J Am Soc Nephrol 15: 1993–2001, 2004

Mechanisms of : The Expanding Role of

E. MARIE FREEL and JOHN M.C. CONNELL MRC Group, Division of Cardiovascular and Medical Sciences, University of Glasgow, Scotland, United Kingdom

Abstract. Hypertension is a common disorder that affects a large aldosterone synthase is associated with hypertension, particularly heterogeneous patient population. Subgroups can be identified on in individuals with a high ratio. However, the most consistent the basis of their responses to hormonal and biologic stimuli. association with this variant is a relative impairment of adrenal These subgroups include low- hypertensives and nonmodu- 11␤-. This review explores the evidence for this and lators. Aldosterone, the principal human mineralocorticoid, is provides a hypothesis linking impaired 11␤-hydroxylation and increasingly recognized as playing a significant role in cardiovas- hypertension with a raised aldosterone to renin ratio. It is also cular morbidity, and its role in hypertension has recently been speculated that there is substantial overlap between this group of reevaluated with studies that suggest that increased aldosterone patients and previously identified low-renin hypertensives and biosynthesis (as defined by an elevated aldosterone to renin nonmodulators. Thus, these groups may form a neurohormonal ratio) is a key phenotype in up to 15% of individuals with spectrum reflecting different stages of hypertension or indeed hypertension. It was reported previously that a polymorphism form sequential steps in the natural history of hypertension in of the gene (C to T conversion at position Ϫ344) encoding genetically susceptible individuals.

High BP remains an important and common clinical problem Aldosterone Biosynthesis and Regulation that affects one in four adults in the United States (1). Histor- Aldosterone, the principal human mineralocorticoid, is pro- ically, hypertension has been subdivided into “essential” and duced in the of the . The “secondary” forms. Essential hypertension (cause unknown) hormone is the product of a series of biosynthetic reactions accounts for 95 to 99% of cases and has traditionally been summarized in Figure 1. The final key steps in aldosterone viewed as a consequence of interaction between environmental synthesis are sequential 11-hydroxylation, 18-hydroxylation, and factors (e.g., sodium intake) and genetic background. How- 18-oxidation of the precursor deoxycorticosterone ever, the identity of the genes that predispose to hypertension (DOC) in zona glomerulosa cells. A single , aldosterone in the great majority of patients remains unknown. A smaller synthase, carries out all of these steps and is encoded by the gene proportion of patients are identified as having secondary hy- CYP11B2. A similar, highly homologous enzyme, 11␤-hydroxy- pertension, as a consequence of some biochemical or mechan- lase (encoded by the gene CYP11B1), acts in parallel in the zona ical pathology that is potentially reversible. More recently, fasciculata to convert 11-deoxycortisol to . The two genes however, the notion that is rare has lie in tandem on 8 in humans and are highly homol- been challenged by the suggestion that ogous; the protein products are also very similar and share ~95% (PA; originally thought to be present in only 1% of individuals identity of primary sequence (3). with hypertension) is present in up to 15% of unselected Angiotensin II (Ang II; regulated by the renin-angiotensin individuals with hypertension (2). In this review, we explore system) and plasma potassium are the principal regulators of the concept that altered regulation of aldosterone production is aldosterone production. Ang II stimulates aldosterone secretion a common feature of essential hypertension and PA, with the in response to sodium depletion and reduced extracellular fluid implication that there is substantial overlap between the two. In volume (4), and even small increments in plasma potassium act turn, this could lead to a shift in therapeutic strategies and as a powerful stimulus for aldosterone production (5). Other increased awareness of a role for aldosterone in cardiovascular factors also influence aldosterone production. In particular, pathophysiology. adrenocorticotrophin (ACTH) exerts an acute effect to stimu- late aldosterone production (6), although its importance in long-term regulation of aldosterone is uncertain. Correspondence to Prof. John M.C Connell, MRC Blood Pressure Group, Western Infirmary, Glasgow, G11 6NT, UK. Phone: ϩ44-141-211-2108; Fax: ϩ44-141-211-1763; E-mail: [email protected] Physiologic Actions of Aldosterone 1046-6673/1508-1993 Aldosterone binds to the mineralocorticoid receptor Journal of the American Society of Nephrology (MR), an intracellular receptor that belongs to the steroid/ Copyright © 2004 by the American Society of Nephrology thyroid/retinoid/orphan receptor superfamily (7). Once DOI: 10.1097/01.ASN.0000132473.50966.14 bound, the ligand/receptor complex translocates to the nu- 1994 Journal of the American Society of Nephrology J Am Soc Nephrol 15: 1993–2001, 2004

