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Interfering with mineralocorticoid receptor activation: the past, present, and future.

Dorrance AM - F1000Prime Rep (2014)

Bottom Line: This lack of specificity caused the use of the first-generation mineralocorticoid receptor antagonists to be fraught with difficulty because of the side effects produced by drug administration.However, in recent years, several advances have been made that could potentially increase the clinical use of agents that inhibit the actions of aldosterone.These will be discussed here along with some examples of the beneficial effects of these new therapeutic agents.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology and Toxicology, Michigan State University, B340 Life Sciences 1355 Bogue Street, East Lansing, MI 48824 USA.

ABSTRACT
Aldosterone is a potent mineralocorticoid produced by the adrenal gland. Aldosterone binds to and activates the mineralocorticoid receptor (MR) in a plethora of tissues, but the cardiovascular actions of aldosterone are of primary interest clinically. Although MR antagonists were developed as antihypertensive agents, they are now considered to be important therapeutic options for patients with heart failure. Specifically, blocking only the MR has proven to be a difficult task because of its similarity to other steroid receptors, including the androgen and progesterone receptors. This lack of specificity caused the use of the first-generation mineralocorticoid receptor antagonists to be fraught with difficulty because of the side effects produced by drug administration. However, in recent years, several advances have been made that could potentially increase the clinical use of agents that inhibit the actions of aldosterone. These will be discussed here along with some examples of the beneficial effects of these new therapeutic agents.

No MeSH data available.


Related in: MedlinePlus

Schematic of the potential sites for inhibiting the actions of aldosterone/mineralocorticoid receptor activationAbbreviations: MR, mineralocorticoid receptor.
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fig-001: Schematic of the potential sites for inhibiting the actions of aldosterone/mineralocorticoid receptor activationAbbreviations: MR, mineralocorticoid receptor.

Mentions: Aldosterone, a mineralocorticoid produced primarily in the adrenal gland, is classically considered to regulate sodium and water balance in the kidney and to control blood pressure. Increases in plasma aldosterone lead to sodium retention, potassium excretion, and hypertension. In recent years, it has become clear that aldosterone, or activation of its receptor, the MR, has several extrarenal effects that are largely detrimental, at least in the setting of heart disease [1-3] and hypertension [4,5]. The increasing knowledge of the effects of aldosterone on the cardiovascular system in particular has led to a renewed interest in developing ways to block its actions. This has led to the development of several new drugs that can potentially interfere with MR signaling. These will be discussed here; for each drug class, I have selected recent studies describing the effects of the drug to highlight their potential usefulness in the treatment of cardiovascular conditions. I will discuss the classic steroidal MR antagonists—spironolactone and eplerenone—and the newer non-steroidal antagonists. I will also discuss the progress in the development of aldosterone synthase inhibitors and will consider the rapid non-genomic effects of aldosterone and their inhibition. The potential sites for inhibition of the actions of aldosterone are summarized in Figure 1.


Interfering with mineralocorticoid receptor activation: the past, present, and future.

Dorrance AM - F1000Prime Rep (2014)

Schematic of the potential sites for inhibiting the actions of aldosterone/mineralocorticoid receptor activationAbbreviations: MR, mineralocorticoid receptor.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4126546&req=5

fig-001: Schematic of the potential sites for inhibiting the actions of aldosterone/mineralocorticoid receptor activationAbbreviations: MR, mineralocorticoid receptor.
Mentions: Aldosterone, a mineralocorticoid produced primarily in the adrenal gland, is classically considered to regulate sodium and water balance in the kidney and to control blood pressure. Increases in plasma aldosterone lead to sodium retention, potassium excretion, and hypertension. In recent years, it has become clear that aldosterone, or activation of its receptor, the MR, has several extrarenal effects that are largely detrimental, at least in the setting of heart disease [1-3] and hypertension [4,5]. The increasing knowledge of the effects of aldosterone on the cardiovascular system in particular has led to a renewed interest in developing ways to block its actions. This has led to the development of several new drugs that can potentially interfere with MR signaling. These will be discussed here; for each drug class, I have selected recent studies describing the effects of the drug to highlight their potential usefulness in the treatment of cardiovascular conditions. I will discuss the classic steroidal MR antagonists—spironolactone and eplerenone—and the newer non-steroidal antagonists. I will also discuss the progress in the development of aldosterone synthase inhibitors and will consider the rapid non-genomic effects of aldosterone and their inhibition. The potential sites for inhibition of the actions of aldosterone are summarized in Figure 1.

Bottom Line: This lack of specificity caused the use of the first-generation mineralocorticoid receptor antagonists to be fraught with difficulty because of the side effects produced by drug administration.However, in recent years, several advances have been made that could potentially increase the clinical use of agents that inhibit the actions of aldosterone.These will be discussed here along with some examples of the beneficial effects of these new therapeutic agents.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology and Toxicology, Michigan State University, B340 Life Sciences 1355 Bogue Street, East Lansing, MI 48824 USA.

ABSTRACT
Aldosterone is a potent mineralocorticoid produced by the adrenal gland. Aldosterone binds to and activates the mineralocorticoid receptor (MR) in a plethora of tissues, but the cardiovascular actions of aldosterone are of primary interest clinically. Although MR antagonists were developed as antihypertensive agents, they are now considered to be important therapeutic options for patients with heart failure. Specifically, blocking only the MR has proven to be a difficult task because of its similarity to other steroid receptors, including the androgen and progesterone receptors. This lack of specificity caused the use of the first-generation mineralocorticoid receptor antagonists to be fraught with difficulty because of the side effects produced by drug administration. However, in recent years, several advances have been made that could potentially increase the clinical use of agents that inhibit the actions of aldosterone. These will be discussed here along with some examples of the beneficial effects of these new therapeutic agents.

No MeSH data available.


Related in: MedlinePlus