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Mineralocorticoid receptor antagonists

2018; Lippincott Williams & Wilkins; Volume: 36; Issue: 5 Linguagem: Inglês

10.1097/hjh.0000000000001686

1473-5598

Gian Paolo Rossi,

Stress Responses and Cortisol

Aldosterone, the major mineralocorticoid hormone, by increasing preload and after-load plays a key role in many forms of arterial hypertension and related cardiovascular damage. These forms include primary aldosteronism – a common but neglected cause of hypertension and particularly of drug-resistant hypertension [1–3] – and secondary aldosteronism. The latter constitutes multiple conditions where renin is activated because of underfilling [4], as heart failure and nephrotic syndrome, and/or because of treatment with diuretics. Furthermore, aldosterone plays a role in primary (essential) hypertension associated with overweight or obesity, where its secretion is held to be inappropriate for the prevailing state of blood pressure (BP) and volume. The mineralocorticoid receptor antagonists (MRAs) have been developed in the last century to block the untoward effects of aldosterone, including BP and congestion. Such agents entail spironolactone, canrenone, potassium canrenoate, and eplerenone [5], all inexpensive drugs that have been around for decades and are now out-of-patent. A further member of the family that has been most recently discovered is finerenone, a dihydropyridine derivative, that is being developed for the treatment of heart failure [6], and diabetic nephropathy [7]. Surprisingly enough, although compelling evidence from a number of randomized clinical trials (RCTs) in heart failure indicates that MRAs save lives [8–10], even in the patients with preserved ejection fraction according to a post hoc analysis of the TOPCAT trial where patients’ adherence to treatment was verified [11], there is no doubt that MRAs remain markedly underused not only in heart failure patients, as shown by a large survey [12], but also as upstream treatment in patients with arterial hypertension. In reality, after some initial enthusiasm in the last century, they have never received due attention by the scientific community and, consequently, even by practicing physicians. In addition to the well known time lag phenomenon whereby translation of scientific evidences into clinical practice takes years, a major reason for the under prescription of MRAs (in spite of unambiguous evidence for their effectiveness) is the fear of side effects. The latter entail hyperkalemia, which, however, occurs in a tiny proportion of the patients, particularly those with chronic kidney disease and/or diabetes, and the side effects related to off-target effects. The estrogen-like effects can cause menstrual irregularities in women, but can be particularly unpleasant in men, as they can range from mild breast discomfort (mastodinia) to gynecomastia, to erectile dysfunction, loss of libido, and impotence, depending on the dose prescribed and individual susceptibility. The lack of large RCTs testing these drugs in arterial hypertension, probably derived from the limited financial interest of the big Pharma industry, as these drugs are now out patent, is a further factor. Thus, possibly because of these motives, the MRAs are not recommended as first-line drugs. The European Society of Hypertension (ESH)/European Society of Cardiology (ESC) guidelines actually placed them as fourth-line agents to be used in resistant hypertension [13], a confinement based on results of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) [14] and of observational studies as, for example, one using 24-h ambulatory BP monitoring by Alvarez-Alvarez et al.[15]. In the ASCOT study in patients who were resistant to an average of three drugs spironolactone effectively lowered BP by 21.9 mmHg (95% CI 20.8–23.0) and by 9.5 mmHg (95% CI 9.0–10.1) on average, for SBP and DBP, respectively [14]. After the publication of the 2013 ESC/ESH guidelines, however, further strong evidence for the effectiveness of the MRA in patients with resistant hypertension was provided by the PATHWAY-2 study, a randomized, double-blind, cross-over trial, in patients with resistant hypertension (e.g. BP not controlled with recommended and/or maximum tolerated doses of triple therapy with ACEI/ARB/Direct renin inhibitor combined with calcium channel blocker and any diuretic except spironolactone) [16]. In this trial, each patient was exposed in a ‘carousel’ fashion to placebo, bisoprolol, doxazosin, or spironolactone as add-on to existing therapy for 12 weeks with up-titration of each drug after 6 weeks, if necessary. Results showed that spironolactone was unequivocally superior to all other regimen for the primary endpoint, average home SBP, recorded in the morning and in the evening, in triplicate, on four consecutive days before study visits. In the Prague-15 Study, another prospective study aimed at testing the effectiveness of renal sympathetic denervation, inclusion of spironolactone in the therapeutic regimen of patients randomized in both arms practically ‘killed’ the effect of the latter procedure, after 1 year [17], and was even more effective than renal sympathetic denervation after 2 years [18]. The high rate of MRA treatment has been advocated as reason for the failure to prove superiority of sympathetic renal denervation in other major trials in patients with resistant hypertension. To date, it can, therefore, be concluded that the effectiveness of MR antagonism in patients with resistant hypertension, is supported by multiple evidence. However, this effectiveness of the MRAs does not come as a surprise as up to 21% of these patients can have undiscovered primary aldosteronism [3]. The results of the meta-analysis by Bazoukis et al.