The gene product(s) resulting from the interaction of aldo- sterone/MR complexes binding to DNA regulatory elements are termed aldosterone-induced protein(s) (AIP). AIP may have effects on the apical membrane, cellular energy produc- tion, and/or the basolateral Na/K-ATPase pump, resulting in increased sodium reabsorption and potassium and hydrogen ion excretion (13) (Figure 2). Recently, a serine/threonine kinase, serum glucocorticoid- regulated kinase (sgk), has been identified as an AIP resulting in an increase in ENaC activity (14). Aldosterone causes phos- phorylation and activation of sgk, which in turn increases ENaC activity by an increase in the number of channels at the cell surface (15). The principal ENaC inhibitory accessory protein is Nedd 4 (neuronal precursor cells expressed devel- opmentally downregulated). This ubiquitin protein ligase binds to the C tails of ␤ and ␥ subunits of ENaC, leading to channel Figure 1. Steroid biosynthetic pathway. Synthesis of cortisol and aldo- internalization and degradation. Recent work suggests that the sterone begins with the conversion of to by the stimulatory action of sgk on ENaC is mediated through phos- p450 side-chain cleavage enzyme located on the inner mi- tochondrial membrane. Sequential dehydrogenation and hydroxylation phorylation of serine residues on Nedd4. Such phosphorylation reactions form deoxycorticosterone (DOC). In the zona fasciculata, not reduces the interaction between Nedd4 and ENaC, leading to all undergoes 17␣ hydroxylation, and so both DOC and the elevated ENaC cell surface expression (16). cortisol precursor 11-deoxycortisol are formed. In humans, both the zona It is likely that aldosterone affects BP regulation by mech- glomerulosa and zona fasciculata can convert DOC to . anisms other than or in addition to simple plasma volume However, formation of aldosterone from DOC through corticosterone is expansion and the associated increase in cardiac output as a unique to the cells of the zona glomerulosa as a result of selective result of its action on sodium homeostasis. For example, acti- a expression of the enzyme aldosterone synthase. 17␣OH ϭ 17 alpha vation of MR in vascular smooth muscle results in alteration in b ␤ ϭ Hydroxylase; 3 HSD Hydroxysteroid dehydrogenase. pressor responsiveness to adrenergic stimulation. Moreover, evidence suggests that aldosterone binding by the MR in car- diac tissue regulates collagen formation (17). It is feasible that cleus and acts as a by direct interaction similar action in peripheral blood vessels might result in re- with DNA regulatory elements (the classical genomic effect modeling, which could sustain an elevated BP. This is sup- of aldosterone) (8). As the MR has similar affinities for ported by evidence suggesting that aldosterone levels are in- aldosterone and cortisol, the 11␤-hydroxysteroid dehydro- versely related to arterial compliance in essential hypertension. genase system acts as a gatekeeper to prevent activation by much higher available levels of cortisol (9). The type 2 isoform of this enzyme is found in the renal distal nephron and converts cortisol to its inactive metabolite, , which has no affinity for the MR. Traditionally, the principal target organ for aldosterone was said to be the ; MR are found in high concentration in the renal distal nephron as well as other epithelial sites, such as the colon and ducts of sweat and salivary glands (10). How- ever, MR have also been identified in nonepithelial sites, such as heart, brain, vascular smooth muscle, liver, and peripheral blood leukocytes (10). The best-characterized physiologic effect of aldosterone is to increase the reabsorption of sodium in the kidney and at other secretory epithelial sites at the expense of potassium and hy- drogen ions (4). The major sites of aldosterone-induced sodium and potassium transport are luminal cells of the cortical col- lecting tubules and the distal convoluted tubule. The apically located epithelial sodium channel (ENaC) is the major deter- minant of renal sodium reabsorption (11). Its availability in Figure 2. Intracellular effects of aldosterone on distal collecting open conformation at the apical membrane of the cell is in- tubule of nephron. AIP, aldosterone-induced protein; 1, effect of AIP creased by aldosterone and also by vasopressin, glucocorti- on apical membrane sodium channel; 2, effect of AIP on mitochon- coids, and insulin; elevated intracellular levels of calcium and drial energy production; 3, effect of AIP on energy-dependent sodium downregulate it (12). Na/K-ATPase. J Am Soc Nephrol 15: 1993–2001, 2004 Mechanisms of Hypertension 1995

