What is the clinical evidence from this study?

Study design: Other. Population: Salt-sensitive hypertension. Intervention: ET(A) receptor antagonist LU135252 vs. High-sodium diet without LU135252. Primary outcome: Systolic blood pressure (p=<.05).

January 1, 1998Open Access

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

Q: What are the key findings of this study?

In salt-sensitive Dahl rats on a high-sodium diet, ET(A) receptor antagonist LU135252 partially reduced systolic blood pressure (168 vs 190 mm Hg, P<0.05) and normalized vascular reactivity.

Key Result

In salt-sensitive Dahl rats on a high-sodium diet, ET(A) receptor antagonist LU135252 partially reduced systolic blood pressure (168 vs 190 mm Hg, P<0.05) and normalized vascular reactivity.

Structured PICO

Does ET(A) receptor antagonist LU135252 prevent vascular dysfunction and aortic hypertrophy in salt-sensitive Dahl rats on a high-sodium diet?

Population

Dahl salt-sensitive and salt-resistant rats treated with a high-sodium diet with or without ET(A) receptor antagonist LU135252 for two months.

Intervention

ET(A) receptor antagonist LU135252 added to a high-sodium diet (NaCl 4%) for two months

Comparator

High-sodium diet (NaCl 4%) without LU135252

Outcome

Systolic blood pressure, vascular endothelin-1 (ET-1) protein content, aortic hypertrophy, and vascular reactivity of isolated aortic ringssurrogate

ET(A) receptor antagonism prevents vascular dysfunction, aortic hypertrophy, and increased tissue ET-1 in a rat model of salt-sensitive hypertension.

Main Result

Absolute Event Rate: 168% vs 190%

p-value: p=<.05

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.