Search Results (43)

The renin–angiotensin–aldosterone system (RAAS) is essential for controlling blood pressure and maintaining fluid balance, driving significant structural changes throughout the cardiovascular system, including the heart and blood vessels. As a result, the RAAS is a key therapeutic target for various chronic cardiovascular diseases, ranging from arterial hypertension (AH) to heart failure (HF). In this review, one of our objectives is to describe the new evidence over the last 4 years regarding the RAAS. Moreover, we pay attention to the structure and function of the angiotensin II type 1 receptor (AT1R) and its role in hypertension, as well as define its active site. Later, we discuss the most potent, selective inhibitors of AT1 receptors, based on in vitro and in vivo experiments, from 2020 to 2024. Large peptide molecules, small non-peptide-like molecules, and sartan derivatives are analyzed. The low IC₅₀ values of the entities that do not resemble sartans showcase the vast chemical space that can be explored for the creation of more potent antihypertensive medications. We have also employed computational chemistry tools in order to identify key molecular interactions between the compounds of the literature studied in order to elucidate the underlying reasons why these different molecules exhibit variations in their binding energies and overall potency. Full article

Pharmaceutical companies keep producing novel drugs and drug treatments for improving the life of every sick individual, most often following a pattern; a specific drug for a specific condition. Evidence suggests that different medications can have a positive effect on different pathological conditions. The full potential of existing therapies can be revealed through drug repurposing—also referred to as drug repositioning, reprofiling, or re-tasking—which involves identifying new therapeutic uses for approved or investigational drugs beyond their original indications. One significant target in this context is the renin–angiotensin–aldosterone system (RAAS), a crucial regulator of blood pressure and fluid homeostasis, and a central focus in the treatment of chronic cardiovascular conditions such as arterial hypertension (AH) and heart failure (HF). Interestingly, novel investigations show that AT1 antagonists (sartans) are able to broaden their therapeutic scope and potentially combat other diseases such as neurodegenerative diseases, cancer, and osteoarthritis, and even help people with methamphetamine and opioid addiction. Full article

Recent bioassay studies have unexpectedly supported the high (computationally predicted) binding affinities of angiotensin receptor blockers (ARBs) at α-adrenergic receptors (αARs) in isolated smooth muscle. Computational predictions from ligand docking studies are consistent with very low concentrations of ARBs (e.g., sartans or bisartans) that partially reduce (20–50%) the contractile response to phenylephrine, suggesting that some ARBs may function as partial inverse agonists at αARs. Virtual ligand screening (docking) and molecular dynamics (MD) simulations were carried out to explore the binding affinities and stabilities of selected non-peptide ligands (e.g., ARBs and small-molecule opioids) for several G-protein coupled receptor (GPCR) types, including angiotensin II (AngII) type 1 receptor (AT₁R), α1AR, α2AR, and μ-(µOR) and ժ-opioid receptors (ժOR). Results: All ligands docked preferentially to the binding pocket on the cell surface domain of the GPCR types investigated. Drug binding was characterized by weak interactions (hydrophobic, hydrogen bonding, pi-pi) and stronger ionic and salt-bridge interactions (cation-pi and cation-anion interactions). Ligands specific to each GPCR category showed considerable cross-binding with alternative GPCRs, with small-molecule medications appearing less selective than their peptide or ARB functional equivalents. ARBs that exhibit higher affinities for AT₁R also demonstrate higher affinities for µORs and ժORs than opiate ligands, such as fentanyl and naltrexone. Moreover, ARBs had a higher affinity for αARs than either alpha agonists (epinephrine and phenylephrine) or inhibitors (prazosin and doxazosin). MD simulations of membrane-embedded ARB-GPCR complexes proved stable over nanosecond time scales and suggested that some ARBs may behave as agonists or antagonists depending on the GPCR type. Based on the results presented in this and related investigations, we propose that agonists bind to the resting A-site of GPCRs, while inverse agonists occupy the desensitizing D-site, which partial agonists like morphine and fentanyl share, contributing to addiction. ARBs block both AngII and alpha receptors, suggesting that they are more potent antihypertensive drugs than ACE inhibitors. ARBs have the potential to inhibit morphine tolerance and appear to disrupt receptor desensitization processes, potentially by competing at the D-site. Our results suggest the possible therapeutic potential of ARBs in treating methamphetamine and opiate addictions. Full article