It is now accepted that, as well as classical genomic effects to be a feature of patients with essential hypertension. In 1985, through ligand/receptor binding of DNA regulatory elements, de Simone et al. (26) demonstrated that ACTH-stimulated plasma aldosterone exerts rapid, nongenomic effects. This has led to levels of DOC were increased in hypertensive patients compared investigation of aldosterone action in tissues other than the with control subjects, a finding similar to that of Honda et al. (27) kidney. Reports of rapid, nongenomic effects of aldosterone 10 yr earlier. More recently, we observed a similar phenomenon have been described in smooth muscle, skeletal muscle, co- in patients with hypertension from Italy, in whom the ratio of lonic epithelial cells, and myocardial cells (18). These effects 11-deoxycortisol to cortisol (a marker of 11␤-hydroxylase activ- have been linked to the development of increased systemic ity) was elevated (28). Although the precise cause of this is vascular resistance and so could, theoretically, contribute to unclear, we suggest later that it may be a consequence of variation hypertension and cardiovascular disease. at the CYP11B1/CYP11B2 loci, which encode 11␤-hydroxylase and aldosterone synthase, respectively. Role of in Essential Hypertension Although the underlying pathophysiology remains incom- Subgroups in Hypertension: Aldosterone as a pletely understood, it is assumed that essential hypertension Key Intermediate Phenotype has a multifactorial cause and that no single cause exists. Over the years, there has been a substantial effort to cate- However, a number of studies draw attention to the adrenal gorize large, heterogeneous groups of individuals with essen- cortex and its contribution to BP elevation. tial hypertension into smaller, homogeneous subgroups on the Functional abnormalities of the were sug- basis of hormonal responses to biologic stimuli. One of the gested as a cause for essential hypertension many years ago earliest classifications was that of low-renin hypertension (29). (19); indeed, early studies reported that adrenal cortex hyper- In this form of hypertension, subjects exhibit low plasma renin plasia was a feature of many hypertensive individuals at post activity, which does not respond normally to sodium restric- mortem examination (20,21). In addition, a number of abnor- tion, and maintain basal aldosterone levels, which, although malities of urinary excretion, plasma levels, and clearance of not elevated, are inappropriate for the principal trophin, Ang II. several adrenal in patients with hypertension have Such a hormonal profile may be due to increased responsive- been identified over the years (22,23). No single defect in ness of aldosterone to Ang II (30,31), although not all patients adrenal biosynthesis has been identified, but it is share this abnormality (30). Classically, individuals with low relevant to consider briefly two rare monogenic syndromes renin have sodium-sensitive hypertension, which tends to respond involving 11␤-hydroxylase and aldosterone synthase that cause better to diuretics than to agents that block the renin-angiotensin- hypertension and help identify candidate mechanisms (Table aldosterone system. Low-renin hypertension is found more fre- 1): (1) Glucocorticoid remediable aldosteronism (GRA) is a quently among black and elderly populations (32). rare autosomal dominant condition characterized by hyperten- A second subset of hypertension was subsequently described sion and aldosterone excess that is regulated by ACTH rather in the mid-1980s by William and Hollenberg (33). In this than Ang II. The molecular basis of this condition was first group, changes in sodium intake fail to produce the anticipated described in 1992 (24). In GRA, a chimeric gene that contains reciprocal changes in adrenal (aldosterone) and renal vascular the 5' promoter sequence of CYP11B1 and functional elements responses to Ang II infusions. Such individuals, who have of CYP11B2 is created, resulting in aldosterone production normal/high renin levels, are termed “nonmodulators.” Non- under control of ACTH. (2)11␤-Hydroxylase deficiency is a modulators tend to be older than modulators, and there is rare cause of congenital adrenal hyperplasia, accounting for 5 to evidence to suggest that nonmodulation has a genetic basis. In 8% of cases (25). In this autosomal recessive disorder, mutations one study of individuals with hypertension, 81% with a posi- in CYP11B1 result in impaired activity of 11␤-hydroxylase, lead- tive family history of hypertension were nonmodulators (34). ing to accumulation of the steroid precursors 11-deoxycortisol and A previous study of sibling pairs with hypertension showed deoxycorticosterone (Figure 1). This leads to mineralocorticoid that nonmodulation tended to aggregate within families and is hypertension in approximately two thirds of cases. independent of sodium intake (35). In common with low-renin In light of these rare syndromes, it is of interest that impaired essential hypertension, nonmodulators also demonstrate salt activity of the enzyme 11␤-hydroxylase has also been reported sensitivity. In contrast to low-renin hypertension, however,

