title: Tubuloglomerular and connecting tubuloglomerular feedback during inhibition of various Na transporters in the nephron.
abstract: Afferent (Af-Art) and efferent arterioles resistance regulate glomerular capillary pressure. The nephron regulates Af-Art resistance via: 1) vasoconstrictor tubuloglomerular feedback (TGF), initiated in the macula densa via Na-K-2Cl cotransporters (NKCC2) and 2) vasodilator connecting tubuloglomerular feedback (CTGF), initiated in connecting tubules via epithelial Na channels (ENaC). Furosemide inhibits NKCC2 and TGF. Benzamil inhibits ENaC and CTGF. In vitro, CTGF dilates preconstricted Af-Arts. In vivo, benzamil decreases stop-flow pressure (PSF), suggesting that CTGF antagonizes TGF; however, even when TGF is blocked, CTGF does not increase PSF, suggesting there is another mechanism antagonizing CTGF. We hypothesize that in addition to NKCC2, activation of Na/H exchanger (NHE) antagonizes CTGF, and when both are blocked CTGF dilates Af-Arts and this effect is blocked by a CTGF inhibitor benzamil. Using micropuncture, we studied the effects of transport inhibitors on TGF responses by measuring PSF while increasing nephron perfusion from 0 to 40 nl/min. Control TGF response (-7.9 ± 0.2 mmHg) was blocked by furosemide (-0.4 ± 0.2 mmHg; P < 0.001). Benzamil restored TGF in the presence of furosemide (furosemide: -0.2 ± 0.1 vs. furosemide+benzamil: -4.3 ± 0.3 mmHg; P < 0.001). With furosemide and NHE inhibitor, dimethylamiloride (DMA), increase in tubular flow increased PSF (furosemide+DMA: 2.7 ± 0.5 mmHg, n = 6), and benzamil blocked this (furosemide+DMA+benzamil: -1.1 ± 0.2 mmHg; P < 0.01, n = 6). We conclude that NHE in the nephron decreases PSF (Af-Art constriction) when NKCC2 and ENaC are inhibited, suggesting that in the absence of NKCC2, NHE causes a TGF response and that CTGF dilates the Af-Art when TGF is blocked with NKCC2 and NHE inhibitors.
authors.affiliation: Division of Hypertension and Vascular Research, Department of Internal Medicine, Henry Ford Hospital, Detroit, Michigan;
authors.forename: Hong
authors.initials: H
authors.lastname: Wang
authors.affiliation: Division of Hypertension and Vascular Research, Department of Internal Medicine, Henry Ford Hospital, Detroit, Michigan;
authors.forename: Martin A
authors.initials: MA
authors.lastname: D'Ambrosio
authors.affiliation: Division of Hypertension and Vascular Research, Department of Internal Medicine, Henry Ford Hospital, Detroit, Michigan;
authors.forename: YiLin
authors.initials: Y
authors.lastname: Ren
authors.affiliation: Division of Hypertension and Vascular Research, Department of Internal Medicine, Henry Ford Hospital, Detroit, Michigan;
authors.forename: Sumit R
authors.initials: SR
authors.lastname: Monu
authors.affiliation: Division of Hypertension and Vascular Research, Department of Internal Medicine, Henry Ford Hospital, Detroit, Michigan;
authors.forename: Pablo
authors.initials: P
authors.lastname: Leung
authors.affiliation: Division of Hypertension and Vascular Research, Department of Internal Medicine, Henry Ford Hospital, Detroit, Michigan;
authors.forename: Kristopher
authors.initials: K
authors.lastname: Kutskill
authors.affiliation: Division of Hypertension and Vascular Research, Department of Internal Medicine, Henry Ford Hospital, Detroit, Michigan; Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, Ohio; and.
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Garvin
authors.affiliation: Division of Hypertension and Vascular Research, Department of Internal Medicine, Henry Ford Hospital, Detroit, Michigan;
authors.forename: Branislava
authors.initials: B
authors.lastname: Janic
authors.affiliation: Department of Public Health Sciences, Henry Ford Hospital, Detroit, Michigan.
authors.forename: Edward L
authors.initials: EL
authors.lastname: Peterson
authors.affiliation: Division of Hypertension and Vascular Research, Department of Internal Medicine, Henry Ford Hospital, Detroit, Michigan; ocarret1@hfhs.org.
authors.forename: Oscar A
authors.initials: OA
authors.lastname: Carretero
mesh_terms: D000584:Amiloride / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D001160:Arterioles / Q000187:drug effects / Q000502:physiology; D062686:Epithelial Sodium Channel Blockers / Q000494:pharmacology*; D053503:Epithelial Sodium Channels / Q000187:drug effects* / Q000378:metabolism; D005246:Feedback; D005665:Furosemide / Q000494:pharmacology*; D007678:Kidney Glomerulus / Q000098:blood supply / Q000187:drug effects* / Q000378:metabolism; D007684:Kidney Tubules / Q000098:blood supply / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D009399:Nephrons / Q000187:drug effects* / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D012079:Renal Circulation / Q000187:drug effects; D012964:Sodium / Q000378:metabolism*; D049994:Sodium Potassium Chloride Symporter Inhibitors / Q000494:pharmacology*; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors* / Q000378:metabolism; D064466:Solute Carrier Family 12, Member 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013997:Time Factors; D014661:Vasoconstriction / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects
chemical_list: D062686:Epithelial Sodium Channel Blockers; D053503:Epithelial Sodium Channels; C578716:Slc12a1 protein, rat; D049994:Sodium Potassium Chloride Symporter Inhibitors; D017923:Sodium-Hydrogen Exchangers; D064466:Solute Carrier Family 12, Member 1; C013407:benzamil; D000584:Amiloride; D005665:Furosemide; D012964:Sodium
keywords: afferent arteriole; benzamil; connecting tubuloglomerular feedback; stop-flow pressure; tubuloglomerular feedback