(Hypertension. 1998;31:499.)
© 1998 American Heart Association, Inc.
Scientific Contributions |
ETA Receptor Blockade Prevents Increased Tissue Endothelin-1, Vascular Hypertrophy, and Endothelial Dysfunction in Salt-Sensitive Hypertension
From Cardiology, University Hospital Zürich, and Cardiovascular Research Laboratory, Instititute of Physiology, University of Zürich; Cardiology and Department of Clinical Research, University Hospital Bern (S.S.); and Department of Ophthalmic Pathology, Eye Clinic, University Hospital Basel (P.M.), Switzerland
Correspondence to Thomas F. Lüscher, MD, FACC, FESC, Professor and Head of Cardiology, University Hospital, CH-8091 Zürich, Switzerland. E-mail 100771.1237{at}compuserve.com
Sodium plays an important role in the pathogenesis and therapy of hypertension, a major risk factor for cardiovascular disease. This study investigated the involvement of endothelin in vascular alterations in salt-induced Dahl hypertension. Salt-sensitive (DS) and salt-resistant (DR) Dahl rats were treated with a high-sodium diet (NaCl 4%) with or without ETA receptor antagonist LU135252 for two months, and effects of treatments on systolic blood pressure, vascular endothelin-1 (ET-1) protein content, aortic hypertrophy, and vascular reactivity of isolated aortic rings were studied. In DS rats, a high-sodium diet increased systolic pressure (190±4 versus 152±2 mm Hg, P<.05) and aortic ET-1 protein content (4.2-fold, P<.0001) and induced aortic hypertrophy as assessed by tissue weight (P<.0001). Sodium diet markedly reduced NO-mediated endothelium-dependent relaxations to acetylcholine (49±4% versus 81±4%, P<.0001) and contractions to ET-1 (92±7 versus 136±8% of KCl, P=.0011). ET-1 tissue levels were highly and inversely correlated with endothelium-dependent relaxations (r=0.931, P<.0001) and contractions to ET (r=0.77, P=.0007). LU135252 treatment reduced systolic blood pressure only in part (168±3 versus 190±4 mm Hg. P<.05) but normalized sodium-induced changes of vascular reactivity, tissue ET-1 protein content, and vascular structure (P<.001 versus sodium). None of these effects were observed in DR rats. These results suggest that ET-1 acts as a local mediator of vascular dysfunction and aortic hypertrophy in Dahl salt-induced hypertension. ETA receptor antagonism may have therapeutic potential for lowering vascular ET-1 content, improving endothelial function, and preventing structural changes in salt-sensitive hypertension.
Key Words: Dahl hypertension • endothelium • endothelin • nitric oxide • sodium • ETA receptors • vascular hypertrophy
Abbreviations: big ET-1 = big endothelin-1 • DOCA = deoxycorticosterone acetate • DR = Dahl salt-resistant rat • DS = Dahl salt-sensitive rat • eNOS = endothelial nitric oxide synthase • ET-1 = endothelin-1 • KCl = potassium chloride • L-NAME = NG-L-nitro arginine methyl ester • LU135252 = ETA receptor antagonist • NO = nitric oxide
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