Effect of Adrenal Suppression with Dexamethasone in Essential Hypertension*

Hamilton, Bruce P.; Zadik, Zvi; Edwin, Chandra; Hamilton, Jennifer H.; Kowarski, A. Avinoam

doi:10.1210/jcem-48-5-848

Cited by 25 publications

(4 citation statements)

References 19 publications

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“…47 It is also relevant that very early studies reported that a proportion of patients with essential hypertension showed a good blood pressure response to low-dose dexamethasone treatment, perhaps consistent with the notion that ACTH was sustaining production of a hypertensinogenic adrenal steroid. 48 Although the precise mechanism of this was never established, it is of interest to speculate that subjects who responded in this way had the defect in 11␤-hydroxylation that we describe. Interestingly, a similar suggestion that a pituitary-derived peptide might lead to adrenal hyperplasia and aldosterone excess in a subgroup of patients with aldosteronism was made Ͼ10 years ago on the basis of histological and biochemical data.…”

Section: Implications Of Altered 11␤-hydroxylation In Hypertensionmentioning

confidence: 79%

Is Altered Adrenal Steroid Biosynthesis a Key Intermediate Phenotype in Hypertension?

et al. 2003

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Abstract-Approximately 10% of patients with hypertension have a high ratio of aldosterone to renin, but the reason for this and the relationships among low-renin essential hypertension, elevation of the ratio, and true primary aldosteronism are unclear. We have previously reported that a polymorphism of the gene (C-to-T conversion at position Ϫ344) encoding aldosterone synthase is associated with hypertension, particularly in patients with a high ratio. However, the most consistent association with this variant is a relative impairment of adrenal 11␤-hydroxylation. In this review, we propose that altered conversion of deoxycortisol to cortisol leads to a subtle, chronic increase in adrenocortrophin drive to the adrenal cortex, with eventual development of hyperplasia. In combination with other genetic or environmental factors (such as dietary sodium intake), we suggest that this might be responsible for the long-term development of a resetting of the aldosterone response to angiotensin II, giving rise to the phenotype of hypertension with a raised ratio.In some subjects, this may progress further to true primary aldosteronism with a dominant adrenal nodule. Thus, there may be a genetically influenced continuum from hypertension with a normal ratio, through hypertension with a raised ratio, and primary aldosteronism. Key Words: hypertension, mineralocorticoid Ⅲ adrenal gland Ⅲ aldosterone Ⅲ adrenocorticotropic hormone Despite many years of research, the pathophysiology of essential hypertension remains uncertain, and it seems likely that no single cause exists. This may best be appreciated by considering the lessons from rodent models of hypertension. Here, selective inbreeding has generated strains that develop high blood pressure through a range of distinct mechanisms. For example, the role of adducin in the Milan hypertensive rat contrasts with the involvement of corticosteroids in the Dahl salt-sensitive strain; in each instance, distinct genetic loci can be identified to account for the development of high blood pressure. 1,2 Nevertheless, in both types of hypertension, the phenotype is exacerbated by sodium loading, and only careful study of the intermediate phenotype (in this instance, measurement of adrenal steroid production) allows the pathogenesis to be understood. The same argument can be applied to human hypertension, and it would be naïve to anticipate that the same underlying mechanism was present in all patients with high blood pressure. However, careful study of subgroups might identify common mechanisms that account for the rise in pressure and offer guidance to the best therapeutic option. In this regard, the contribution of adrenal steroids deserves careful review. At a gross level, of course, corticosteroids clearly do have an important role in the development of hypertension. Patients with Addison's disease are hypotensive, 3 glucocorticoid excess in patients with Cushing's syndrome is associated with high blood pressure, 4 and the role of a major excess of aldosterone in classic Conn's synd...

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Section: Implications Of Altered 11␤-hydroxylation In Hypertensionmentioning

confidence: 79%

Is Altered Adrenal Steroid Biosynthesis a Key Intermediate Phenotype in Hypertension?

et al. 2003

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“…Thus, over a very long period, the genetic change in 11β-hydroxylation efficiency (along with an additional environmental or genetic influence) might result in ACTH-driven adrenal zonal hyperplasia and an alteration (steepening of the dose–response relationship) of the response of aldosterone to Ang II and potassium. It is pertinent that very early studies reported that a proportion of patients with essential hypertension showed a good BP response to low-dose dexamethasone treatment, seemingly supporting the suggestion that ACTH was sustaining production of a hyper-tensinogenic adrenal steroid (64). Furthermore, there are reports of increased levels of dehydroepiandrosterone sulfate (an adrenal androgen driven by ACTH) in patients with hypertension (65).…”

