Selective Modulators on the Renin–Angiotensin–Aldosterone System: Comparison
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The renin–angiotensin–aldosterone system (RAAS) plays a crucial role in maintaining various physiological processes in the body, including blood pressure regulation, electrolyte balance, and overall cardiovascular health. However, any compounds or drugs known to perturb the RAAS might have an additional impact on transmembrane ionic currents. Herein, a selection of chemical compounds or medications that have long been recognized as interfering with the RAAS are presented.

  • renin–angiotensin–aldosterone system
  • small molecules
  • off-target effect

1. Introduction

The renin–angiotensin–aldosterone system (RAAS) plays a crucial role in regulating various physiological processes in the body, primarily related to blood pressure and fluid balance. It is a complex hormonal system that involves the interaction of several hormones and enzymes [1]. When blood pressure drops or blood flow to the kidneys is reduced, the RAAS is activated to help restore blood pressure and maintain adequate perfusion to vital organs. The dysregulation of this system can lead to various medical conditions [2,3][2][3]. For example, overactivation of the RAAS is associated with hypertension, heart failure, and kidney disease [1,3,4,5][1][3][4][5]. Alternatively, inhibiting certain components of the RAAS, such as ACE inhibitors or blockers of angiotensin II type 1 (AT1) receptors, is a common approach in managing hypertension and heart failure [6].

2. Apocynin (Acetovanillone, 4′-Hydroxy-3′-methoxyacetophenone)

Apocynin (aPO), a polyphenolic compound, is a naturally occurring ortho-methoxy-substituted catechol isolated from a variety of plant sources, including Apocynum cannabinum, Pierorhiza kurioa, and so on [16][7]. This compound has been used as a selective inhibitor of NADPH-dependent oxidase (NOX) [17][8]. The excessive or dysregulated production of reactive oxygen species caused by NOX activity can be detrimental to cells and tissues. aPO is recognized as one of the most promising compounds in a variety of pathophysiological disorders, such as inflammatory and neurodegenerative diseases, glioma, and cardiac failure [16,17][7][8]. Previous studies have shown the ability of aPO to attenuate the angiotensin II-induced activation of epithelial Na+ channels in human umbilical vein endothelial cells and to blunt the activation of these channels caused by epidermal growth factor, insulin growth factor-1, and insulin [18,19][9][10].
However, recent studies have shown that this compound can result in the differential stimulation of peak or late-amplitude INa activated by rapid step depolarization in pituitary tumor (GH3) cells [7][11]. aPO-accentuated INa was reversed by ranolazine, an inhibitor of late INa. Additionally, the aPO presence could increase the high- or low-threshold amplitude of persistent INa (INa(P)) elicited by the isosceles-triangular ramp at either the upsloping or downsloping limb, respectively [7][11]. These findings thus allow us to see that aPO-stimulated changes in the amplitude, gating, and voltage-dependent hysteresis of INa(P) appear to be unlinked to and upstream of its inhibitory action on NOX activity. These effects, including the attenuation of angiotensin II actions [18[9][10],19], could potentially participate in adjustments of varying functional activities in electrically excitable cells (e.g., GH3 cells), presuming that similar in vivo findings exist.
From previous pharmacokinetic studies on mice [20][12], following the intravenous injection of aPO (5 mg/kg), the peak plasma aPO level was detected at 1 min, reaching around 33.1 μM. aPO was reported to be a selective inhibitor of NOX2 activity with an IC50 of 10 μM. Moreover, the IC50 value required for the aPO-stimulated peak or late INa was 13.2 or 2.8 μM, respectively, while the KD value estimated on the basis of a minimal reaction scheme was 3.4 μM [7][11]. Therefore, it is important to note that the stimulation of INa by aPO tends to emerge in a manner largely independent of its inhibitory effect on NOX activity. The aPO molecule can exert an interaction at the binding site(s) residing on NaV channels. This study thus highlights an important alternative aspect that has to be taken into account, inasmuch as there is a beneficial or ameliorating effect from aPO in various pathologic disorders, such as inflammatory or neurodegenerative diseases, and heart failure [16,17][7][8].

