Influence of aldosterone vs endothelin receptor antagonism on renovascular function in liquorice‐induced hypertension

Quaschning, Thomas; Ruschitzka, Frank; Niggli, Bernhard; Lunt, Carolyn Mb; Shaw, Sidney; Christ, Michael; Wehling, Martin; Lüscher, Thomas F.

doi:10.1093/ndt/16.11.2146

Cited by 18 publications

(10 citation statements)

References 23 publications

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“…Based on evidence derived from animal models [12,13] and in particular from treatment studies with ET receptor antagonists [14,44,45] , ET-1 is known to contribute to various forms of hypertension, especially to malignant hypertension, salt-sensitive hypertension [46] and pregnancy-induced hypertension [47] . Our present data suggest that it is not the activity of the ET system on its own but rather an imbalance between the ET and NO system that contributes to the development of hypertension.…”

Section: Discussionmentioning

confidence: 99%

Lack of iNOS Impairs Endothelial Function in Endothelin-1 Transgenic Mice

Quaschning

Voß²,

Herzfeld³

et al. 2008

Kidney Blood Press Res

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Background: Endothelin-1 (ET-1) is one of the most potent biologic vasoconstrictors. Nevertheless, transgenic mice overexpressing ET-1 exhibit normal blood pressure. We hypothesized that in states of ET-1 overproduction, the lack of counterregulatory mediators such as nitric oxide (NO), produced by the inducible NO synthase (iNOS), may critically impair endothelial function and may result in blood pressure elevation. Methods: We generated crossbred animals of ET transgenic mice (ET+/+) and iNOS knockout mice (iNOS–/–) and evaluated blood pressure and endothelial function in these animals. Endothelium-dependent and -independent vascular function was assessed as relaxation/contraction of isolated preconstricted aortic rings to acetylcholine, sodium nitroprusside, and ET-1, alone or in the presence of BQ123 or BQ788. Results: Systolic blood pressure was similar in ET+/+, iNOS–/– and wild-type mice, but was significantly elevated in ET+/+ iNOS–/– crossbred animals versus ET+/+ mice. Maximum endothelium-dependent relaxation was enhanced in ET+/+ mice (95 ± 5 vs. 78 ± 5% of preconstriction in wild-type littermates; p < 0.05). Additional knockout of iNOS led to a significant decrease of endothelium-dependent relaxation in combined ET+/+ iNOS–/– animals (75 ± 6%; p < 0.05 vs. ET+/+ mice). Endothelium-independent relaxation was comparable among all groups. Maximum vascular contraction to ET-1 was reduced in ET+/+ mice (33 ± 4%), iNOS–/– mice (38 ± 5%) and ET+/+ iNOS–/– mice (44 ± 4%) to a similar extent as compared with wild-type littermates (66 ± 4%; p < 0.05). Conclusions: Our data show for the first time that in transgenic mice overexpressing human ET-1, additional knockout of iNOS results in impaired endothelium-dependent vasodilatation thus contributing to elevated blood pressure in ET+/+ iNOS–/– animals.

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Section: Discussionmentioning

confidence: 99%

Lack of iNOS Impairs Endothelial Function in Endothelin-1 Transgenic Mice

Quaschning

Voß²,

Herzfeld³

et al. 2008

Kidney Blood Press Res

Self Cite

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“…Animal models have also provided experimental evidence that aldosterone is capable of inducing endothelial dysfunction. Aortic rings and isolated renal artery segments have been shown to exhibit endothelial dysfunction upon exposure to high mineralocorticoid levels, and spironolactone restored normal endothelial function (51). Further evidence in support of the ability of aldosterone to cause endothelial dysfunction comes from rabbits fed a pro‐atherosclerotic diet; in these animals, endothelial function as well as superoxide formation were improved by spironolactone therapy (52).…”

Section: Aldosterone and Heart Failurementioning

confidence: 99%

Neurohormones and heart failure: the importance of aldosterone

Odedra

Ferro

2008

International Journal of Clinical Practice

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Heart failure is a major cause of cardiovascular morbidity and mortality and its incidence is on the increase. The pathophysiology of heart failure is multi-factorial but recent studies suggest that aldosterone plays an important and independent role in its progression. Emerging evidence now suggests that aldosterone exerts renal-independent effects. It binds to its mineralocorticoid receptor to produce direct effects on the myocardium and vasculature, leading to damaging processes such as hypertrophy, necrosis, fibrosis and endothelial dysfunction, factors known to contribute to the pathophysiology of heart failure. Mineralocorticoid receptor antagonists have thus emerged as a new paradigm for the treatment of heart failure. The benefits of these agents on both morbidity and mortality when used in patients with chronic symptomatic heart failure have been demonstrated by recent trials.

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“…Dexamethasone decreases endothelin receptors in the kidney and the nonselective endothelin antagonist, bosentan, does not modify ACTHinduced hypertension in rats [21••]. However, chronic use of a specific ETA receptor antagonist normalizes BP in 11β HSD inhibitor-induced hypertension in the rat [35]. Such an approach deserves evaluation in hypercortisolemic humans.…”

Section: Effects On Vasopressor Action In the Systemic Vasculaturementioning

confidence: 99%

Glucocorticoid excess and hypertension

Baid

Nieman

2004

Current Science Inc

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Cushing's syndrome is a rare disorder characterized by chronic, excess glucocorticoid exposure. Hypertension is one of the most discriminating features of the disease, as it is present in 80% of patients. Patients with Cushing's syndrome have a mortality rate four times that of the general population, most likely secondary to an increased number of cardiovascular risk factors, including hypertension. In this article, we review several pathogenetic mechanisms of glucocorticoid-induced hypertension, including the role of sodium/water and mineralocorticoid excess, as well as involvement of the vasculature and kidney. Although treatment of hypertension with available antihypertensive medications is only moderately successful, after cure of Cushing's syndrome, approximately 30% of patients have persistent hypertension.

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Influence of aldosterone vs endothelin receptor antagonism on renovascular function in liquorice‐induced hypertension

Abstract: In GA-induced hypertension, both aldosterone receptor antagonism and endothelin receptor antagonism normalize blood pressure and improve renovascular function and, thus, may represent a new therapeutic approach in cardiovascular disease associated with impaired 11beta-HSD2 activity.

Cited by 18 publications

References 23 publications

Lack of iNOS Impairs Endothelial Function in Endothelin-1 Transgenic Mice

Lack of iNOS Impairs Endothelial Function in Endothelin-1 Transgenic Mice

Neurohormones and heart failure: the importance of aldosterone

Glucocorticoid excess and hypertension

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