Chronic endothelin A receptor blockade attenuates contribution of sympathetic nervous system to salt hypertension development in adult but not in young Dahl rats

Abstract

Endothelin-1 (ET-1) plays an important role in the pathogenesis of salt-dependent forms of hypertension in adult rats, but its participation in salt hypertension elicited in immature rats is still unknown. Therefore, we compared ET-1 role in the development or the maintenance of salt hypertension induced in young (4-week-old) or adult (12-week-old) Dahl rats. The contribution of pressor ET-1 effects to the maintenance of high blood pressure (BP) was studied using acute injection of ET(A) receptor antagonist ambrisentan (BSF 208075, 1 mg kg(-1) iv) to young or adult rats with established salt hypertension. Furthermore, using chronic ambrisentan treatment (30 mg kg(-1) day(-1) in the drinking fluid during 5 weeks of high salt intake), we investigated the age-dependent involvement of ET(A) receptors in salt hypertension development in these two age groups. Acute ET(A) receptor blockade lowered BP in both age groups of salt hypertensive Dahl rats more than in rats fed a low-salt diet (but without any age-dependent difference). Chronic ET(A) receptor blockade strongly attenuated the development of salt hypertension and cardiac hypertrophy in adult rats, but it had no significant effects on salt hypertension in young animals. Pronounced BP reduction induced in adult salt hypertensive rats by chronic ambrisentan treatment was attributed to attenuated sympathetic BP component, without changes in nitric oxide (NO)-dependent BP regulation. In contrast, chronic ambrisentan treatment of young animals did not modify sympathetic BP component but substantially attenuated NO-dependent vasodilatation. ET(A) receptor-mediated ET-1 effects play an important role in salt hypertension of adult but not young Dahl rats.