3. Esaxerenone (7α-[(2R,4R,5S,7S)-7-(2-Carboxyethyl)-2,3-dihydroxy-5,6-dimethyl-4-(2-oxo-1-pyrrolidinyl)oxytetrahydro-2H-pyran-4-yl]-5β,6β-dihydrospiro[naphthalene-1(2H),2′-pyrrolizine]-3′,5′-dione)

Esaxerenone (ESAX; Minnebro®, CS-3150, XL-560) is a new oral, non-steroidal selective blocker of the activity of mineralocorticoid receptors (MRs). By blocking MRs, ESAX reduces the effects of aldosterone, leading to several important physiological effects, such as blood pressure regulation, diuretic effects, and potassium regulation. This drug has seen increasing use in the management of certain medical conditions related to hormone imbalances and kidney function. These disorders include primary aldosteronism (also known as Conn’s disease), refractory hypertension, chronic kidney disease, diabetic nephropathy, and heart failure [21,22,23,24,25,26][13][14][15][16][17][18].
Of interest, a recent study [8][19] demonstrated that, despite its effectiveness in antagonizing the activity of MRs, the ESAX presence exerted an immediate depressant action on INa in pituitary GH3 cells, together with a significant shortening of the inactivation time course of the current. The strength of voltage-dependent hysteresis of INa(P) evoked by the triangular ramp voltage was also depressed by ESAX’s presence. With the continued presence of tefluthrin, the further addition of ESAX effectively counteracted the tefluthrin-induced stimulation of INa. Tefluthrin, a type-I pyrethroid insecticide, is viewed as an activator of INa [27,28][20][21]. The distinguishable inhibition of peak and late INa by ESAX may thus be caused by one of several ionic mechanisms underlying its marked perturbations on physiological processes in different excitable cells (e.g., GH3 cells), assuming that similar observations exist in vivo.
It also needs to be mentioned that the presence of neither dexamethasone, a synthetic glucocorticoid, nor aldosterone had any effects on INa in GH3 cells [8][19]. However, despite the continued exposure to aldosterone, the subsequent application of ESAX resulted in a further decrease in the amplitude of peak INa. It, therefore, seems unlikely that the ESAX-mediated inhibition of the amplitude and gating kinetics of INa was largely associated with its blockade of MRs. It is also important to mention that the maximal plasma concentration of ESAX was reported to reach around 3 μM after a 10-day administration with a dose of 100 mg/d [29][22]. As such, the inhibitory effect of ESAX on peak and late INa could noticeably be of clinical or therapeutic relevance [23,25][15][17]. In concert with its antagonistic action on MRs, ESAX may exert an additional ameliorating action on the salt-induced elevation of blood pressure or on kidney injuries [22,26][14][18].