Table 1. Monogenic forms of hypertension involving CYP11B locus

Genetics Phenotype

GRAa Hybrid gene of CYP11B1/B2 Steroid-responsive hypertension 11␤-Hydroxylase deficiency 2 bp insertion exon 7 of CYP11B1 Congenital adrenal hyperplasia Dahl salt-sensitive rat Mutations in CYP11B1/B2 Salt-sensitive hypertension Raised 18-hydroxylated steroids

a GRA, glucocorticoid remediable aldosteronism. 1996 Journal of the American Society of Nephrology J Am Soc Nephrol 15: 1993–2001, 2004 nonmodulators clinically respond best to angiotensin-convert- which dominate the ratio. Thus, in a careful analysis of the ing enzyme inhibitors as opposed to diuretics (Table 2) (36). mathematical derivation of the ARR, Montori and Young (47) Thus, within the large population of individuals with essen- demonstrated that the renin measurement was the determinant tial hypertension, two significant, salt-sensitive phenotypes of the ratio, so its positive predictive power for PA was have been identified with different optimal therapeutic agents. relatively low. Indeed, in many patients, the level of aldoste- We suggest there is an additional subgroup of individuals with rone is within the “normal” range, and it is uncertain whether hypertension that may be relatively common and that may they would meet earlier criteria for the diagnosis of PA. How- relate to the previously described low-renin population such ever, in many such individuals, dynamic tests of the renin- that there is a continuum in which a common genetic predis- angiotensin system are abnormal, confirming an altered rela- position is modified by other factors over many years to result tionship between renin and aldosterone. How this group differs in a range of seemingly distinct clinical presentations. from the subgroup of low-renin hypertension previously de- scribed is unclear. In these patients, levels of aldosterone are Primary Aldosteronism (PA) higher than predicted from the prevailing renin in common PA can be defined as overproduction of aldosterone inde- with individuals with a raised ARR, and there is likely to be pendent of its normal chronic regulator, Ang II (37). Classi- substantial overlap between the two groups. This theory reit- cally, Conn’s syndrome was reported in subjects with aldoste- erates previous arguments by Padfield et al. (48), who claimed rone-producing adrenal adenomas and was previously thought that PA as a result of bilateral adrenal hyperplasia was a variant to be the most common cause of PA. However, recent studies not of classical Conn’s adrenal adenoma but of low-renin have led to a reevaluation of its prevalence and suggest that essential hypertension. In keeping with this, it should be noted bilateral adrenal hyperplasia (also known as idiopathic hyper- that nodular change in the adrenal gland with or without aldosteronism) is more common than first thought (38). This hyperplasia is not specific for idiopathic aldosteronism, having change in emphasis has been provoked by wider use of the been described in individuals with essential hypertension, low- aldosterone to renin ratio (ARR) as a screening and diagnostic renin hypertension, and even normotension (49). Furthermore, test. Using this, several groups worldwide now have reported pathologic studies in adrenal tissue removed from individuals the prevalence of PA, as defined by an ARR value above a with apparent solitary adenomas show that there is often hy- given cutoff, in unselected individuals with hypertension to be perplasia of the adjacent zona glomerulosa and formation of between 5 and 15%. For example, one study of unselected multiple nodules throughout the gland, suggesting that a soli- individuals with hypertension in Dundee, Scotland, suggested tary adenoma may arise in an already abnormal gland (50). a prevalence of 10% in both a primary and a secondary care In summary, an elevated ARR can be demonstrated in ~10% setting (39). Independent groups in Australia (40), the United of unselected individuals with hypertension, making it the most States (41), South East Asia (42), South Africa (43), and South common cause of secondary hypertension. It is unclear how America (44) have made similar claims. Indeed, such figures many of these individuals have “classical” PA with elevated are reminiscent of claims by Conn in 1960s that normokalemic plasma levels of aldosterone, but all clearly have demonstrable PA is present in up to 20% of all patients with hypertension—a abnormalities in renin-angiotensin-aldosterone dynamics, and claim that was generally discredited at the time (45). Thus, it may be more appropriate to redesignate such patients as aldosterone excess may be an increasingly significant contrib- having “aldosterone-associated hypertension.” utor to cardiovascular morbidity. The ARR was first introduced as a screening tool for PA in Possible Genetic Basis for Elevated ARR the early 1990s. This ratio seems to be fairly robust and is less Debate over the exact physiologic differences and similari- affected by day-to-day or diurnal variation and posture than ties between subgroups is largely academic. Individuals who plasma renin activity or aldosterone levels individually (46). are identified by an increased ARR have an inappropriately However, use of this ratio is not without problems. In partic- high aldosterone concentration for its principal trophin, Ang II; ular, the ratio can obviously be affected by concomitant drug whatever gives rise to this disproportionate renin for aldoste- administration. Furthermore, in the majority of patients iden- rone level could clearly have pathogenic and therapeutic im- tified by a raised ARR, the real reason is low levels of renin, plications and deserves further investigation (51). The corticosteroid biosynthetic pathway and the crucial role of aldosterone synthase (encoded by CYP11B2) and 11␤-hy- Table 2. Subgroups in essential hypertensiona droxylase (CYP11B1) in catalyzing the terminal steps of aldo- sterone and cortisol biosynthesis, respectively, have already Low Renin Nonmodulators been discussed (see Figure 1). These genes are obvious candi- dates that might be involved in hypertensive disorders as Plasma renin levels Low Normal-high confirmed by monogenic forms of hypertension described ear- Salt sensitive Yes Yes lier (Table 1). Animal models, in particular the Dahl salt- Antihypertensive Diuretics ACE inhibitors sensitive rat (51), also suggest a role for this locus (Table 1). In Phenotype Elderly MenϾwomen the past few years, studies have focused on two common Response to all Normal Reduced polymorphisms within the CYP11B2 gene (Figure 3). One is a a ACE, angiotensin-converting enzyme. single nucleotide polymorphism in the 5' promoter region at J Am Soc Nephrol 15: 1993–2001, 2004 Mechanisms of Hypertension 1997