[19], published in the current issue of the Journal of Hypertension, are timely and important: they confirm the clear-cut BP-lowering effects of MRAs in patients with resistant hypertension in a wide range of studies: in six of the RCTs (950 patients) that were meta-analyzed for the effect of spironolactone on BP reduction compared with placebo, spironolactone significantly lowered SBP by −16.10 mmHg (95% CI − 22.26 to −9.94), and DBP by −5.06 mmHg (95% CI −7.32 to −2.47). Moreover, in six RCTs (1046 patients) examined for the effect of spironolactone on BP reduction compared with other antihypertensive agents, spironolactone treatment significantly lowered SBP by −7.27 mmHg (−11.07 to −3.46), and DBP by −4.59 mmHg (95% CI −8.68 to −0.50). These results are even more relevant because with the strength of a large number of patients from multiple studies, they did not show any difference between the effects of MRAs in patients with and without resistant hypertension, a comparison that was never undertaken in previous studies. Thus, although a compelling evidence to recommend MRAs in resistant hypertension exists, the findings by Bazoukis et al.[19] suggest that MRAs can be ‘allround’ drugs, which are useful in a wide range of hypertensive patients, not just those that are labelled as ‘treatment-resistant,’ an observation that does not come unexpected as it is becoming increasingly appreciated that an inappropriate activation of the MR, not just by aldosterone but also by other agonists, is a common mechanism to many forms of arterial hypertension. Of interest, our group recently reported that primary aldosteronism can present itself with normal values of plasma aldosterone concentration [20], a fact already acknowledged, albeit unsupported by evidence, in the Endocrine Society clinical practice guidelines [21]. Moreover, recent data from Japan [22] and the Harvard group [23,24] suggest that primary aldosteronism has a long natural history that likely starts as a subclinical disease with normotension, where plasma aldosterone can appear to be ‘normal’ and the only clue is low plasma renin, and then evolve into high-normal BP, stage I and stage II hypertension, and eventually transform into stage III and/or resistant hypertension with a florid primary aldosteronism phenotype and prominent target organ damage and cardiovascular events. Thus, these data suggest that many cases that are currently labelled as low-renin essential hypertension, in fact, represent undiagnosed cases of primary aldosteronism, which respond well to MRAs. The inverse relationship between plasma concentration of active renin and the BP response to spironolactone in the aforementioned PATHWAY-2 Study is fully consistent with this contention [16]. It has also to be considered that the MR is the target not only of aldosterone but also of other steroids, including cortisol, which circulates in plasma at concentrations 100–1000 fold higher than aldosterone. Of note, not only the MR is inherently nonselective but the MR-responsive elements appear to be similarly nondiscriminating among agonists [25]. Thus, the MR can bind cortisol with the same affinity of aldosterone, which would lead to cortisol-dependent activation of the MR and downstream signaling. Under physiological conditions in aldosterone target organs, as the renal tubule, salivary gland, and colon, this does not result into MR-mediated activation of transcription because cortisol is rapidly inactivated to cortisone by 11ßOHsteroid dehydrogenase type 2 (11ß-HSD2), an enzyme located in close proximity with the MR that requires NAD as a cofactor. With the consumption of licorice, carbenoxolone, and possibly other (yet unknown) substances, or in patients with loss of function mutations in the gene coding for this enzyme, inactivation of cortisol does not occur properly and the patients develop a MR-mediated volume-dependent form of high BP, yet with no aldosterone elevation, the so-called apparent mineralocorticoid excess (AME) syndrome (Fig. 1).FIGURE 1: According to Funder's hypothesis, under physiological conditions in aldosterone target organ tissues the activation of the MR-mediated transcriptional effects of cortisol, which circulates in plasma at a concentration 100-fold to1000-fold higher than aldosterone, is prevented by the conversion operated by (11ß-HSD2) of cortisol to its 11-keto congener cortisone, which is receptor inactive. Thus, the agonist for the MR is aldosterone in spite of its lower