Mechanism of STEROID HORMONE action
Interfering with mineralocorticoid receptor activation: the past, present, and futureAldosterone 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. Steroid kur kosten los MR antagonists were developed as antihypertensive agents, they are now steroid hormone action vs non steroid hormone action 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.
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.
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. Aldosterone is produced primarily in the adrenal zona glomerulosa.
There is some evidence that other tissues, including the vasculature, heart, brain, and adipose tissues, produce aldosterone [ 6 - 13 ]. However, these findings are controversial and have largely been refuted [ 14 , 15 ]. Aldosterone secretion is controlled by several factors. The most prominent are angiotensin II and potassium. Increases in both of these factors cause an increase in the production of aldosterone, but the actions of angiotensin II and potassium are independent of each other [ 16 ].
Acute increases in the adrenocorticotrophic hormone ACTH also increase aldosterone production, but sustained stimulation of the adrenal gland with ACTH inhibits aldosterone production [ 16 ]. There are several other aldosterone secretagogues, which include endothelin, vasopressin, and serotonin; these are less potent than angiotensin II and potassium and their physiological roles remain ill-defined [ 17 ].
Aldosterone causes its effects by binding to the MR. The MR belongs to the steroid receptor superfamily that contains the progesterone, estrogen, androgen, and glucocorticoid receptors [ 18 ]. These receptors have a common structure, and this has made the development of highly specific MR antagonists difficult. The MR is unique in this family in that it has two ligands—aldosterone and cortisol or corticosterone in rodents —that bind to the MR with the same affinity [ 19 ].
There have been several excellent review articles describing the pre-receptor regulation of MR signaling [ 20 , 22 ]. The MR has been the least studied of the steroid receptor family for reviews of MR signaling, see [ 18 , 23 ]. These trials showing that spironolactone and eplerenone reduced the morbidity and mortality in patients with heart failure and left ventricular dysfunction led to a renewed interest in MR biology and to a new search for novel ways to inhibit the system.
There is a real interest in finding ways to inhibit the cardiovascular effects of MR activation, while leaving the physiological effects on the kidney intact. The competitive MR antagonist spironolactone was developed as an antihypertensive agent in the s and became commercially available in Although spironolactone is a potent MR antagonist, it also binds to other members of the steroid receptor family.
It has significant anti-androgenic and progestogenic effects [ 26 ] that lead to gynecomastia, impotence, and menstrual irregularities [ 27 - 29 ].
The side effects associated with spironolactone meant that there was a need for a more selective MR antagonist that could mimic the beneficial effects of spironolactone in the population with essential hypertension without the related side effects [ 30 ]. The search for this drug led to the development of eplerenone, which entered phase 1 clinical trials in [ 31 ] and was first marketed in the United States in Although eplerenone is a more selective MR antagonist than spironolactone, it has a fold lower affinity for the receptor, which makes it a less potent antagonist than spironolactone [ 32 , 33 ].
It seems that the 42 years from the approval of spironolactone to the approval of the second-generation drug is a pharmaceutical industry record [ 34 ]. Even with this really long wait, it is not clear that the successor is any better than the parent compound for the treatment of human hypertension [ 35 , 36 ].
However, it should be noted that the long search for new MR blockers yielded some other useful drugs, including drospirenone, which has progestogenic activity and is included in several forms of birth control pills [ 37 ]. One of the differences between spironolactone and eplerenone is their metabolism. Spironolactone is metabolized to two compounds, which also have anti-MR activity [ 32 ], whereas eplerenone has no active metabolites [ 38 ]. One of the active metabolites of spironolactone, canrenone [ 39 ], is currently in clinical use and effectively reduces blood pressure, insulin resistance, and markers of inflammation in patients with metabolic syndrome [ 40 ].
From an experimental standpoint, several labs, including our own, have begun to utilize canrenone or potassium canrenoate, which is converted to canrenone, in long-term animal studies because of their ease of administration. Both can be administered in the drinking water without the need for additional vehicles [ 41 , 42 ]. Importantly, canrenone has less anti-androgenic effects than spironolactone [ 43 - 45 ]. One of the suggested mechanisms responsible for the beneficial effects of MR antagonists is a reduction in vascular inflammation.
It has been clear for some time that inflammation is increased in mineralocorticoid-dependent hypertension, such as the deoxycorticosterone DOCA -salt hypertensive rats and much of this research has focused on macrophages. Early studies showed that MR activation increases intracellular adhesion molecule-1 ICAM-1 expression and leukocyte adhesion in endothelial cells [ 46 ], and we have shown that spironolactone reduces ICAM-1 messenger RNA mRNA expression in cerebral arteries from hypertensive rats [ 47 ].
Several studies have shown that MR activation is linked to macrophage infiltration into the heart in DOCA-salt rats and that eplerenone inhibits this action [ 52 - 54 ]. More recent studies of the effects of MR activation on macrophages have focused on the MR within the macrophage itself and on the concept that MR activation can alter macrophage polarity, leading to a more proinflammatory phenotype. The first studies using myeloid cell-specific MR knockout mice were published by Rickard and colleagues [ 55 ] in Later studies using myeloid cell-specific MR knockout mice showed that, in the absence of the MR, the macrophages took on an anti-inflammatory wound-healing phenotype [ 56 ].
