ETA RECEPTOR BLOCKADE PREVENTS INCREASED TISSUE ENDOTHELIN-1, VASCULAR HYPERTROPHY, AND ENDOTHELIAL DYSFUNCTION IN SALT-SENSITIVE HYPERTENSION

Sodium plays an important role in the pathogenesis and therapy of hype rtension, a major risk factor for cardiovascular disease. This study i nvestigated the involvement of endothelin in vascular alterations in s alt-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 o f treatments on systolic blood pressure, vascular endothelin-1 (ET-1) protein content, aortic hypertrophy, and vascular reactivity of isolat ed 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 N O-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 co rrelated with endothelium-dependent relaxations (r=0.931, P<.0001) and contractions to ET (r=0.77, P=.0007). LU135252 treatment reduced syst olic blood pressure only in part (168+/-3 versus 190+/-4 mmHg, P<.05) but normalized sodium-induced changes of vascular reactivity, tissue E T-1 protein content, and vascular structure (P<.001 versus sodium). No ne of these effects were observed in DR rats. These results suggest th at ET-1 acts as a local mediator of vascular dysfunction and aortic hy pertrophy in Dahl salt-induced hypertension. ETA receptor antagonism m ay have therapeutic potential for lowering vascular ET-1 content, impr oving endothelial function, and preventing structural changes in salt- sensitive hypertension.