Effects of isoprostane on tubuloglomerular feedback: roles of TP receptors, NOS, and salt intake.
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 F(2alpha) (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 [DeltaTGF%, 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 (DeltaTGF%, 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-PGF(2alpha) enhances TGF. In addition, the effect of U-46,619 was salt dependent, whereas the effect of 8-Iso-PGF(2alpha) was salt independent. However, stimulation of NO by 8-isoprostanes masks its salt-sensitive effect on TGF.
Welch
William J
WJ
Division of Nephrology and Hypertension, Georgetown Univ. Medical Center, Bldg. D-395, 4000 Reservoir Rd. NW, Washington, DC 20057, USA. welchw@georgetown.edu
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D000818:Animals; D015237:Dinoprost / Q000031:analogs & derivatives* / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D025461:Feedback, Physiological / Q000187:drug effects; D007678:Kidney Glomerulus / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism*; D007684:Kidney Tubules / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D052248:Nitric Oxide Synthase Type I; D051381:Rats; D017207:Rats, Sprague-Dawley; D017482:Receptors, Thromboxane / Q000378:metabolism*; D012079:Renal Circulation / Q000187:drug effects / Q000502:physiology; D017673:Sodium Chloride, Dietary / Q000494:pharmacology; D014662:Vasoconstrictor Agents / Q000494:pharmacology*; D019323:omega-N-Methylarginine / Q000494:pharmacology
D004791:Enzyme Inhibitors; D009419:Nerve Tissue Proteins; D017482:Receptors, Thromboxane; D017673:Sodium Chloride, Dietary; D014662:Vasoconstrictor Agents; C075750:8-epi-prostaglandin F2alpha; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D015237:Dinoprost; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; C496322:Nos1 protein, rat