4. Dexamethasone (9α-Fluoro-11β,17α,21-trihydroxy-16α-methylpregna-1,4-diene-3,20-dione)

The large-conductance Ca2+-activated K+ (BKCa) channel is responsive to both membrane depolarization and intracellular Ca2+ elevation and is activated during the action potentials of neuroendocrine and endocrine cells. When this channel is opened, K+ ions flow out of the cell through the pore, generating an ion current (i.e., a Ca2+-activated K+ current) that hyperpolarizes the cell. This hyperpolarization subsequently reduces cell excitability, limiting its responsiveness to stimuli [30,31,32][23][24][25]. Hyperpolarization, observed in endocrine or neuroendocrine cells, can thus serve as a negative feedback mechanism, effectively halting exocytosis by turning off voltage-gated Ca2+ currents [30,31][23][24].
Glucocorticoids have been shown to modify the sensitivity of BKCa channels to protein phosphorylation in freshly isolated pituitary cells [33][26]. Previous work demonstrated the ability of cortisol to decrease intracellular Ca2+ and prolactin release in pituitary cells [34][27]. Moreover, another notable study reported that dexamethasone (DEX), a synthetic glucocorticoid, was effective in increasing the open-state probability of BKCa channels observed in pituitary GH3 and AtT-20 cells, which was thought to be through a non-genomic mechanism [9][28]. DEX was found to increase the open-state probability of BKCa channels with no change in single-channel conductance. This compound also depressed the firing of spontaneous action potentials in GH3 cells through the stimulation of whole-cell Ca2+-activated K+ currents.
The profile of BKCa channel subunits present in these endocrine cells appears to be similar because β-subunits are lacking, and α-subunits were found to express the STREX-1 exon [35][29]. While DEX is primarily used for its anti-inflammatory effects, it can also have some mineralocorticoid (aldosterone-like) effects at higher doses or with prolonged use. DEX can bind to mineralocorticoid receptors (MRs) in the same way as aldosterone does, and it exerts similar effects on the kidneys [36,37,38][30][31][32]. However, the immediate stimulation of BKCa channels by DEX or other glucocorticoids might partly be responsible for its rapid inhibition of hormone release because such an effect facilitates Ca2+-induced feedback hyperpolarization and prevents voltage-activated Ca2+ entry [9,31,38,39][24][28][32][33].
The DEX concentration used to stimulate BKCa-channel activity might not align with the physiological levels of endogenous glucocorticoids that exhibit similar potency. However, during severe injuries, the daily production rate of glucocorticoids can significantly increase, up to at least tenfold. Additionally, previous research has indicated that locally produced steroids in the brain and endocrine glands, known as neurosteroids, may play a role in regulating cell excitability [40,41,42][34][35][36]. The DEX suppression test has been widely used to screen for adrenal hyperfunction because it is a potent synthetic glucocorticoid. High-dosage glucocorticoids have been used for immunologically mediated diseases [43][37]. The concentrations of plasma glucocorticoids obtained after single infusions can range between 16 and 72 μM [43][37]. Therefore, the stimulatory properties of BKCa channels induced by glucocorticoids may be clinically and therapeutically relevant. Glucocorticoids can also be interesting tools used to characterize the properties of BKCa channels.

