Dysfunctional renal nitric oxide synthase as a determinant of salt-sensitive hypertension: mechanisms of renal artery endothelial dysfunction and role of endothelin for vascular hypertrophy and Glomerulosclerosis.
This study investigated the role of renal nitric oxide synthase (NOS), endothelin, and possible mechanisms of renovascular dysfunction in salt-sensitive hypertension. Salt-sensitive (DS) and salt-resistant (DR) Dahl rats were treated for 8 wk with high salt diet (4% NaCl) alone or in combination with the ET(A) receptor antagonist LU135252 (60 mg/kg per d). Salt loading markedly increased NOS activity (pmol citrulline/mg protein per min) in renal cortex and medulla in DR but not in DS rats by 270 and 246%, respectively. Hypertension in DS rats was associated with renal artery hypertrophy, increased vascular and renal endothelin-1 (ET-1) protein content, and glomerulosclerosis. In the renal artery but not in the aorta of hypertensive DS rats, endothelium-dependent relaxation to acetylcholine was unchanged; however, endothelial dysfunction due to enhanced prostanoid-mediated, endothelium-dependent contractions and attenuation of basal nitric oxide release was present. Treatment with LU135252 reduced hypertension in part, but completely prevented activation of tissue ET-1 without affecting ET-3 levels. This was associated with a slight increase of renal NOS activity, normalization of endothelial dysfunction and renal artery hypertrophy, and marked attenuation of glomerulosclerosis. Thus, DS rats fail to increase NOS activity in response to salt loading. This abnormality may predispose to activation of the tissue ET-1 system, abnormal renal vasoconstriction, and renal injury. Chronic ET(A) receptor blockade normalized salt-induced changes in the renal artery and reduced glomerular injury, suggesting therapeutic potential for ET antagonists in salt-sensitive forms of hypertension.
Barton
Matthias
M
Cardiology, University Hospital Zürich and Cardiovascular Research, Institute of Physiology, University of Zürich, Switzerland.
Vos
Ingrid
I
Nephrology and Hypertension, University Hospital Utrecht, The Netherlands.
Shaw
Sidney
S
Department of Clinical Research, University Hospital Bern, Switzerland.
Boer
Peter
P
Nephrology and Hypertension, University Hospital Utrecht, The Netherlands.
D'Uscio
Livius V
LV
Cardiology, University Hospital Zürich and Cardiovascular Research, Institute of Physiology, University of Zürich, Switzerland.
Gröne
Hermann-Josef
HJ
Department of Pathology, Philipps-University Marburg, Germany.
Rabelink
Ton J
TJ
Nephrology and Hypertension, University Hospital Utrecht, The Netherlands.
Lattmann
Thomas
T
Cardiology, University Hospital Zürich and Cardiovascular Research, Institute of Physiology, University of Zürich, Switzerland.
Moreau
Pierre
P
Cardiology, University Hospital Zürich and Cardiovascular Research, Institute of Physiology, University of Zürich, Switzerland.
Lüscher
Thomas F
TF
Cardiology, University Hospital Zürich and Cardiovascular Research, Institute of Physiology, University of Zürich, Switzerland.
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000503:physiopathology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005923:Glomerulosclerosis, Focal Segmental / Q000209:etiology / Q000473:pathology; D006973:Hypertension / Q000150:complications / Q000473:pathology / Q000503:physiopathology*; D006984:Hypertrophy; D007668:Kidney / Q000201:enzymology* / Q000473:pathology; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000096:biosynthesis; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D010666:Phenylpropionates; D011743:Pyrimidines; D051381:Rats; D020303:Rats, Inbred Dahl; D012077:Renal Artery / Q000503:physiopathology*; D017673:Sodium Chloride, Dietary / Q000008:administration & dosage; D014665:Vasodilator Agents / Q000494:pharmacology
D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D004791:Enzyme Inhibitors; D010666:Phenylpropionates; D011743:Pyrimidines; D017673:Sodium Chloride, Dietary; D014665:Vasodilator Agents; D009569:Nitric Oxide; C107831:darusentan; D019001:Nitric Oxide Synthase; D000109:Acetylcholine; D019331:NG-Nitroarginine Methyl Ester