cortisol, respectively, by 11␤-hydroxylase within the zona fasciculata (Figure 1). This evidence, which initially seems paradoxical, suggests that the T allele of CYP11B2 is associ- ated with impaired activity of the enzyme 11␤-hydroxylase, which is encoded by the adjacent gene, CYP11B1. Although Figure 3. CYP11B2 and its common polymorphisms. the exact molecular mechanism that accounts for this is not understood, we have hypothesized that the Ϫ344 T polymor- phism in the promoter region of CYP11B2 is in close linkage Ϫ 344 (C-T) that alters a putative recognition site for the disequilibrium with a key quantitative trait locus in CYP11B1 transcription factor SF-1 (52). It is unclear whether this has any adversely affecting its expression or function, resulting in physiologic significance: binding of SF-1 is reduced fourfold increased levels of 11-deoxysteroids (60). Definitive studies to with the T allele, and there is no detectable effect on gene examine the pattern of variation across the entire locus are transcription when studied in vitro (53). The other polymor- currently in progress. phism involves intron 2 of CYP11B2, which is partly replaced by the corresponding intron of CYP11B1 (52). These two polymorphisms are in close linkage disequilibrium such that Hypothesis Linking Altered 11␤-Hydroxylase the common haplotypes generated are T/conversion (38%), Activity and Hypertension with a Raised ARR T/wild type (16%), and C/wild type (45%) (54). The theory that 11␤-hydroxylation may be impaired in in- The physiologic significance of these polymorphisms re- dividuals with hypertension is not novel (26,27). However, mains controversial. In our study of 138 individuals with until now, there has been no suggestion that this biochemical hypertension, there was a highly significant excess of TT abnormality is related to variation at the CYP11B locus. These homozygosity compared with CC homozygosity when com- data also lead us to speculate on the link between a minor pared with individually matched normotensive control subjects change in 11-hydroxylase efficiency and hypertension with (54). Other groups reported similar findings (55). Moreover, aldosterone excess. It is unlikely that the minor increases in subsequent assessment of aldosterone excretion (as its urinary DOC and 11-deoxycortisol will have significant biologic ef- metabolite, tetrahydroaldosterone) in an unrelated population fects. However, impaired conversion of deoxycortisol to cor- demonstrated a strong association between the T allele and tisol as a consequence of reduced 11␤-hydroxylase activity higher excretion rates (54). Further investigations have re- should result in a slight reduction in cortisol levels in response ported that plasma levels of aldosterone are raised in individ- to ACTH. In turn, normal feedback regulation should result in uals with the T allele (56), although other groups have failed to a resetting of the hypothalamic-pituitary-adrenal axis such that confirm these findings (57). In addition, we have reported an cortisol levels are maintained. Consequently, there will be a association between T allele frequency and elevated ARR with subtle increase in ACTH drive to the adrenal cortex (Figure 5). a population of patients with hypertension (Table 3) (58). Thus, if this were a genetically determined phenomenon, In addition to the data on aldosterone and BP, we and others then we would predict that individuals with less efficient have consistently shown that the T allele and intron 2 conver- cortisol synthesis will maintain a slightly enhanced ACTH sion are associated with raised basal and ACTH-stimulated drive to the adrenal (effectively, a minor variant of classical levels of the 11-deoxysteroids, DOC, and deoxycortisol (Fig- 11␤-hydroxylase deficiency). In the long term, this is likely to ure 4) (59). These steroids are converted to corticosterone and cause hyperplasia of both zona fasciculata and zona glomeru-

