Aldosterone synthase inhibitors: a new option for antihypertensive, cardio-renal protection

Hypertension Research https://doi.org/10.1038/s41440-026-02671-z REVIEW ARTICLE Aldosterone synthase inhibitors: a new option for antihypertensive, cardio-renal protection Atsuhisa Sato1 Mitsuhiro Nishimoto2 ● 1234567890();,: 1234567890();,: Received: 12 February 2026 / Revised: 21 April 2026 / Accepted: 25 April 2026 © The Author(s) 2026. This article is published with open access Abstract Hypertension and organ damage caused by an inappropriate balance between aldosterone and salt are deeply involved in pathologies such as chronic heart failure, chronic kidney disease, and vascular disorders. Mineralocorticoid receptor antagonists are effective not only as antihypertensives, but also as organ-protective drugs, blocking direct aldosteroneinduced organ damage independent of blood pressure. In recent years, research into selective aldosterone synthase inhibitors has progressed, resulting in the development of drugs such as baxdrostat, lorundrostat, and vicadrostat. These drugs are highly selective for aldosterone synthase with little inhibition of 11β-hydroxylase, making them promising antihypertensive and organ-protecting drugs. This article summarizes the basic and clinical research on aldosterone synthase inhibitors to date and reviews their characteristics. Aldosterone synthase inhibitors are drugs with the unprecedented characteristic of reducing blood aldosterone levels. Many studies have shown that low serum aldosterone levels are associated with a reduced risk of cardiovascular events. In fact, clinical trials of aldosterone synthase inhibitors have shown that lowering serum aldosterone levels by 50–70% results in lower blood pressure and organ protection. Even a small reduction in serum or local aldosterone levels is highly likely to improve hypertension and organ damage. Clinically, lowering blood aldosterone levels is very important. Compared to the clinical evidence for mineralocorticoid receptor antagonists, clinical evidence for aldosterone synthase inhibitors remains insufficient. How these two drug types should be used given their differences thus remains unresolved. Discussing the differences in clinical effects in the future is thus important. Keywords Aldosterone synthase inhibitor Mineralocorticoid receptor antagonist Hypertension Chronic kidney disease Cortisol. ● Introduction Hypertension and organ damage caused by an inappropriate balance between aldosterone and salt are deeply involved in pathologies such as chronic heart failure, chronic kidney disease (CKD), and vascular disorders [1–7]. Mineralocorticoid receptor (MR) antagonists are effective not only as antihypertensives, but also as organ-protective drugs, blocking direct aldosterone-induced organ damage * Atsuhisa Sato 1 Department of Internal Medicine, Division of Nephrology and Hypertension, International University of Health and Welfare School of Medicine, Yaita city, Tochigi, Japan 2 Department of Internal Medicine, Division of Nephrology, International University of Health and Welfare School of Medicine, Mita Hospital, Minato-ku, Tokyo, Japan ● ● ● independent of blood pressure [8, 9]. MR-mediated adverse effects are only observed in the presence of both aldosterone and salt. Laboratory studies have shown that even with high concentrations of aldosterone, complete elimination of salt from experimental systems prevents hypertension, inflammation, and fibrosis [10–12]. Therefore, while salt reduction is important, neutralizing the harmful effects of aldosterone is difficult unless salt intake is strictly limited. For example, some individuals with extremely low salt intake reportedly exhibit hyperaldosteronism without developing hypertension [13]. However, salt intake in those cases appears to have been so low that it is unfeasible in modern society and only possible under extremely controlled environments. Conversely, the fact that individuals can survive on such low salt intake shows the importance of the aldosterone/MR cascade in a salt-free environment. In such an environment, an enhanced renin-angiotensinaldosterone system acts as a valuable salt-recycling system within the body. A. Sato, M. Nishimoto Graphical Abstract The site of action of aldosterone synthase inhibitors (ASIs), and differences in mineralocorticoid receptors (MR)mediated actions in epithelial and non-epithelial tissues. Although the MR in epithelial and non-epithelial tissues are genetically identical, their physiological functions differ significantly. In epithelial tissues, aldosterone is the physiological ligand because cortisol is inactivated to cortisone by the enzyme 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2). In contrast, in non-epithelial tissues, this enzyme is absent or present at low levels, making cortisol, which has approximately 100-fold higher free circulating levels, the physiological ligand. The actions of aldosterone and cortisol are mediated by intracellular classical MR, but the existence of a putative membrane MR with high affinity exclusively for aldosterone is also thought to exist. Upon binding to the ligand, MR translocates to the nucleus, and acts through transcriptional activity. On the other hand, membrane MR is thought to mediate rapid, non-genomic effects that do not involve transcriptional activity. ASIs may attenuate aldosterone actions without significantly affecting cortisol actions in epithelial tissues. In non-epithelial tissues, aldosterone actions are not major, and ASIs do not affect the physiological actions of cortisol via MR. Further investigation is needed to determine the pharmacological effects of this mechanism, and how it differs from MR antagonists (The recruitment of co-activators and co-repressors in transcriptional activity is omitted) Non-epithelial tissues Epithelial tissues Rapid, non-genomic effects Cortisol Aldosterone ASIs Membrane MR? 11β-HSD2 Genomic-effects Classical MR Nucleus transcriptional activation Hypertension, Cerebro-cardiovascular disorders Given these limitations of salt restriction, another major strategy is to lower aldosterone levels. Aldosterone is produced in the zona glomerulosa of the adrenal cortex, but the brain is known a site of aldosterone production outside the adrenal gland [14–16]. While production in other areas has been reported, the amounts are extremely low and not clinically significant [17]. Aldosterone synthesis within the brain is widely recognized, but occurs at levels orders of magnitude lower than that in the adrenal gland, and circulating aldosterone can be considered to be almost entirely synthesized by the adrenal gland. Aldosterone synthase, encoded by the CYP11B2 gene, synthesizes 18βhydroxycorticosterone and then aldosterone from corticosterone. Meanwhile, 11β-hydroxylase, encoded by CYP11B1, synthesizes cortisol from deoxycortisol. These two enzymes share 94% amino acid identity [18, 19]. Drugs that inhibit aldosterone synthase therefore also suppress cortisol synthesis, making thei (...truncated)