References

  1. Hall, J.E.; Coleman, T.G.; Guyton, A.C. The renin-angiotensin system. Normal physiology and changes in older hypertensives. J. Am. Geriatr. Soc. 1989, 37, 801–813.
  2. Ferrario, C.M. Role of angiotensin II in cardiovascular disease therapeutic implications of more than a century of research. J. Renin Angiotensin Aldosterone Syst. 2006, 7, 3–14.
  3. Ortiz, R.M.; Satou, R.; Zhuo, J.L.; Nishiyama, A. The Renin-Angiotensin-Aldosterone System in Metabolic Diseases and Other Pathologies. Int. J. Mol. Sci. 2023, 24, 7413.
  4. Bhandari, S.; Mehta, S.; Khwaja, A.; Cleland, J.G.F.; Ives, N.; Brettell, E.; Chadburn, M.; Cockwell, P. Renin–Angiotensin System Inhibition in Advanced Chronic Kidney Disease. N. Engl. J. Med. 2022, 387, 2021–2032.
  5. Miura, S.-I. The renin-angiotensin-aldosterone system: A new look at an old system. Hypertens. Res. 2023, 46, 932–933.
  6. Ferrario, C.M.; Mullick, A.E. Renin angiotensin aldosterone inhibition in the treatment of cardiovascular disease. Pharmacol. Res. 2017, 125 Pt A, 57–71.
  7. Yang, T.; Zang, D.W.; Shan, W.; Guo, A.C.; Wu, J.P.; Wang, Y.J.; Wang, Q. Synthesis and Evaluations of Novel Apocynin Derivatives as Anti-Glioma Agents. Front. Pharmacol. 2019, 10, 951.
  8. Du, Z.D.; Yu, S.; Qi, Y.; Qu, T.F.; He, L.; Wei, W.; Liu, K.; Gong, S.S. NADPH oxidase inhibitor apocynin decreases mitochondrial dysfunction and apoptosis in the ventral cochlear nucleus of D-galactose-induced aging model in rats. Neurochem. Int. 2019, 124, 31–40.
  9. Ilatovskaya, D.V.; Pavlov, T.S.; Levchenko, V.; Staruschenko, A. ROS production as a common mechanism of ENaC regulation by EGF, insulin, and IGF-1. Am. J. Physiol. Cell Physiol. 2013, 304, C102–C111.
  10. Downs, C.A.; Johnson, N.M.; Coca, C.; Helms, M.N. Angiotensin II regulates δ-ENaC in human umbilical vein endothelial cells. Microvasc. Res. 2018, 116, 26–33.
  11. Chuang, T.H.; Cho, H.Y.; Wu, S.N. Effective Accentuation of Voltage-Gated Sodium Current Caused by Apocynin (4′-Hydroxy-3′-methoxyacetophenone), a Known NADPH-Oxidase Inhibitor. Biomedicines 2021, 9, 1146.
  12. Liu, F.; Fan, L.M.; Michael, N.; Li, J.M. In vivo and in silico characterization of apocynin in reducing organ oxidative stress: A pharmacokinetic and pharmacodynamic study. Pharmacol. Res. Perspect. 2020, 8, e00635.
  13. Duggan, S. Esaxerenone: First Global Approval. Drugs 2019, 79, 477–481.
  14. Ito, S.; Itoh, H.; Rakugi, H.; Okuda, Y.; Yoshimura, M.; Yamakawa, S. Double-Blind Randomized Phase 3 Study Comparing Esaxerenone (CS-3150) and Eplerenone in Patients With Essential Hypertension (ESAX-HTN Study). Hypertension 2020, 75, 51–58.
  15. Rahman, A.; Sawano, T.; Sen, A.; Hossain, A.; Jahan, N.; Kobara, H.; Masaki, T.; Kosaka, S.; Kitada, K.; Nakano, D.; et al. Cardioprotective Effects of a Nonsteroidal Mineralocorticoid Receptor Blocker, Esaxerenone, in Dahl Salt-Sensitive Hypertensive Rats. Int. J. Mol. Sci. 2021, 22, 2069.
  16. Wan, N.; Rahman, A.; Nishiyama, A. Esaxerenone, a novel nonsteroidal mineralocorticoid receptor blocker (MRB) in hypertension and chronic kidney disease. J. Hum. Hypertens. 2021, 35, 148–156.
  17. Janković, S.M.; Janković, S.V. Clinical Pharmacokinetics and Pharmacodynamics of Esaxerenone, a Novel Mineralocorticoid Receptor Antagonist: A Review. Eur. J. Drug Metab. Pharmacokinet. 2022, 47, 291–308.
  18. Ojha, U.; Ruddaraju, S.; Sabapathy, N.; Ravindran, V.; Worapongsatitaya, P.; Haq, J.; Mohammed, R.; Patel, V. Current and Emerging Classes of Pharmacological Agents for the Management of Hypertension. Am. J. Cardiovasc. Drugs 2022, 22, 271–285.
  19. Chang, W.T.; Wu, S.N. Characterization of Direct Perturbations on Voltage-Gated Sodium Current by Esaxerenone, a Nonsteroidal Mineralocorticoid Receptor Blocker. Biomedicines 2021, 9, 549.
