Mechanisms of hypertension: the expanding role of aldosterone

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 -344) 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 11beta-hydroxylation. This review explores the evidence for this and provides a hypothesis linking impaired 11beta-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.

Figure 1

Steroid biosynthetic pathway. Synthesis of cortisol and aldosterone begins with the conversion of cholesterol to pregnenolone by the cytochrome p450 side-chain cleavage enzyme located on the inner mitochondrial membrane. Sequential dehydrogenation and hydroxylation reactions form deoxycorticosterone (DOC). In the zona fasciculata, not all progesterone undergoes 17α hydroxylation, and so both DOC and the cortisol precursor 11-deoxycortisol are formed. In humans, both the zona glomerulosa and zona fasciculata can convert DOC to corticosterone. However, formation of aldosterone from DOC through corticosterone is unique to the cells of the zona glomerulosa as a result of selective expression of the enzyme aldosterone synthase. ^a17αOH = 17 alpha Hydroxylase; ^b3βHSD = Hydroxysteroid dehydrogenase.

Figure 2

Intracellular effects of aldosterone on distal collecting tubule of nephron. AIP, aldosterone-induced protein; 1, effect of AIP on apical membrane sodium channel; 2, effect of AIP on mitochondrial energy production; 3, effect of AIP on energy-dependent Na/K-ATPase.

Figure 3

CYP11B2 and its common polymorphisms.

Figure 4

11-Deoxycorticosteroid responses (increase over basal concentration at 30 min) to ACTH (250 μg intravenously). (A) SF-1 polymorphism (CC/TT). (B) Intron conversion versus normal intron 2.

Figure 5

Possible sequence linking impaired 11β hydroxylase activity and hypertension with raised ARR