ET A Receptor Blockade Prevents Increased Tissue Endothelin-1, Vascular Hypertrophy, and Endothelial Dysfunction in Salt-Sensitive Hypertension

Abstract

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 ET A 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. ET A receptor antagonism may have therapeutic potential for lowering vascular ET-1 content, improving endothelial function, and preventing structural changes in salt-sensitive hypertension.