Primary Aldosteronism and Resistant Hypertension: A Pathophysiological Insight

Abstract

Primary aldosteronism (PA) is a pathological condition characterized by an excessive aldosterone secretion; once thought to be rare, PA is now recognized as the most common cause of secondary hypertension. Its prevalence increases with the severity of hypertension, reaching up to 29.1% in patients with resistant hypertension (RH). Both PA and RH are "high-risk phenotypes", associated with increased cardiovascular morbidity and mortality compared to non-PA and non-RH patients. Aldosterone excess, as occurs in PA, can contribute to the development of a RH phenotype through several mechanisms. First, inappropriate aldosterone levels with respect to the hydro-electrolytic status of the individual can cause salt retention and volume expansion by inducing sodium and water reabsorption in the kidney. Moreover, a growing body of evidence has highlighted the detrimental consequences of "non-classical" effects of aldosterone in several target tissues. Aldosterone-induced vascular remodeling, sympathetic overactivity, insulin resistance, and adipose tissue dysfunction can further contribute to the worsening of arterial hypertension and to the development of drug-resistance. In addition, the pro-oxidative, pro-fibrotic, and pro-inflammatory effects of aldosterone may aggravate end-organ damage, thereby perpetuating a vicious cycle that eventually leads to a more severe hypertensive phenotype. Finally, neither the pathophysiological mechanisms mediating aldosterone-driven blood pressure rise, nor those mediating aldosterone-driven end-organ damage, are specifically blocked by standard first-line anti-hypertensive drugs, which might further account for the drug-resistant phenotype that frequently characterizes PA patients.

Keywords: aldosterone; arterial hypertension; pathophysiology; primary aldosteronism; resistant hypertension; secondary hypertension.

Figure 1

Physiological regulators of aldosterone secretion. Several stimuli can induce the release of aldosterone by the adrenal cortex via the renin-angiotensin system. These include a reduction in renal perfusion pressure, sensed by juxtaglomerular cells, a decrease in NaCl delivery to the macula densa and an increase in sympathetic activity. Moreover, hyperkalemia can directly stimulate aldosterone secretion from adrenal cortex. Finally, the adrenocorticotropic hormone (ACTH) can act as an aldosterone secretagogue, although it plays a minor role in its regulation.

Figure 2

Mechanisms underlying the pro-oxidant and pro-fibrotic effect of aldosterone. By binding to the mineralocorticoid receptor (MR), aldosterone (ALD) can induce the production of reactive oxygen species (ROS) through several mechanisms. First of all, aldosterone can promote the generation of ROS by activating the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. Moreover, MR activation increases the production of ROS by the mitochondria and can also determine the uncoupling of nitric oxide synthase (NOS), thereby leading to the production of superoxide instead of nitric oxide. Finally, aldosterone can reduce glucose-6-phosphate dehydrogenase (G6PDH) expression, thereby impairing the generation of reduced glutathione (GSH), one of the main defensive mechanisms of the cell against oxidative stress. Eventually, increased ROS production triggers the activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB), that in turn induces the transcription of pro-inflammatory and pro-fibrotic genes. Activated MR can also directly stimulate NF-kB, probably via serum/glucocorticoid regulated kinase 1 (SGK1).

Figure 3

Potential pathophysiological mechanisms linking aldosterone excess and resistant hypertension (RH). At a renal level, aldosterone induces chronic sodium and water retention, leading to intravascular volume expansion; moreover, aldosterone can contribute to vascular and tubular inflammation and fibrosis, thereby impairing kidney function. At a vascular level, aldosterone induces endothelial dysfunction, oxidative stress, inflammation and fibrosis thereby leading to arterial stiffening. Additionally, aldosterone excess can directly influence sympathetic activity and can also have a role in the development of insulin resistance and metabolic syndrome. Eventually, these detrimental effects of aldosterone excess on several target tissues can contribute to the development and maintenance of resistant hypertension.