PMID- 26887831
OWN - NLM
STAT- MEDLINE
DCOM- 20170629
LR  - 20240325
IS  - 1522-1466 (Electronic)
IS  - 1931-857X (Print)
IS  - 1522-1466 (Linking)
VI  - 310
IP  - 8
DP  - 2016 Apr 15
TI  - Angiotensin II-mediated hypertension impairs nitric oxide-induced NKCC2 
      inhibition in thick ascending limbs.
PG  - F748-F754
LID - 10.1152/ajprenal.00473.2015 [doi]
AB  - In thick ascending limbs (THALs), nitric oxide (NO) decreases NaCl reabsorption 
      via cGMP-mediated inhibition of Na-K-2Cl cotransporter (NKCC2). In angiotensin 
      (ANG II)-induced hypertension, endothelin-1 (ET-1)-induced NO production by THALs 
      is impaired. However, whether this alters NO's natriuretic effects and the 
      mechanisms involved are unknown. In other cell types, ANG II augments 
      phosphodiesterase 5 (PDE5)-mediated cGMP degradation. We hypothesized that 
      NO-mediated inhibition of NKCC2 activity and stimulation of cGMP synthesis are 
      blunted via PDE5 in ANG II-induced hypertension. Sprague-Dawley rats were infused 
      with vehicle or ANG II (200 ng.kg(-1).min(-1)) for 5 days. ET-1 reduced NKCC2 
      activity by 38 +/- 13% (P < 0.05) in THALs from vehicle-treated rats but not from 
      ANG II-hypertensive rats (Delta: -9 +/- 13%). A NO donor yielded similar results as 
      ET-1. In contrast, dibutyryl-cGMP significantly decreased NKCC2 activity in both 
      vehicle-treated and ANG II-hypertensive rats (control: Delta-44 +/- 15% vs. ANG II: 
      Delta-41 +/- 10%). NO increased cGMP by 2.08 +/- 0.36 fmol/mug protein in THALs from 
      vehicle-treated rats but only 1.06 +/- 0.25 fmol/mug protein in ANG II-hypertensive 
      rats (P < 0.04). Vardenafil (25 nM), a PDE5 inhibitor, restored NO's ability to 
      inhibit NKCC2 activity in THALs from ANG II-hypertensive rats (Delta: -60 +/- 9%, P < 
      0.003). Similarly, NO's stimulation of cGMP was also restored by vardenafil 
      (vehicle-treated: 1.89 +/- 0.71 vs. ANG II-hypertensive: 2.02 +/- 0.32 fmol/mug 
      protein). PDE5 expression did not differ between vehicle-treated and ANG 
      II-hypertensive rats. We conclude that NO-induced inhibition of NKCC2 and 
      increases in cGMP are blunted in ANG II-hypertensive rats due to PDE5 activation. 
      Defects in the response of THALs to NO may enhance NaCl retention in ANG 
      II-induced hypertension.
CI  - Copyright (c) 2016 the American Physiological Society.
FAU - Ramseyer, Vanesa D
AU  - Ramseyer VD
AD  - Hypertension and Vascular Research Division, Department of Internal Medicine, 
      Henry Ford Health System, Detroit, Michigan; vramseye@med.wayne.edu.
AD  - Department of Physiology, School of Medicine, Wayne State University, Detroit, 
      Michigan; and.
FAU - Ortiz, Pablo A
AU  - Ortiz PA
AD  - Hypertension and Vascular Research Division, Department of Internal Medicine, 
      Henry Ford Health System, Detroit, Michigan.
AD  - Department of Physiology, School of Medicine, Wayne State University, Detroit, 
      Michigan; and.
FAU - Carretero, Oscar A
AU  - Carretero OA
AD  - Hypertension and Vascular Research Division, Department of Internal Medicine, 
      Henry Ford Health System, Detroit, Michigan.
FAU - Garvin, Jeffrey L
AU  - Garvin JL
AD  - Hypertension and Vascular Research Division, Department of Internal Medicine, 
      Henry Ford Health System, Detroit, Michigan.
AD  - Department of Physiology and Biophysics, Case Western Reserve University, 
      Cleveland, Ohio.
LA  - eng
GR  - P01 HL028982/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20160217
PL  - United States
TA  - Am J Physiol Renal Physiol
JT  - American journal of physiology. Renal physiology
JID - 100901990
RN  - 0 (Endothelin-1)
RN  - 0 (Nitric Oxide Donors)
RN  - 0 (Phosphodiesterase 5 Inhibitors)
RN  - 0 (Solute Carrier Family 12, Member 1)
RN  - 11128-99-7 (Angiotensin II)
RN  - 31C4KY9ESH (Nitric Oxide)
RN  - 3616-08-8 (Cyclic CMP)
RN  - 5O8R96XMH7 (Vardenafil Dihydrochloride)
RN  - 64649-87-2 (dibutyryl cyclic-3',5'-cytidine monophosphate)
RN  - EC 3.1.4.35 (Cyclic Nucleotide Phosphodiesterases, Type 5)
RN  - EC 3.1.4.35 (Pde5a protein, rat)
RN  - H2D2X058MU (Cyclic GMP)
SB  - IM
MH  - *Angiotensin II
MH  - Animals
MH  - Cyclic CMP/analogs & derivatives/pharmacology
MH  - Cyclic GMP/metabolism
MH  - Cyclic Nucleotide Phosphodiesterases, Type 5/metabolism
MH  - Endothelin-1/*pharmacology
MH  - Hypertension/chemically induced/*metabolism
MH  - Loop of Henle/drug effects/*metabolism
MH  - Male
MH  - Nitric Oxide/*metabolism
MH  - Nitric Oxide Donors/pharmacology
MH  - Phosphodiesterase 5 Inhibitors/pharmacology
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Solute Carrier Family 12, Member 1/*metabolism
MH  - Vardenafil Dihydrochloride/pharmacology
PMC - PMC4835923
OTO - NOTNLM
OT  - cGMP
OT  - endothelin-1
OT  - kidney
OT  - phosphodiesterase 5
OT  - sodium transport
EDAT- 2016/02/19 06:00
MHDA- 2017/07/01 06:00
PMCR- 2017/04/15
CRDT- 2016/02/19 06:00
PHST- 2015/10/19 00:00 [received]
PHST- 2016/02/05 00:00 [accepted]
PHST- 2016/02/19 06:00 [pubmed]
PHST- 2017/07/01 06:00 [medline]
PHST- 2016/02/19 06:00 [entrez]
PHST- 2017/04/15 00:00 [pmc-release]
AID - ajprenal.00473.2015 [pii]
AID - F-00473-2015 [pii]
AID - 10.1152/ajprenal.00473.2015 [doi]
PST - ppublish
SO  - Am J Physiol Renal Physiol. 2016 Apr 15;310(8):F748-F754. doi: 
      10.1152/ajprenal.00473.2015. Epub 2016 Feb 17.