title: Inhibition of ROMK blocks macula densa tubuloglomerular feedback yet causes renal vasoconstriction in anesthetized rats.
abstract: The Na+-K+-2Cl-cotransporter (NKCC2) on the loop of Henle is the site of action of furosemide. Because outer medullary potassium channel (ROMK) inhibitors prevent reabsorption by NKCC2, we tested the hypothesis that ROMK inhibition with a novel selective ROMK inhibitor (compound C) blocks tubuloglomerular feedback (TGF) and reduces vascular resistance. Loop perfusion of either ROMK inhibitor or furosemide caused dose-dependent blunting of TGF, but the response to furosemide was 10-fold more sensitive (IC50= 10-6M for furosemide and IC50= 10-5M for compound C). During systemic infusion, both diuretics inhibited TGF, but ROMK inhibitor was 10-fold more sensitive (compound C: 63% inhibition; furosemide: 32% inhibition). Despite blockade of TGF, 1 h of constant systemic infusion of both diuretics reduced the glomerular filtration rate (GFR) and renal blood flow (RBF) by 40-60% and increased renal vascular resistance (RVR) by 100-200%. Neither diuretic altered blood pressure or hematocrit. Proximal tubule hydrostatic pressures (PPT) increased transiently with both diuretics (compound C: 56% increase; furosemide: 70% increase) but returned to baseline. ROMK inhibitor caused more natriuresis (3,400 vs. 1,600% increase) and calciuresis (1,200 vs. 800% increase) but less kaliuresis (33 vs. 167% increase) than furosemide. In conclusion, blockade of ROMK or Na+-K+-2Cl-transport inhibits TGF yet increases renal vascular resistance. The renal vasoconstriction was independent of volume depletion, blood pressure, TGF, or PPT.
authors.affiliation: Hypertension Research Center and Division of Nephrology and Hypertension, Georgetown University, Washington, District of Columbia; and araujo.magali@gmail.com.
authors.forename: Magali
authors.initials: M
authors.lastname: Araujo
authors.affiliation: Hypertension Research Center and Division of Nephrology and Hypertension, Georgetown University, Washington, District of Columbia; and.
authors.forename: William J
authors.initials: WJ
authors.lastname: Welch
authors.affiliation: Department of Cardiometabolic Diseases, Merck & Company, Incorporated, Kenilworth, New Jersey.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Department of Cardiometabolic Diseases, Merck & Company, Incorporated, Kenilworth, New Jersey.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Sullivan
authors.affiliation: Department of Cardiometabolic Diseases, Merck & Company, Incorporated, Kenilworth, New Jersey.
authors.forename: Shawn
authors.initials: S
authors.lastname: Walsh
authors.affiliation: Department of Cardiometabolic Diseases, Merck & Company, Incorporated, Kenilworth, New Jersey.
authors.forename: Alexander
authors.initials: A
authors.lastname: Pasternak
authors.affiliation: Hypertension Research Center and Division of Nephrology and Hypertension, Georgetown University, Washington, District of Columbia; and.
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Wilcox
mesh_terms: D000768:Anesthesia, General; D000818:Animals; D002118:Calcium / Q000652:urine; D004232:Diuretics / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005246:Feedback; D005665:Furosemide / Q000494:pharmacology; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006874:Hydrostatic Pressure; D007678:Kidney Glomerulus / Q000098:blood supply* / Q000187:drug effects* / Q000378:metabolism; D007684:Kidney Tubules / Q000098:blood supply* / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D023421:Models, Animal; D009318:Natriuresis / Q000187:drug effects; D011188:Potassium / Q000652:urine; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D024661:Potassium Channels, Inwardly Rectifying / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D012079:Renal Circulation / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D049994:Sodium Potassium Chloride Symporter Inhibitors / Q000494:pharmacology; D064466:Solute Carrier Family 12, Member 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D014655:Vascular Resistance / Q000187:drug effects; D014661:Vasoconstriction / Q000187:drug effects*; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
chemical_list: D004232:Diuretics; C510692:Kcnj1 protein, rat; D026902:Potassium Channel Blockers; D024661:Potassium Channels, Inwardly Rectifying; C578716:Slc12a1 protein, rat; D049994:Sodium Potassium Chloride Symporter Inhibitors; D064466:Solute Carrier Family 12, Member 1; D014662:Vasoconstrictor Agents; D005665:Furosemide; D011188:Potassium; D002118:Calcium
keywords: glomerular filtration rate; outer medullary potassium channel; tubuloglomerular feedback; vasoconstriction