoprostanes masks its salt-sensitive effect on TGF.

8-Isoprostaglandin F₂; oxygen radicals; oxidative stress; tubuloglomerular feedback response; thromboxane A₂; nitric oxide synthase; ifetroban