Endogenous ouabain and aldosterone are coelevated in the circulation of patients with essential hypertension

Tentori, Stefano; Messaggio, Elisabetta; Brioni, Elena; Casamassima, Nunzia; Simonini, Marco; Zagato, Laura; Hamlyn, John M.; Manunta, Paolo; Lanzani, Chiara

doi:10.1097/hjh.0000000000001042

Cited by 22 publications

(17 citation statements)

References 33 publications

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“…45 Hypertensive patients have elevated circulating EO levels which are positively correlated with higher BP, higher plasma Na concentrations and increased proximal tubular reabsorption. 46,47 EO is also higher in patients with kidney failure 48 , myocardial infarction 49 and congestive heart failure. 50 Multiple studies have described the association of genetic variants in HSD3B1 with hypertension or BP variation.…”

Section: Discussionmentioning

confidence: 97%

Genome-Wide and Gene-Based Meta-Analyses Identify Novel Loci Influencing Blood Pressure Response to Hydrochlorothiazide

Wang¹,

Rizzi²,

Gong³

et al. 2017

Hypertension

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This study aimed to identify novel loci influencing the antihypertensive response to hydrochlorothiazide monotherapy. A genome-wide meta-analysis of blood pressure response to hydrochlorothiazide was performed in 1739 white hypertensives from six clinical trials within the International Consortium for Antihypertensive Pharmacogenomics Studies (ICAPS), making it the largest study to date of its kind. No signals reached genome-wide significance (P<5×10−8) and the suggestive regions (P<10−5) were cross-validated in two black cohorts treated with hydrochlorothiazide. Additionally, a gene-based analysis was performed on candidate genes with previous evidence of involvement in diuretic response, in blood pressure regulation or in hypertension susceptibility. Using the genome-wide meta-analysis approach, with validation in blacks, we identified two suggestive regulatory regions linked to GJA1 and FOXA1, relevant for cardiovascular and kidney function. With the gene-based approach, we identified HSD3B1 as significantly associated with blood pressure response (P<2.28×10−4). HSD3B1 encodes the 3beta-HSD enzyme and plays a crucial role in the biosynthesis of aldosterone and endogenous ouabain. By amassing all of the available pharmacogenomic studies of blood pressure response to hydrochlorothiazide, and using two different analytical approaches, we identified three novel loci influencing blood pressure response to hydrochlorothiazide. The gene-based analysis, never before applied to pharmacogenomics of antihypertensive drugs to our knowledge, provided a powerful strategy to identify a locus of interest, and which was not identified in the single-SNP analysis due to high allelic heterogeneity. These data pave the way for future investigations on new pathways and drug targets to enhance the current understanding of personalized antihypertensive treatment.

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Section: Discussionmentioning

confidence: 97%

Genome-Wide and Gene-Based Meta-Analyses Identify Novel Loci Influencing Blood Pressure Response to Hydrochlorothiazide

Wang¹,

Rizzi²,

Gong³

et al. 2017

Hypertension

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“…Another incompletely solved issue represents endogenous ouabain (EO) or ouabain-like compounds. These compounds were reported to be released in response to ACTH, angiotensin II and sodium administration and to be linked to aldosterone levels [58,69,70]. On the one hand, the secretion of EO is supposed to cause vasoconstriction and hypertension and thus could explain synergistic effects of aldosterone and high dietary salt intake.…”