For the interaction of angiotensin II (AngII) with AngII type 1 receptors (AT₁R), two potential proton hopping pathways have been identified, each associated with distinct physiological outcomes. The octapeptide AngII (Asp¹-Arg²-Val³-Tyr⁴-Ile⁵-His⁶-Pro⁷-Phe⁸) appears to form a charge relay system (CRS) in solution in which the C-terminal carboxylate abstracts a proton from the His⁶ imidazole group, which, in turn, abstracts a proton from the Tyr⁴ hydroxyl (OH) group, creating a tyrosinate anion. When AngII binds to the AT₁R, the CRS can be reconstituted with D281 of the receptor taking up the role of the Phe⁸ carboxylate in the tripartite interaction, whilst the Phe⁸ carboxylate forms a salt bridge with K199 of the receptor. As a consequence, the Tyr⁴ OH of AngII is positioned with accessibility to either the Phe⁸ carboxylate (bound to K199) or the His⁶ imidazole (activated by D281), thereby creating a potential gating mechanism for AT₁R receptor signaling. This study summarizes evidence based on structure activity data for various analogs wherein Tyr⁴ OH interaction with His⁶ imidazole (CRS formation) leads to G protein sequestration and vasoconstriction, whereas Tyr⁴ OH interaction with Phe⁸ carboxylate (bound to K199) engenders arrestin-mediated vasodilation and receptor desensitization. These findings, combined with quantum mechanical (semiempirical) calculations of CRS proton transfer presented herein, provide insights for the therapeutic targeting of angiotensin receptor blockers (sartans) and the development of second-generation drugs (bisartans). Full article

Despite extensive research, the exact cause of oral lichenoid lesions remains unknown. The chronic inflammatory tissue reaction mediated by T cells is the basis of the etiological process. However, oral lichenoid lesions often occur in the presence of certain drugs. Our aim was to conduct a preliminary retrospective study to assess the correlation between the administration of statins or HMG-inhibitor CoA reductase, which are commonly used for treating hypercholesterolemia, and the sartans or blockers of the angiotensin II receptor, which are used for treating hypertension, in relation to the occurrence of oral lichenoid lesions. This preliminary retrospective study included 2158 patients who attended the Oral Medicine and Maxillofacial Surgery (Mo-Max) Department of Oral Science and Maxillofacial Surgery, Sapienza University of Rome, from 2019 to 2022. A significant association was found between the presence of oral lichenoid lesions and the simultaneous administration of sartans and statins (χ² = 46.49; p < 0.001). Of the 2158 patients, 118 (5.5%) were diagnosed with oral lichenoid lesions. In the analysis of standardized residues, we found that pathology developed in 16.3% of patients taking statins and 15.9% of those taking sartans. Oral lichenoid lesions only developed in 4.4% of those not taking these drugs. Full article

Angiotensin II receptor antagonists are tetrazole derivatives used in the treatment of high blood pressure, and are also indicated for the treatment of heart failure (NYHA class II-IV). They are used alone or in combination with other classes of antihypertensives or diuretics for the effective management of high blood pressure. In this study, we aim to evaluate the thermal stability and degradation kinetics for the principal compounds used in therapy from this class, namely telmisartan, valsartan, olmesartan medoxomil, and losartan potassium. To obtain the thermoanalytical data for the kinetic investigations, the TG and DTG curves were registered at five different heating rates (β = 2, 4, 6, 8, and 10 °C min⁻¹). The kinetic methods used were a preliminary ASTM E698 method and two isoconversional methods: Flynn–Wall–Ozawa and Friedman. For each molecule, the results showed complex decomposition processes consisting of complex reaction sequences. Full article