It is, however, interesting that MR antagonism with eplerenone in macrophages from healthy patients and patients with heart failure does not completely recapitulate the effects of genetic ablation of the MR [ 59 , 60 ]. Although most studies have focused on macrophages, some studies suggest that T cells are also an important part of the vascular inflammatory response associated with hypertension [ 61 ]. Recent studies assessed the mechanisms responsible for T cell activation in DOCA-salt hypertensive rats.
These studies showed that MR activation caused the activation of T helper 17 Th17 cells and a downregulation of regulatory T Treg cells; this occurred in a blood pressure-independent manner. Spironolactone ameliorated the response to DOCA-salt, but blood pressure lowering through a non-renin angiotensin II-dependent mechanism had no effect.
This suggests that the effects of spironolactone on the T cell populations are MR -- and not blood pressure -- dependent. MR blockade is useful in patients with heart failure and chronic kidney disease [ 3 , 24 , 63 ].
However, the risk of side effects, hyperkalemia development, and renal dysfunction makes eplerenone and spironolactone the least frequently prescribed medications among all those recommended for the treatment of heart failure [ 64 - 68 ]. This means that the search for new MR antagonists has been focused on finding drugs that have greater effects on the heart than on the kidney.
This is essentially a repurposing of MR antagonists; they have moved on from their initial roles as blood pressure-lowering agents to become cardio-protective agents. The goal of these companies was to identify compounds with greater specificity at the MR than spironolactone but that were more efficacious than eplerenone. Interestingly, some of the answers to this question were found in a class of drug that was already in use clinically.
The dihydropyridines, which are L-type calcium channel blockers, were found to act as MR antagonists in vitro and in vivo [ 70 - 73 ]. This led to a surge of drug development activity using the basic structure of the dihydropyridines as a backbone for the development of new drugs. For Bayer, this led to the development of BAY [ 74 ].
This drug, also known as finerenone, is a potent antagonist at the human MR; it has a half maximal inhibitory concentration IC 50 of 18 nM for the MR and no activity at any of the other steroid hormone receptors or at 65 other receptors and ion channels [ 74 ]. Thus far, the results of this trial appear favorable. The mineralocorticoid Receptor Antagonist Tolerability Study ARTS assessed the safety and tolerability of BAY in patients with reduced left ventricular ejection fraction and chronic kidney disease [ 76 ].
Although the trial was too short to assess mortality from heart failure, the analysis of cardiac markers of failure, including brain natriuretic peptide BNP and N-terminal pro-BNP, suggests beneficial cardiovascular effects of BAY The incidence of hyperkalemia and reduced renal function was lower in the patients treated with BAY than it was in patients treated with spironolactone [ 76 ].
The choice of spironolactone as the comparator drug is, however, considered to be a negative feature of this study. In the future, it will be important to conduct a head-to-head comparison between BAY and eplerenone [ 77 ]. Preclinical studies using BAY are also producing promising results. A recent study using rats with mineralocorticoid-dependent hypertension and rats with heart failure showed that BAY has remarkable effects at very low doses.
This study was a head-to-head comparison with eplerenone, and the authors matched the drugs for natriuretic effects. The authors found that the tissue distribution of BAY is different than that for eplerenone. Spironolactone and eplerenone preferentially accumulate in the kidney compared with the heart [ 69 ], whereas BAY accumulates in both organs to a similar extent [ 78 ]. This differential accumulation pattern may be part of the reason why the patients in the ARTS trial experienced less renal dysfunction when taking BAY compared with spironolactone [ 76 ].
Interestingly, BAY does not appear to be as good an antihypertensive agent as eplerenone. It appears that, although BAY does not lower blood pressure, its effects on the heart are much more marked than those of eplerenone: BAY also had marked beneficial effects on the kidney. The cardiac injury in a chronic myocardial infarction model was also significantly reduced by BAY [ 78 ]. In this study, the fact that BAY did not cause as large a reduction in blood pressure as spironolactone was considered a positive because in patients with worsening heart failure, the blood pressure is already low [ 66 ].
There are several reasons to consider aldosterone synthase inhibitors as potential therapeutic agents for hypertension and heart failure.
The issues with side effects from the steroidal MR antagonists and the need to identify a way to inhibit both the genomic and non-genomic actions see below of aldosterone make inhibiting aldosterone production an attractive concept [ 79 ]. Also, some patients receiving angiotensin-converting enzyme inhibitors ACEIs or angiotensin receptor blockers ARBs experience aldosterone breakthrough, where aldosterone levels increase with drug administration [ 80 , 81 ]; this negative effect of ACEIs and ARBs could be negated by blocking the production of aldosterone.
The development of an aldosterone synthase inhibitor has been a particularly difficult task to achieve. The enzyme aldosterone synthase, encoded by the CYP11B2 gene, catalyzes the rate-limiting step in aldosterone production, the conversion of deoxycorticosterone to aldosterone. Thus, a non-specific inhibitor could interfere with cortisol production and this could impair the stress response while also impacting the inflammatory response and metabolism.
The search for a specific aldosterone synthase blocker has led to the development of two potential therapeutic candidates. FAD showed great potential initially in preclinical trials where it was shown to reduce aldosterone production [ 83 ] and to have beneficial effects in various models of hypertension and heart failure [ 84 - 86 ].
Unfortunately, FAD was also found to have significant inhibitory effects on cortisol production and this limits the clinical usefulness of this compound [ 87 ]. This led to the development of LCI, an aldosterone synthase inhibitor that is similar in structure to FAD but is approved for human use.
This inhibitor is currently in phase 2 clinical trials, and the results are mixed. Despite the potential effects on cortisol production, LCI was deemed safe and well tolerated.
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