Table 3. Genotype distribution stratified by aldosterone to renin ratioa

SF-1 CC CT TT ␹2 P Value

ARR Ն750 14 (0.15) 42 (0.46) 35 (0.39) 8.6 0.014 ARR Ͻ750 52 (0.22) 129 (0.55) 53 (0.23) ARR Ն1000 8 (0.14) 26 (0.46) 23 (0.40) 6.5 0.039 ARR Ͻ1000 58 (0.22) 145 (0.54) 65 (0.24) Intron Conversion 11 (Wild Type) 12 22 (Conversion) ␹2 P Value

ARR Ն750 26 (0.29) 40 (0.45) 23 (0.26) 3.2 0.205 ARR Ͻ750 81 (0.35) 111 (0.48) 40 (0.17) ARR Ն1000 14 (0.25) 24 (0.43) 18 (0.32) 7.1 0.029 ARR Ͻ1000 93 (0.35) 127 (0.48) 45 (0.17)

a ARR, aldosterone to renin ratio. A total of 375 hypertensive patients underwent genotyping and assessment of ARR. Patients with a raised ARR had a statistically significant excess of the T allele at the SF-1 site. A similar pattern was seen with the intron conversion allele, although this reached statistical significance only at a higher threshold of ARR. 1998 Journal of the American Society of Nephrology J Am Soc Nephrol 15: 1993–2001, 2004

