Aldosterone and the Vasculature: Mechanisms Mediating Resistant Hypertension

Abstract

The renin‐angiotensin‐aldosterone system appears to be one of the key factors in the development of hypertensive vascular disease. Identification of mineralocorticoid receptors in the heart, vasculature, and brain has raised speculation that aldosterone may directly mediate its detrimental effects in these target organs independent of angiotensin II. Aldosterone increases vascular tone due to endothelial dysfunction and enhances the pressor response to catecholamines and up‐regulation of angiotensin II receptors. It induces electrolyte transport over the vascular smooth cell membrane and plays a crucial role in vascular remodeling of small and large arteries. Moreover, aldosterone is involved in vascular injury and promotes collagen synthesis, which leads to increased arterial stiffness and elevation of blood pressure. Aldosterone has also been shown to exert a number of effects in the central nervous system. Several human studies have shown that aldosterone is related to baroreflex resetting. Thus, in cases of severe hypertension, there would be fewer compensatory mechanisms to offset blood pressure elevation and ensuing vascular damage. Endothelial and vascular smooth muscle cells have the potential to synthesize aldosterone, and tissue aldosterone could play a more important role in resistant hypertension and target organ damage than circulating aldosterone. Understanding aldosterone synthase polymorphism may provide insight into blood pressure patterns and their consequences. Understanding the vascular mechanisms of aldosterone in resistant hypertension may explain why selective aldosterone receptor blockers might have beneficial effects in resistant hypertension.

An increase in peripheral vascular resistance has traditionally been viewed as the hallmark of resistant hypertension. ¹ , ² This increase in resistance is generally attributed to an increase in vascular tone. ³ Abnormalities of the arterial vasculature that precede cardiovascular morbid events are likely to occur in sequence. The initial abnormalities appear to be functional, in large part related to endothelial dysfunction associated with decreased bioavailability of nitric oxide (NO), which maintains reduced small artery tone. ⁴ Although a decrease in constitutive release of NO may be the initial abnormality, it is soon accompanied by a decrease in stimulated release of endothelial vasodilators, as manifested by a reduction in flow‐mediated dilation of conduit arteries. ⁵ , ⁶ These functional abnormalities of the vasculature precede and are mechanistic precursors of the structural alterations that are responsible for thickening of the conduit artery wall, ⁷ increases in pulse pressure, ⁸ and atherosclerotic plaque development. ⁹

The concept of hypertension as primarily a consequence of altered hemodynamics has changed. Many factors are now implicated in the development of hypertensive vascular disease. The renin‐angiotensin‐aldosterone system (RAAS) appears to be one of the most significant of these factors. ¹⁰ Until the last decade, aldosterone has often been neglected in investigating the pathophysiologic consequences of the activated RAAS in arterial hypertension. ¹¹ There is now evidence that aldosterone plays a key role in the pathogenesis of resistant hypertension. ¹² , ¹³ The Figure summarizes the potential pathologic mechanisms of aldosterone in resistant hypertension.

Figure.

Potential pathologic mechanisms of aldosterone in resistant hypertension. ↑ indicates increases; BP, blood pressure.

ALDOSTERONE AND ARTERIAL TONE

Identification of mineralocorticoid receptors in the heart, vasculature, and brain has raised speculation that aldosterone may directly mediate its detrimental effects in these target organs independent of the regulatory roles of angiotensin II and aldosterone in kidney function and blood pressure (BP). ¹⁴

