Involvement of endothelins in deoxycorticosterone acetate–salt hypertension through the modulation of noradrenergic transmission in the rat posterior hypothalamus

Abstract

What is the central question of this study? Does ex vivo administration of endothelin-1 and endothelin-3 regulate noradrenergic transmission in the posterior hypothalamus of deoxycorticosterone acetate–salt hypertensive rats compared with normotensive rats? What is the main finding and its importance? Endothelin-1 and endothelin-3 enhanced diverse mechanisms leading to increased noradrenergic transmission in the posterior hypothalamus of deoxycorticosterone acetate–salt hypertensive rats. Unveiling the role of brain endothelins in hypertension would probably favour the development of new therapeutic targets for the treatment of essential hypertension, which still represents a challenging disease with high mortality. Brain catecholamines participate in diverse biological functions regulated by the hypothalamus. We have previously reported that endothelin-1 and endothelin-3 (ET-1 and ET-3) modulate catecholaminergic activity in the anterior and posterior hypothalamus of normotensive rats. The aim of the present study was to evaluate the interaction between endothelins and noradrenergic transmission in the posterior hypothalamus of deoxycorticosterone acetate (DOCA)–salt hypertensive rats. We assessed the effects of ET-1 and ET-3 on tyrosine hydroxylase activity and expression, neuronal noradrenaline (NA) release, neuronal NA transporter (NAT) activity and expression, monoamine oxidase activity and NA endogenous content and utilization (as a marker of turnover) in the posterior hypothalamus of DOCA–salt hypertensive rats. In addition, levels of ETA and ETB receptors were assayed in normotensive and hypertensive rats. Results showed that tyrosine hydroxylase activity and total and phosphorylated levels, NAT activity and content, NA release, monoamine oxidase activity and NA utilization were increased in DOCA–salt rats. Both ET-1 and ET-3 further enhanced all noradrenergic parameters except for total tyrosine hydroxylase level and NA endogenous content and utilization. The expression of ETA receptors was increased in the posterior hypothalamus of DOCA–salt rats, but ETB receptors showed no changes. These results show that ET-1 and ET-3 upregulate noradrenergic activity in the posterior hypothalamus of DOCA–salt hypertensive rats. Our findings suggest that the interaction between noradrenergic transmission and the endothelinergic system in the posterior hypothalamus may be involved in the development and/or maintenance of hypertension in this animal model.