Figure 4. 11-Deoxycorticosteroid responses (increase over basal con- centration at 30 min) to ACTH (250 ␮g intravenously). (A) SF-1 poly- morphism (CC/TT). (B) Intron conversion versus normal intron 2. losa of the adrenal cortex, resulting in increased synthetic capacity for both cortisol and aldosterone. Importantly, expres- sion of a number of genes necessary for aldosterone produc- tion, including steroidogenic acute regulatory protein, p450 side-chain cleavage (CYP11A), and p450–21-hydroxylase (CYP21), is responsive to ACTH, emphasizing the potential for increased synthetic capacity of aldosterone (61). Importantly, we do not propose that ACTH is a principal stimulator of excess aldosterone production by the adrenal. Indeed, previous studies have demonstrated the ability of phar- macologic doses of ACTH to stimulate aldosterone production Figure 5. Possible sequence linking impaired 11␤ hydroxylase activity in the short term, but aldosterone production decreases within and hypertension with raised ARR a few days (62). However, these experiments concentrated on very unphysiologic exposure of the adrenal to grossly exces- sive amounts of ACTH. In ACTH-dependent Cushing’s dis- favor zona glomerulosa hyperplasia and may enhance aldoste- ease, in which there is chronic sustained exposure of the rone secretion in response to other, more conventional tro- adrenal cortex, aldosterone concentrations are not diminished phins, such as Ang II or potassium. Thus, over a very long (63). Other proopiomelanocortin (POMC) breakdown prod- period, the genetic change in 11␤-hydroxylation efficiency ucts, such as joining peptide and ␤-endorphin, have also been (along with an additional environmental or genetic influence) shown to stimulate aldosterone production by human adrenal might result in ACTH-driven adrenal zonal hyperplasia and an cells in vitro. Thus, we suggest that increased levels of a alteration (steepening of the dose–response relationship) of the POMC-related product (either ACTH or a related peptide) response of aldosterone to Ang II and potassium. It is pertinent J Am Soc Nephrol 15: 1993–2001, 2004 Mechanisms of Hypertension 1999 that very early studies reported that a proportion of patients vival Study showed that eplerenone could provide substantial with essential hypertension showed a good BP response to benefit (15% reduction in mortality) in patients after acute low-dose dexamethasone treatment, seemingly supporting the myocardial infarction (68). It may be that selective aldosterone suggestion that ACTH was sustaining production of a hyper- receptor antagonists have a wider role in the therapy of hyper- tensinogenic adrenal steroid (64). Furthermore, there are re- tension, a concept that merits further evaluation. ports of increased levels of dehydroepiandrosterone sulfate (an adrenal driven by ACTH) in patients with hypertension Conclusion (65). Finally, it is significant that adrenal gland hyperplasia is a As a result of increased use of the ARR as a diagnostic tool, common histologic finding in patients with hypertension post the contribution of aldosterone in hypertension has been more mortem and even in patients with seemingly “solitary” adrenal widely recognized. This may be important in up to 10% of adenomas (20,21). unselected individuals with hypertension. There is likely to be The concept of “tertiary aldosteronism,” whereby there is a substantial degree of overlap between this group and other sustained and prolonged stimulation of the adrenal by Ang II, well-defined hypertension subgroups (low-renin essential hy- is already recognized in renovascular hypertension (38). It has pertension and nonmodulators), and it may well be that these been suggested that the phenotype of hypertension with a form sequential steps in the natural history of hypertension in raised ARR could be redefined as a form of tertiary aldoste- genetically predisposed individuals. As a result, the classical ronism, perhaps preceded by low-renin hypertension over a subdivision of hypertension into essential and secondary forms much longer time. Although this theory focuses on a single has become diffuse. genetic polymorphism, it is widely accepted that hypertension There is now greater recognition of the adverse effects of is a polygenic disorder. It is likely, therefore, that other genes aldosterone on endothelial, renal, cardiac, and central nervous may interact in a synergistic manner to lead to the phenotype system tissues. Many of these effects may be independent of of hypertension with an elevated ARR. BP elevation and plasma volume expansion. Thus, develop- In summary, we propose that within the heterogeneous pop- ment of new, more selective aldosterone receptor antagonists is ulation of essential hypertension, there may be three distinct a major therapeutic challenge to optimize BP control, minimize subgroups, which are currently classified on a hormonal or side effects, and improve cardiovascular morbidity in an in- biochemical basis: individuals with low-renin hypertension, creasing number of patients. nonmodulators (normal to high renin), and individuals with hypertension and an elevated ARR. These three groups may Acknowledgments form a neurohormonal spectrum that reflects differing stages of J.C. is supported by a Medical Research Council program grant. hypertension, the rate of progression of which depends on M.F. is a clinical research fellow funded by the Wellcome Trust (grant other genetic and environmental factors. Hence, the natural no. 069205). history of hypertension may proceed from essential (high to normal renin) hypertension through to low-renin hypertension References and finally to tertiary aldosteronism. Clearly, longitudinal stud- 1. Burt VL, Cutler JA, Higgins M, Horan MJ, Labarthe D, Whelton ies that compare groups of patients of different ages followed P, Brown C, Roccella EJ: Trends in the prevalence, awareness, up over time are needed to investigate this theory. treatment and control of hypertension in the adult US population: Data from the health examination surveys, 1960 to 1991. 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