Section: Primary Aldosteronism (Pa)mentioning

confidence: 99%

Mechanisms of Hypertension

Freel

Connell

2004

Journal of the American Society of Nephrology

103

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Abstract. Hypertension is a common disorder that affects a large heterogeneous patient population. Subgroups can be identified on the basis of their responses to hormonal and biologic stimuli. These subgroups include low-renin hypertensives and nonmodulators. Aldosterone, the principal human mineralocorticoid, is increasingly recognized as playing a significant role in cardiovascular morbidity, and its role in hypertension has recently been reevaluated with studies that suggest that increased aldosterone biosynthesis (as defined by an elevated aldosterone to renin ratio) is a key phenotype in up to 15% of individuals with hypertension. It was reported previously that a polymorphism of the gene (C to T conversion at position Ϫ344) encoding aldosterone synthase is associated with hypertension, particularly in individuals with a high ratio. However, the most consistent association with this variant is a relative impairment of adrenal 11␤-hydroxylation. This review explores the evidence for this and provides a hypothesis linking impaired 11␤-hydroxylation and hypertension with a raised aldosterone to renin ratio. It is also speculated that there is substantial overlap between this group of patients and previously identified low-renin hypertensives and nonmodulators. Thus, these groups may form a neurohormonal spectrum reflecting different stages of hypertension or indeed form sequential steps in the natural history of hypertension in genetically susceptible individuals.High BP remains an important and common clinical problem that affects one in four adults in the United States (1). Historically, hypertension has been subdivided into "essential" and "secondary" forms. Essential hypertension (cause unknown) accounts for 95 to 99% of cases and has traditionally been viewed as a consequence of interaction between environmental factors (e.g., sodium intake) and genetic background. However, the identity of the genes that predispose to hypertension in the great majority of patients remains unknown. A smaller proportion of patients are identified as having secondary hypertension, as a consequence of some biochemical or mechanical pathology that is potentially reversible. More recently, however, the notion that secondary hypertension is rare has been challenged by the suggestion that primary aldosteronism (PA; originally thought to be present in only 1% of individuals with hypertension) is present in up to 15% of unselected individuals with hypertension (2). In this review, we explore the concept that altered regulation of aldosterone production is a common feature of essential hypertension and PA, with the implication that there is substantial overlap between the two. In turn, this could lead to a shift in therapeutic strategies and increased awareness of a role for aldosterone in cardiovascular pathophysiology.

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“…It is found in approximately 80% of patients with Cushing's syndrome [1]. In addition, there is some evidence that cortisol may play a role in the pathogenesis of primary hypertension [3,4]. In addition, there is some evidence that cortisol may play a role in the pathogenesis of primary hypertension [3,4].…”

Section: Introductionmentioning

confidence: 99%

“…In healthy normotensive subjects oral cortisol administration results in an increased blood pressure [2]. In addition, there is some evidence that cortisol may play a role in the pathogenesis of primary hypertension [3,4].…”

Section: Introductionmentioning

confidence: 99%

Short‐term cortisol infusion in the brachial artery, with and without inhibiting 11β‐hydroxysteroid dehydrogenase, does not alter forearm vascular resistance in normotensive and hypertensive subjects

Uum¹,

Hermus²,

Sweep³

et al. 2002

Eur J Clin Investigation

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In both normotensive and hypertensive subjects, high-dose cortisol infusion both with and without 11 beta-HSD inhibition did not change FVR either immediately or after 2 h. We could not demonstrate in vivo 11 beta-HSD activity in the forearm vascular tissues. When binding of cortisone to CBG is changed, e.g. during cortisol infusion, arterio-venous changes in cortisone cannot reliably be used to assess (alterations in) local 11 beta-HSD activity.

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Effect of Adrenal Suppression with Dexamethasone in Essential Hypertension*

Cited by 25 publications

References 19 publications

Is Altered Adrenal Steroid Biosynthesis a Key Intermediate Phenotype in Hypertension?

Is Altered Adrenal Steroid Biosynthesis a Key Intermediate Phenotype in Hypertension?

Mechanisms of Hypertension

Short‐term cortisol infusion in the brachial artery, with and without inhibiting 11β‐hydroxysteroid dehydrogenase, does not alter forearm vascular resistance in normotensive and hypertensive subjects

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