Endothelial Dysfunction

The vascular endothelium plays a fundamental role in the basal and dynamic regulation of the circulation. Thus, it has a crucial role in the pathogenesis of hypertension due to its position between the BP and smooth muscle cells responsible for peripheral vascular resistance. The endothelium is thought to be both victim and offender in arterial hypertension. Current studies indicate that mineralocorticoid receptors are present not only in epithelial cells, but that aldosterone also acts on nonepithelial tissues, including the heart, blood vessels, and brain. In the vascular system, mineralocorticoid receptors and the enzyme 11‐[β]hydroxy‐steroid dehydrogenase type 2, which confers aldosterone specificity to the mineralocorticoid receptor, could be localized in endothelial and vascular smooth muscle cells. ¹⁵ Culturing human endothelial cells with aldosterone results in the enhanced generation of reactive oxygen species through activation of nicotinamide adenine dinucleotide phosphate (reduced) (NAD[P]H) oxidase. ¹⁶ Mineralocorticoid receptor blockade increases NO bioavailability and improves impaired endothelial function by decreasing oxidative stress in hypertension, atherosclerosis, and heart failure. ¹⁷ , ¹⁸

Vascular Smooth Muscle Cells

Excess aldosterone secretion results in hypertension, which may be due in part to its direct actions on the cardiovascular system. In the vascular system, aldosterone is known to modulate vascular tone, possibly by increasing the pressor response to catecholamines and impairing the vasodilatory response to acetylcholine, or by up‐regulation of angiotensin II receptors. ¹⁹ Aldosterone seems to affect intracellular electrolytes genomically to induce electrolyte transport through the cell membrane of the vascular smooth muscle cells. It induces nongenomically mediated alterations of cell function (eg, vasoconstriction) by rapid effects on intracellular electrolytes such as free intracellular calcium. ²⁰

Adventitia

Aldosterone promotes collagen deposition in blood vessels, enhancing vascular remodeling at the expense of arterial elasticity. This remodeling was originally regarded as an adaptation to the arterial hypertension caused by aldosterone excess. Chronic aldosterone administration in the presence of NaCl has been shown, however, to stimulate perivascular and interstitial cardiac fibrosis and cardiac hypertrophy independent of changes in BP. ²¹ , ²² The mechanism of aldosterone‐induced fibrosis is unclear, but aldosterone has been shown to increase collagen I synthesis in cardiac fibroblasts. ²³ It may also increase the number of endothelin receptors, which increases collagen synthesis. ²⁴

ALDOSTERONE AND VASCULAR INJURY

Aldosterone induces oxidative stress in vascular cells through NAD(P)H oxidase activation, which plays a central role in endothelial dysfunction and atherosclerotic vascular disease. ²⁵ Aldosterone causes vascular injury by directly acting on the vasculature, in addition to causing injury by raising BP. Bone marrow‐derived endothelial progenitor cells have been shown to exert an important role in the repair of the endothelium. The effects of aldosterone on endothelial progenitor cells were evaluated by examining the progenitor cell formation from bone marrow mononuclear cells ex vivo. ²⁶ Aldosterone (10–1000 nmol/L) reduced the formation of progenitor cells in a concentration dependent manner. This effect of aldosterone was attenuated by treatment with spironolactone. These data indicated that aldosterone inhibits the formation of bone marrow‐derived progenitor cells. Conversely, reduction of aldosterone levels by blockade of mineralocorticoid receptors may enhance vascular regeneration by endothelial progenitor cells.

REMODELING OF LARGE AND SMALL ARTERIES

A succession of pathologic effects accompanies the structural and functional changes that characterize vascular remodeling of hypertensive vessels. Remodeling of small resistance arteries in hypertension may be one of the earliest manifestations of target organ damage, occurring before clinically apparent manifestations such as heart failure and renal failure. ²⁷ In heart failure patients chronically treated with angiotensin‐converting enzyme (ACE) inhibitors and diuretics, there is decreased arterial compliance or elasticity of the aorta and its major branches, which is inversely correlated with the aldosterone escape phenomenon. ²⁸

In hypertensive patients, enhanced plasma aldosterone and arterial stiffness are positively associated. The influence of polymorphism in the gene encoding aldosterone synthase (CYP11B2) on the age‐related changes in BP and arterial stiffness has been investigated. ²⁹ In hypertensive subjects, the TC and CC genotype of the aldosterone synthase polymorphism are involved, by comparison with the TT genotype, and associated with a higher heart rate and a reduced stroke volume index. In men with the C allele, reduced stroke volume index then compensates for the steep increase of the pulse wave velocity with age. These results are consistent with the local role of endogenous aldosterone on both heart and vessels.