  20. Wu, S.N.; Wu, Y.H.; Chen, B.S.; Lo, Y.C.; Liu, Y.C. Underlying mechanism of actions of tefluthrin, a pyrethroid insecticide, on voltage-gated ion currents and on action currents in pituitary tumor (GH3) cells and GnRH-secreting (GT1-7) neurons. Toxicology 2009, 258, 70–77.
  21. So, E.C.; Wu, S.N.; Lo, Y.C.; Su, K. Differential regulation of tefluthrin and telmisartan on the gating charges of INa activation and inactivation as well as on resurgent and persistent INa in a pituitary cell line (GH3). Toxicol. Lett. 2018, 285, 104–112.
  22. Kato, M.; Furuie, H.; Shimizu, T.; Miyazaki, A.; Kobayashi, F.; Ishizuka, H. Single- and multiple-dose escalation study to assess pharmacokinetics, pharmacodynamics and safety of oral esaxerenone in healthy Japanese subjects. Br. J. Clin. Pharmacol. 2018, 84, 1821–1829.
  23. Wu, S.N. Large-conductance Ca2+- activated K+ channels:physiological role and pharmacology. Curr. Med. Chem. 2003, 10, 649–661.
  24. Zang, K.; Zhang, Y.; Hu, J.; Wang, Y. The Large Conductance Calcium- and Voltage-activated Potassium Channel (BK) and Epilepsy. CNS Neurol. Disord. Drug Targets 2018, 17, 248–254.
  25. Orfali, R.; Albanyan, N. Ca(2+)-Sensitive Potassium Channels. Molecules 2023, 28, 885.
  26. Tian, L.; Duncan, R.R.; Hammond, M.S.; Coghill, L.S.; Wen, H.; Rusinova, R.; Clark, A.G.; Levitan, I.B.; Shipston, M.J. Alternative splicing switches potassium channel sensitivity to protein phosphorylation. J. Biol. Chem. 2001, 276, 7717–7720.
  27. Hyde, G.N.; Seale, A.P.; Grau, E.G.; Borski, R.J. Cortisol rapidly suppresses intracellular calcium and voltage-gated calcium channel activity in prolactin cells of the tilapia (Oreochromis mossambicus). Am. J. Physiol. Endocrinol. Metab. 2004, 286, E626–E633.
  28. Huang, M.-H.; So, E.C.; Liu, Y.-C.; Wu, S.-N. Glucocorticoids stimulate the activity of large-conductance Ca2+-activated K+ channels in pituitary GH3 and AtT-20 cells via a non-genomic mechanism. Steroids 2006, 71, 129–140.
  29. Shipston, M.J.; Duncan, R.R.; Clark, A.G.; Antoni, F.A.; Tian, L. Molecular components of large conductance calcium-activated potassium (BK) channels in mouse pituitary corticotropes. Mol. Endocrinol. 1999, 13, 1728–1737.
  30. Armanini, D.; Zennaro, C.M.; Martella, L.; Pratesi, C.; Scali, M.; Zampollo, V. Regulation of aldosterone receptors in hypertension. Steroids 1993, 58, 611–613.
  31. Kazama, I.; Shoji, M. Targeting colonic BK channels: A novel therapeutic strategy against hyperkalemia in chronic kidney disease. Nefrología, 2019; in press.
  32. Pofi, R.; Caratti, G.; Ray, D.W.; Tomlinson, J.W. Treating the side effects of exogenous glucocorticoids; Can we separate the good from the bad? Endocr. Rev. 2023; online ahead of print.
  33. Loechner, K.J.; Knox, R.J.; McLaughlin, J.T.; Dunlap, K. Dexamethasone-mediated inhibition of calcium transients and ACTH release in a pituitary cell line (AtT-20). Steroids 1999, 64, 404–412.
  34. Compagnone, N.A.; Mellon, S.H. Neurosteroids: Biosynthesis and Function of These Novel Neuromodulators. Front. Neuroendocrinol. 2000, 21, 1–56.
  35. Gulyaeva, N.V. Glucocorticoids Orchestrate Adult Hippocampal Plasticity: Growth Points and Translational Aspects. Biochemistry 2023, 88, 565–589.
  36. Lisakovska, O.; Labudzynskyi, D.; Khomenko, A.; Isaev, D.; Savotchenko, A.; Kasatkina, L.; Savosko, S.; Veliky, M.; Shymanskyi, I. Brain vitamin D(3)-auto/paracrine system in relation to structural, neurophysiological, and behavioral disturbances associated with glucocorticoid-induced neurotoxicity. Front. Cell. Neurosci. 2023, 17, 1133400.
  37. Baylis, E.M.; Williams, I.A.; English, J.; Marks, V.; Chakraborty, J. High dose intravenous methylprednisolone “pulse” therapy in patients with rheumatoid disease. Plasma methylprednisolone levels and adrenal function. Eur. J. Clin. Pharmacol. 1982, 21, 385–388.
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