Section: Synergistic Effects Of Aldosterone Excess and High Salt Dietmentioning

confidence: 99%

Salt Appetite and its Effects on Cardiovascular Risk in Primary Aldosteronism

et al. 2020

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First described in 1955 by Jerome W. Conn, primary aldosteronism (PA) today is well established as a relevant cause of secondary hypertension and accounts for about 5–10 % of hypertensives. The importance of considering PA is based on its deleterious target organ damage far beyond the effect of elevated blood pressure and on PA being a potentially curable form of hypertension. Aside the established contributory role of high dietary salt intake to arterial hypertension and cardiovascular disease, high salt intake is mandatory for aldosterone-mediated deleterious effects on target-organ damage in patients with primary aldosteronism. Consequently, counselling patients on the need to reduce salt intake represents a major component in the treatment of PA to minimize cardiovascular damage. Unfortunately, in PA patients salt intake is high and far beyond the target values of 5 g per day, recommended by the World Health Organization. Insufficient patient motivation for lifestyle interventions can be further complicated by enhancing effects of aldosterone on salt appetite, via central and gustatory pathways. In this context, treatment for PA by adrenalectomy results in a spontaneous decrease in dietary salt intake and might therefore provide further reduction of cardiovascular risk in PA than specific medical treatment alone. Furthermore, there is evidence from clinical studies that even after sufficient treatment of PA dietary salt intake remains a relevant prognostic factor for cardiovascular risk. This review will focus on the synergistic benefits derived from both blockade of aldosterone-mediated effects and reduction in dietary salt intake on cardiovascular risk.

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“…Are the latter humoral features present among some patients with hypertension? In a recent study involving 590 patients with never-treated mild-to-moderate essential hypertension, co-elevated circulating levels of EO and aldosterone were found in approximately one-third of the patients ( 82 ). In addition, it has long been known that co-elevated levels of EO and aldosterone occur in ~50% of patients with aldosterone-producing adrenal adenomas but, intriguingly, not among patients with hyperaldosteronism due to bilateral hyperplasia ( 83 , 84 , 85 ).…”

Section: Brain Ang II and Neuroendocrine Control Of The Circulationmentioning

confidence: 99%

Update on angiotensin II: new endocrine connections between the brain, adrenal glands and the cardiovascular system

Leenen

Blaustein

Hamlyn

2017

Endocrine Connections

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In the brain, angiotensinergic pathways play a major role in chronic regulation of cardiovascular and electrolyte homeostasis. Increases in plasma angiotensin II (Ang II), aldosterone, [Na+] and cytokines can directly activate these pathways. Chronically, these stimuli also activate a slow neuromodulatory pathway involving local aldosterone, mineralocorticoid receptors (MRs), epithelial sodium channels and endogenous ouabain (EO). This pathway increases AT1R and NADPH oxidase subunits and maintains/further increases the activity of angiotensinergic pathways. These brain pathways not only increase the setpoint of sympathetic activity per se, but also enhance its effectiveness by increasing plasma EO and EO-dependent reprogramming of arterial and cardiac function. Blockade of any step in this slow pathway or of AT1R prevents Ang II-, aldosterone- or salt and renal injury-induced forms of hypertension. MR/AT1R activation in the CNS also contributes to the activation of sympathetic activity, the circulatory and cardiac RAAS and increase in circulating cytokines in HF post MI. Chronic central infusion of an aldosterone synthase inhibitor, MR blocker or AT1R blocker prevents a major part of the structural remodeling of the heart and the decrease in LV function post MI, indicating that MR activation in the CNS post MI depends on aldosterone, locally produced in the CNS. Thus, Ang II, aldosterone and EO are not simply circulating hormones that act on the CNS but rather they are also paracrine neurohormones, locally produced in the CNS, that exert powerful effects in key CNS pathways involved in the long-term control of sympathetic and neuro-endocrine function and cardiovascular homeostasis.

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Endogenous ouabain and aldosterone are coelevated in the circulation of patients with essential hypertension

Abstract: Among patients with essential hypertension, circulating endogenous ouabain and Aldo are typically coelevated and their BP is salt-sensitive. In conditions where Aldo is inappropriately elevated, both Aldo and endogenous ouabain may contribute to adverse cardiovascular and renal outcomes.

Cited by 22 publications

References 33 publications

Genome-Wide and Gene-Based Meta-Analyses Identify Novel Loci Influencing Blood Pressure Response to Hydrochlorothiazide

Genome-Wide and Gene-Based Meta-Analyses Identify Novel Loci Influencing Blood Pressure Response to Hydrochlorothiazide

Salt Appetite and its Effects on Cardiovascular Risk in Primary Aldosteronism

Update on angiotensin II: new endocrine connections between the brain, adrenal glands and the cardiovascular system

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