Arterial Hypertension: Novel Pharmacological Targets and Future Perspectives
Abstract
:1. Introduction
2. New Drug Targets in Arterial Hypertension
2.1. Natriuretic Peptide and Neprilysin
2.2. Stimulation of Soluble Guanylyl Cyclase A
2.3. Nonsteroidal Mineralocorticoid Receptor Antagonists (MRAs)
2.4. Sodium/Glucose Cotransporter-2 Inhibitors (SGLT2i)
2.5. Aminopeptidase of the Brain Renin-Angiotensin System
2.6. Vasoactive Intestinal Peptide (VIP) Receptor
2.7. Intestinal Sodium (Na+)/Hydrogen (H+) Exchanger 3 (NHE3)
2.8. Endothelin Receptor (ETR)
2.9. Dual L-Type Calcium Channel Blocker/Endothelin A/B2 Receptor Antagonist
2.10. Drugs Targeting the NO Pathway
2.11. Dopamine β-Hydroxylase (DβH) Inhibitor
2.12. Ouabain Inhibitors
2.13. Leptin
2.14. Insulin-Resistant Aminopeptidase (IRAP)
2.15. Gastrointestinal Microbiota
2.16. Vaccines
Target | Drug | Mechanism | Main Findings | Clinical Trial/Study |
---|---|---|---|---|
NP, pGC-A | CRRL269 MANP (ZD100) ANX042 | pGC-A activator | - Vasorelaxation and antihypertensive properties in a canine model of ischemia-induced acute renal dysfunction - Effective at lowering BP, with considerable renal protective function and decreased aldosterone levels - Significant diuretic and natriuretic effects lacking vasodilatory hypotensive features - Higher decreases in office SBP and DBP and 24-h ambulatory SBP than valsartan alone | Chen et al. MANP-HTN-MS (completed 2020) Chen et al. |
Neprilysin+ Angiotensin II Receptor Blockers | Valsartan/sacubitril (LCZ 696) | Angiotensin receptor-neprilysin inhibitors | NCT00549770 (completed 2015) | |
Guanylyl cyclase A | Praliciguat (IW1973) | Stimulator of guanylate cyclase | - Attenuated hypertension and NO deficiency-related diseases | Shea et al. |
Nonsteroidal mineralocorticoid receptors (MRAs) | Finerenone Esaxerenone KBP-5074 | Mineralocorticoid receptor antagonist | - Suppresses mineralocorticoid receptor-mediated fibrotic remodeling in mice cardiac fibroblasts - As monotherapy or as an addition to RAAS inhibitor treatment showed significant antihypertensive benefits - Dose-dependently decreased BP and 24-h urinary albumin excretion in the Dahl salt-sensitive hypertensive rat model - Substantially decreased SBP at the completion of the human study | Lavall et al. NCT02722265 (completed 2019) Chow et al. BLOCK-CKD (Phase 2b—completed 2024) |
Sodium/glucose cotransporter-2 | Canagliflozin Dapagliflozin Empagliflozin | SGLT2 inhibitor | - A decrease in SBP was observed. - Considerably lowered BP and HbA1c and was comparable to placebo in terms of tolerability - Reduced SBP and DBP versus placebo | NCT00642278 (completed 2013) NCT01195662 (completed 2016) EMPA-REG BP (completed 2016) |
Aminopeptidase A | Firibastat (RB150) NI956 | APA inhibitor | - The following was observed in experimental models of hypertension: (1) a reduction in vasopressin release from the posterior pituitary into the circulation, resulting in enhanced diuresis and lowered extracellular volume; (2) a reduction in sympathetic tone, and, thus, lower vascular resistance; and (3) an improvement in baroreflex activity. - In human trials, it failed to demonstrate efficacy in lowering unattended office systolic BP. - Ten times more potent and effective than firibastat in inhibiting brain APA enzymatic activity in vitro and in vivo in hypertensive rats | FRESH (completed 2022) Keck et al. |
Vasoactive intestinal peptide | Vasomera (PB1046) | VIP inhibitor agonists | - Dose-dependently lowers both SBP and DBP, with no clinically relevant dose-dependent changes in HR | NCT01523067 (completed 2013) |
Na+/H+ exchanger 3 (NHE3) | Tenapanor SAR 218034 AVE-0657 | NHE3 inhibitor | - Lowers BP, fluid volume, albuminuria, and left ventricular hypertrophy in rats with nephrectomized kidneys that have been given a salty diet - Enhances fecal sodium excretion, decreases urine sodium excretion and intestinal sodium uptake, and significantly decreases SBP in rats - Causes natriuresis and substantially lowers hypertension in Ang II-infused, high-salt-fed rats | Spencer et al. Gao et al. Li et al./Zhuo et al. |
