Mineralocorticoid receptor antagonists and endothelial function

Abstract

Hyperaldosteronism is associated with endothelial dysfunction and impaired vascular reactivity in patients with hypertension or congestive heart failure. When present, endothelial dysfunction is an independent predictor of adverse cardiovascular events. The mineralocorticoid receptor (MR) antagonists spironolactone and eplerenone reduce morbidity and mortality, and it has been suggested that this occurs, in part, as a result of improved vascular function. The routine use of MR antagonists in patients with cardiovascular disease, however, is limited by the development of gynecomastia with spironolactone use and hyperkalemia with the use of both agents. Therefore, the development of newer agents with more favorable side-effect profiles is needed.

Figures

Figure 1

Biological effects of aldosterone in vascular endothelial cells. Aldosterone (ALDO) binds to and activates the mineralocorticoid receptor (MR) to stimulate electrolyte flux and intracellular signaling pathways. These effects may occur through binding of the MR to a MR response element (MRRE) to initiate de novo gene transcription (genomic) or through receptor-mediated pathways in the absence of transcription (non-genomic). The net result is an increase in cell swelling and rigidity with the appearance of gaps between cells resulting in a loss of endothelial barrier function. Aldosterone increases endothelial oxidant stress by enhancing reactive oxygen species (ROS) production and decreasing expression of glucose-6-phosphate dehydrogenase (G6PD), a key antioxidant enzyme in the vascular endothelium. There is a decrease in levels of bioavailable nitric oxide (NO•) owing to diminished activity of the endothelial isoform of nitric oxide synthase (eNOS) as well as sequestration of NO• by ROS. These deleterious effects of aldosterone on endothelial vasodilator signaling pathways is augmented further by increased expression of the vasoconstrictor mediators endothelin-1, cyclooxygenase-2 (COX-2) metabolites, angiotensin converting enzyme (ACE) and angiotensin II receptors.

Figure 2

Chemical structure and pharmacologic profile of spironolactone and eplerenone. The nonselective mineralocorticoid receptor antagonist spironolactone is structurally similar to progesterone and, as such, binds to the progesterone, androgen, and mineralocorticoid receptors. Eplerenone, a derivative of spironolactone with a 9,11-epoxy in the lactone ring and the substitution of a carboxymethyl group in place of the 17α-thioacetyl group, is selective for the mineralocorticoid receptor. The differences in chemical structure between these drugs accounts for their distinct pharmacological profiles. MR, mineralocorticoid receptor; GR, glucocorticoid receptor; AR, androgen receptor; PR, progesterone receptor; Aldo, aldosterone; Dex, dexamethasone; MT, methyltrienolone; PG, progesterone.