ALDOSTERONE AND RENAL VASCULATURE

There is increasing evidence for the importance of rapid nongenomic effects of aldosterone on the human vasculature. ³⁰ In vitro animal experiments in renal arterioles suggest the presence of such effects on the renal vasculature. To explore these effects in vivo in humans, aldosterone (500 μg) or placebo was injected intravenously with or without coinfusion of N^G‐monomethyl‐l‐arginine (l‐NMMA) in a randomized, double‐blinded, 4‐fold crossover design in healthy male subjects. ³¹ l‐NMMA is an NO synthase blocker and is associated with endothelial dysfunction. Renal plasma flow and glomerular filtration rate were measured by constant infusion clearance technique using inulin and para‐aminohippuric acid. Injection of aldosterone without concomitant infusion of l‐NMMA changed the renal plasma flow and glomerular filtration rate (but not statistically significantly) compared with placebo. Coinfusion of l‐NMMA unmasked the effect of aldosterone: aldosterone with l‐NMMA decreased the glomerular filtration rate slightly, whereas infusion of l‐NMMA alone increased the glomerular filtration rate. l‐NMMA alone decreased renal plasma flow, and aldosterone with l‐NMMA decreased renal plasma flow. Accordingly, aldosterone with l‐NMMA increased renal vascular resistance much more than l‐NMMA alone. These data indicate that aldosterone acts via rapid nongenomic effects in vivo in humans at the renal vasculature. Antagonizing endothelial NO synthase unmasks these effects. Rapid nongenomic aldosterone effects increase renal vascular resistance and thereby mediate arterial hypertension if endothelial dysfunction is present. The precise mechanisms need still to be explored because of different views in the literature. More studies are necessary to confirm these findings in patients with endothelial dysfunction per se.

A recent clinical study in diabetic patients with albuminuria demonstrates the clinical applicability of these considerations. Epstein et al ³² demonstrated that aldosterone blockade using the selective aldosterone blocker eplerenone reduced urinary albumin excretion over and above that produced ACE inhibition alone.

ALDOSTERONE AND THE AUTONOMIC NERVOUS SYSTEM

Aldosterone has been shown to exert a number of effects in the central nervous system. ³³ Facilitated by its lipophilic properties, aldosterone can cross the blood‐brain barrier relatively easily. There is strong evidence to support the production of aldosterone in the central nervous system, and progress has been made in identifying regulatory factors that influence local production. It is more difficult, however, to establish whether locally produced aldosterone exerts any significant physiologic or pathophysiologic effects.

Several human studies have shown that aldosterone is related to baroreflex impairment. ³⁴ , ³⁵ Baroreflex resetting in the case of severe hypertension would result in fewer compensatory mechanisms to offset the BP rise and accompanying vascular damage, and would also result in less reversible vascular changes, leading to further systolic BP increase. Baroreflex sensitivity is not well explained by cardiovascular risk factors or lifestyle. The RAAS plays an important role in cardiovascular autonomic regulation. Baroreflex sensitivity as measured from the overshoot phase of the Valsalva maneuver and genetic polymorphisms were examined in a random sample of women and men aged 36–61 years. ³⁶ An insertion/deletion polymorphism of ACE, M235T variants of angiotensinogen, and 2 diallelic polymorphisms in CYP11B2, 1 in the promoter (−344C/T) and the other in the second intron, were identified by polymerase chain reaction. In the older population, baroreflex sensitivity differed significantly across CYP11B2 genotype groups in women in genotypes −344TT, CT, and CC, and in the intron 2 genotypes 1/1, 1/2, and 2/2, but not in men. No comparable associations were found for baroreflex sensitivity with the insertion/deletion polymorphism of ACE or the M235T variant of angiotensinogen. In the younger population, baroreflex sensitivity was even more strongly related to the CYP11B2 promoter genotype. The association was statistically significant in both men and in women. Future research is needed to examine the role of aldosterone synthase polymorphism in relation to resistant hypertension.

