The role of ET-1 in HTN was initially observed in models of experimental HTN, and more recently by using genetically modified mouse models in which a component of the endothelin system was either knockdown or overexpressed in certain specific organs or tissues [27]. It should be noted that when ET-1 is overexpressed in the endothelium of transgenic mice, BP is significantly higher than in wild-type mice [28]. Moreover, selective knockout of ET-1 in the collecting duct of the nephron was associated with a higher BP and the development of salt-sensitive HTN [29]. A similar BP phenotype was obtained with the deletion of ETB or both ETA/ETB receptors in collecting duct cells, suggesting the important role of the renal endothelin system in the development of salt-sensitive HTN ^[30][31][30,31]. In non-transgenic animals, elevated ET-1 production was found in salt-sensitive and some other models of experimental HTN, such as deoxycorticosterone (DOCA)-salt HTN, DOCA-salt-treated spontaneously hypertensive rats (SHR), and Dahl salt-sensitive rats, 1-kidney 1 clip (1K1C) Goldblatt hypertensive rats, SHR 2-kidney 1 clip (2K1C) Goldblatt hypertensive rats, angiotensin II-infused rats, and stroke-prone SHR [32]. In the models known to overexpress vascular ET-1, BP significantly decreases upon the administration of selective ETA or mixed ETA/ETB receptor antagonists [33].

One of the first comparisons of ET-1 concentrations in people with HTN was made between pheochromocytoma patients and healthy controls. Higher levels of ET-1 were observed in patients with pheochromocytoma. In this report, the authors note that HTN in patients with pheochromocytoma is mainly catecholamine dependent, but may be secondarily ET-1 dependent [34]. These data are supported by previously reported cases in patients with hemangioendothelioma who have significantly elevated ET-1 levels along with HTN [35]. Elevated ET-1 levels and high BP in patients from these studies returned to normal after surgical removal of the tumors ^[34][35][34,35]. In addition, resistant HTN with elevated ET-1 levels has been observed more frequently in patients of African-American descent or those with obesity, in whom the risk of developing cardiovascular and renal diseases is increased [36]. Furthermore, in individuals with normal BP, high plasma ET-1 levels are associated with the development of HTN [37]. The role of ET-1 in the development of the hypertensive process is also supported by data in patients with essential HTN or resistant HTN, which show that when treated with a nonselective ET-receptor antagonist bosentan [38] or with the selective ETA receptor antagonist darusentan ^[39][40][41][39,40,41], BP is significantly reduced. These data are also consistent with the meta-analyses, which show that HTN patients have higher plasma concentrations of ET-1 than control subjects [42]. Other authors have reported that the levels of ET-1 are normal in patients with essential HTN, but point out that the local levels of ET-1 in the vascular wall are elevated ^[36][43][44][36,43,44]. The controversial and not always consistent results regarding ET-1 concentrations in patients with HTN are probably related to two main reasons. The first is that its elimination from the blood is too fast (plasma half-life 1–2 min) [45]. The second is that the secretion of ET-1 by ECs is polarized mainly to the underlying VSMCs, leading to a minimal increase in its circulating levels [46]. Other possible causes of these disparate results are the specificity of the antibodies used in the immunoassay, the degree of cardiovascular damage, dietary salt intake, obesity, diabetes, and race [24]. All of the above findings support the hypothesis that ET-1 may have an important pathogenetic role in the development of HTN (Table 1).