concentration and a similar affinity of the MR for cortisol and aldosterone (a). The activity of HSD2 generates NADH from NAD, which intracellularly is 700-fold more abundant than NADH (b). Whenever the activity of HSD2 is genetically deficient, as in the apparent mineralocorticoid excess syndrome, or inhibited, for example, by licorice or carbenoxolone, cortisol can act as a MR agonist (c). The same can occur under conditions of increased intracellular oxidative stress. Thus, a decrease of NADPH generation leads to glucocorticoid-activated MR-dependent transcription. The MRAs can obviously be effective under these conditions. Modified from [25].The same may occur under conditions of enhanced generation of reactive oxygen species as in patients with diabetes mellitus, metabolic syndrome, hypercholesterolemia, and advanced atherosclerosis. In fact, the cortisol-activated MR-mediated transcription factors seem to be sensitive to the intracellular redox status [25]. On the whole, it is becoming increasingly appreciated that an inappropriate activation of the MR by cortisol and possibly other agonists, is a mechanism common to many forms of arterial hypertension. MRAs are obviously effective in patients with these forms of arterial hypertension, which are characterized by low or very low plasma renin. As most meta-analyses, the study by Bazoukis et al.[19] was based on summary data and not on individual patients’ data. Therefore, it falls short in identifying the predictors of the BP lowering with the MRAs. However, some help in this regard can come from the aforementioned PATHWAY-2 Study results in that they showed that the response to spironolactone was significantly and inversely related to plasma renin [16]. This suggests that at least among the patients with resistant hypertension, undetected primary aldosteronism and/or volume expansion are the key factors responsible for high BP. Surprisingly enough, neither the plasma aldosterone concentrations nor the rate of patients with primary aldosteronism were reported in the study [16]. Yet, there is little doubt that low renin is a proxy for a salt and water (volume)-dependent form of high BP, as suggested by John Laragh many decades ago. The assessment of low plasma renin has been hampered by methodological problems when the only available assay was plasma renin activity. However, of much interest, the recent introduction into clinical practice of chemiluminescent methods that use a sandwich approach to directly measure active renin concentration in plasma has allowed to circumvent these problems. As we recently showed in a relatively large prospective study, one such methods, which allows the simultaneous assay of active renin and also of aldosterone in an automated way, provides an accurate measurement of renin even in the patients, as those with primary aldosteronism, where renin is very low or even undetectable [26]. Thus, physicians now are endowed with an inexpensive tool that can allow them to pinpoint the hypertensive patients with low plasma renin that are most likely to respond to MRAs. Unfortunately, recent data from a survey carried out among Italian and German general practitioners showed that only less than 2% of their hypertensive patients are ever submitted to a measurement of plasma renin and aldosterone [2]. The study by Bazoukis et al.[19] does not allow to establish if available MRAs are equally effective in BP lowering, or if there are differences in their potency, and therefore, in the dose required to lower BP. It is well established, however, that eplerenone requires twice daily administration and is less potent than the older agents, and therefore, needs to be up-titrated to provide a BP lowering similar to spironolactone, canrenone, and potassium canrenoate [5]. Whether finerenone is similarly effective in lowering BP is uncertain because, as mentioned above, this drug is being developed in heart failure and could be less effective on the kidney, which can explain its lower tendency to cause hyperkalemia [27]. What is less uncertain is that all MRAs require an individual uptitration of the dose in order to reach the maximum effect of BP. Whether the increase in plasma renin can be a useful index, alongside BP changes, to guide the uptitration of these drugs could not be clarified by the meta-analysis of Bazoukis et al.[19]. It is altogether evident that multiple drugs are generally needed in the fight against arterial hypertension to reach the low target values of BP with treatment, which are indicated in the most recent American Heart Association guidelines [28]. The MRAs are key tools to achieve these goals, particularly in the low-income countries, as these are inexpensive drugs. Whenever used at low doses, their side effects are minimal. The fact that in multiple conditions, in addition to those characterized by hyperaldosteronism, the high BP involved MR-mediated activation of transcription factors provides a straightforward explanation of the effectiveness of MRAs as allround drugs for the treatment of arterial hypertension. ACKNOWLEDGEMENTS Conflicts of interest There are no conflicts of interest.