TISSUE VS CIRCULATING ALDOSTERONE

A fact that remains puzzling is the intensifying role of a high salt/volume environment for the deleterious effects of aldosterone in the cardiovascular system. This relationship becomes clinically relevant when patients display plasma aldosterone levels that are inappropriate for the amount of dietary salt consumption or the magnitude of intravascular volume. Patients presenting any degree of volume retention or those consuming a high‐salt diet should demonstrate low levels of circulating aldosterone. Serum aldosterone has been related to prognosis for cardiovascular morbidity and mortality in heart failure patients. ³⁶

Aldosterone has been found to diffuse directly across the plasma membrane and bind to inactive cytoplasmic forms of mineralocorticoid receptor. This binding dissociates the mineralocorticoid receptor from a multiprotein complex, which in turn mediates translocation of the mineralocorticoid receptor through the nuclear pores to the chromatin. In the nucleus, the activated receptor acts as a positive transcription factor to modulate expression of multiple proteins, including the serum and glucocorticoid inducible kinase‐1 (sgk‐1). Aldosterone‐induced sgk‐1 expression triggers a cascade of events that ultimately increase the absorption of sodium ions and water through the epithelial sodium channel and indirectly increase potassium excretion. At the end of this cascade, intravascular volume expands and BP rises.

The preceding view remains substantially intact today, but a recent ongoing change in our understanding of aldosterone biology has led to a deeper appreciation of the nonclassical aspects of this hormone. ³⁷ Moreover, extra‐adrenal synthesis of aldosterone in these same tissues has been documented, and a localized paracrine role has been proposed. It has been known that the vascular wall—in particular, the vascular smooth muscle cell—expresses not only mineralocorticoid receptors but also the aldosterone selectivity‐conferring enzyme 11β‐hydroxysteroid dehydrogenase. ³⁸ Recently, in vitro and in vivo studies on human blood vessels have confirmed their status as aldosterone target tissues. These findings suggest that tissue aldosterone could be more important in causing cardiovascular damage than the slightly elevated plasma aldosterone in resistant hypertension. Novel adipose‐derived factors that contribute to aldosterone regulation offer an explanation for the overproduction of aldosterone that occurs in hypertension. The significance of this mechanism in human physiologic regulation is a topic that requires future study.

CONCLUSIONS

Although aldosterone was discovered more than 50 years ago, it is only within the past decade that the role of aldosterone in the pathogenesis of cardiovascular disease has been better understood. ³⁹ , ⁴⁰ Research into the action of aldosterone has challenged the original belief that aldosterone acts solely on specific receptors in epithelial tissues and modulates electrolyte and water balance via a genomic mechanism. Indeed, extra‐adrenal biosynthesis, alternative nonepithelial target tissues, and rapid nongenomic mechanisms of action have now been revealed. It is likely that there is synergy between the classic effects of aldosterone and these novel mechanisms. Despite this wide range of target tissues and mechanism of actions, all of the effects of aldosterone are targeted toward regulation of the cardiovascular system. The role of aldosterone as a key cardiovascular hormone is now recognized, especially in the presence of increased salt intake. New research has focused on the actions of aldosterone in target organs beyond the kidney, inducing endothelial dysfunction, vascular inflammation, fibrosis, and necrosis. This pathologic process leads to functional and structural changes of small and large arteries, leading to further BP increases that may prove resistant to most antihypertensive treatment. This evidence suggests that blocking the effects of aldosterone on the vasculature by selective aldosterone receptor blockers could have beneficial effects in resistant hypertension.