Endothelin receptor | Bosentan Darusentan Aprocitentan | Nonselective ETR antagonists Selective ETR antagonist Dual ETAR/ETBR antagonist | - The antihypertensive effect of bosentan was equivalent to that of enalapril. - The addition of darusentan led to a considerable reduction in BP in patients with RHTN. - Placebo and darusentan did not vary substantially after 14 weeks regarding the main endpoints, especially sitting office BP. - It was well tolerated and superior to a placebo in decreasing blood pressure at week 4, with a maintained effect at week 40 in individuals with RHTN. | Krum et al. DORADO (NCT00330369-completed 2014) DORADO-AC (NCT00389779-completed 2014) PRECISION (NCT03541174- completed 2023) |
Dual L-Type Calcium Channel /Endothelin A/B2 Receptor | Sargachromenol-D | Dual L-type calcium channel blocker/ET A/B2 antagonist | - Lowers ET-1 and K+ depolarization-induced vasoconstriction in rabbit basilar arteries and lowers BP in rodent models of hypertension | Park et al. |
Nitric oxide (NO) | Sphingosine-1 phosphate (FTY702) L-arginine or L-citrulline | S1PR1 antagonist NO synthase activator | - Might enhance BP and worsen HTN in an ANG II rat model - May reduce BP in hypertensive rats | Gao et al. Dumont et al. |
Dopamineβ-hydroxylase (DβH) | Etamicastat (BIA 5–453) | Dopamine β-hydroxylase inhibitor | - In healthy males and individuals with mild to moderate HTN, 24-h ambulatory BP was reduced dose-dependently. | Almeida et al. |
Ouabain | Rostafuroxin | Ouabain inhibitors | - Patients with the genetic profile P2a or LSS AA genotype responded more favorably (greater SBP drop) to rostafuroxin 50 μg than to losartan. | PEARL-HT |
Insulin-resistant aminopeptidase | HFI-419 | Insulin-resistant aminopeptidase (IRAP) inhibitor | - Superiority to candesartan cilexetil in antifibrotic effectiveness and renoprotection and to the ACE inhibitor, perindopril, in mouse kidney injury produced by abnormally high salt concentrations | Gaspari et al. |
3. Other Possible Targets in Hypertension
3.1. Chemerin
3.2. Autophagy
3.3. Acetylation
3.4. Angiogenesis
3.5. Antioxidative Nutraceuticals Supplementation
4. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Conflicts of Interest
References
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Popa, I.P.; Clim, A.; Pînzariu, A.C.; Lazăr, C.I.; Popa, Ș.; Tudorancea, I.M.; Moscalu, M.; Șerban, D.N.; Șerban, I.L.; Costache-Enache, I.-I.; et al. Arterial Hypertension: Novel Pharmacological Targets and Future Perspectives. J. Clin. Med. 2024, 13, 5927. https://doi.org/10.3390/jcm13195927
Popa IP, Clim A, Pînzariu AC, Lazăr CI, Popa Ș, Tudorancea IM, Moscalu M, Șerban DN, Șerban IL, Costache-Enache I-I, et al. Arterial Hypertension: Novel Pharmacological Targets and Future Perspectives. Journal of Clinical Medicine. 2024; 13(19):5927. https://doi.org/10.3390/jcm13195927
Chicago/Turabian StylePopa, Irene Paula, Andreea Clim, Alin Constantin Pînzariu, Cristina Iuliana Lazăr, Ștefan Popa, Ivona Maria Tudorancea, Mihaela Moscalu, Dragomir N. Șerban, Ionela Lăcrămioara Șerban, Irina-Iuliana Costache-Enache, and et al. 2024. "Arterial Hypertension: Novel Pharmacological Targets and Future Perspectives" Journal of Clinical Medicine 13, no. 19: 5927. https://doi.org/10.3390/jcm13195927
APA StylePopa, I. P., Clim, A., Pînzariu, A. C., Lazăr, C. I., Popa, Ș., Tudorancea, I. M., Moscalu, M., Șerban, D. N., Șerban, I. L., Costache-Enache, I.-I., & Tudorancea, I. (2024). Arterial Hypertension: Novel Pharmacological Targets and Future Perspectives. Journal of Clinical Medicine, 13(19), 5927. https://doi.org/10.3390/jcm13195927