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), influenza, and respiratory syncytial virus (RSV) are significant global health threats. The need for low-cost, easily synthesized oral drugs for rapid deployment during outbreaks is crucial. Broad-spectrum therapeutics, or pan-antivirals, are designed to target multiple viral pathogens simultaneously by focusing on shared molecular features, such as common metal cofactors or conserved residues in viral catalytic domains. This study introduces a new generation of potent sartans, known as bisartans, engineered in our laboratories with negative charges from carboxylate or tetrazolate groups. These anionic tetrazoles interact strongly with cationic arginine residues or metal cations (e.g., Zn²⁺) within viral and host target sites, including the SARS-CoV-2 ACE2 receptor, influenza H1N1 neuraminidases, and the RSV fusion protein. Using virtual ligand docking and molecular dynamics, we investigated how bisartans and their analogs bind to these viral receptors, potentially blocking infection through a pan-antiviral mechanism. Bisartan, ACC519TT, demonstrated stable and high-affinity docking to key catalytic domains of the SARS-CoV-2 NSP3, H1N1 neuraminidase, and RSV fusion protein, outperforming FDA-approved drugs like Paxlovid and oseltamivir. It also showed strong binding to the arginine-rich furin cleavage sites S1/S2 and S2′, suggesting interference with SARS-CoV-2’s spike protein cleavage. The results highlight the potential of tetrazole-based bisartans as promising candidates for developing broad-spectrum antiviral therapies. Full article

Cardiovascular drugs have been a burning topic in the field of environmental analytical chemistry in the last few decades. Growing modern healthcare has led to the widespread use of pharmaceuticals. Among these, antihypertensives (sartans, angiotensin-converting enzyme inhibitors) and lipid-regulating drugs (fibrates and statins) are the most frequently consumed and, thus, excreted into wastewater. Their chemical fate during conventional and advanced wastewater treatment, such as ozonation, remains unclear. Analytical chemistry, providing sample pretreatment followed by instrumental analysis, has a tremendous role in water treatment evaluation, mostly from the perspective of parent contaminants’ removals and also assessment of transformation pathways. Ultrasensitive liquid chromatography–mass spectrometry (LC-MS) systems provide many opportunities. By carefully using planned workflows for chromatographic and mass-spectrometric data processing, i.e., suspect and non-target screening approaches, LC-MS allows for the identification and structural elucidation of unknown, predicted, suspected or selected transformation products. Accordingly, some examples and case studies on selected cardiovascular drugs in this review are presented to show the applicability of the used analytical approaches and workflows. Full article

Objective: Hypertensionis one of the most common chronic diseases, affecting more than 20% of the population. The side effects experienced due to antihypertensive medications, such as tiredness, muscle pain, and insomnia, are often a significant predictor of poor adherence to therapy. The goal of the current study is to present the frequency, type, seriousness, and severity of adverse drug reactions reported to the BDA via Individual Case Safety Reports (ICSRs) and following differentiation of messages found in more than one patient. Methods: We conducted a retrospective analysis of the reported adverse drug reactions (ADRs) reported in the Bulgarian Drug Agency database after treatment with antihyperlipidemic medicines, angiotensin-converting enzyme (ACE) inhibitors, and sartans for the period 2017–2021. Each ICSR form was observed, and data for suspected medicine and type of adverse reaction was analyzed. Results: The total number of processed notifications for adverse drug reactions (ADRs) included in the database is 142. The highest number of ADRs was reported for ARB (58), followed by antihyperlipidemic medicines (55) and ACE inhibitors (29). Most of the assessed adverse events experienced by more than one patient fall into the probable and related categories based on the Global Introspection method classification. Therefore, they have been investigated and are consistent with exposure in the population. Conclusions: Cardiovascular medicines from the groups of ACE inhibitors, sartans, and statins have a high share of reported ADRs in the BDA system. Some of them are severe and need further investigation. Full article

Furins are serine endoproteases that are involved in many biological processes, where they play important roles in normal metabolism, in the activation of various pathogens, while they are a target for therapeutic intervention. Dichlorophenyl-pyridine “BOS” compounds are well known drugs that are used as inhibitors of human furin by an induced-fit mechanism, in which tryptophan W254 in the furin catalytic cleft acts as a molecular transition energy gate. The binding of “BOS” drug into the active center of furin has been computationally studied using the density functional theory (DFT) and ONIOM multiscaling methodologies. The binding enthalpies of the W254 with the furin-BOS is −32.8 kcal/mol (“open”) and −18.8 kcal/mol (“closed”), while the calculated torsion barrier was found at 30 kcal/mol. It is significantly smaller than the value of previous MD calculations due to the relaxation of the environment, i.e., nearby groups of the W254, leading to the reduction of the energy demands. The significant lower barrier explains the experimental finding that the dihedral barrier of W254 is overcome. Furthermore, sartans were studied to evaluate their potential as furin inhibitors. Sartans are AT1 antagonists, and they effectively inhibit the hypertensive effects induced by the peptide hormone Angiotensin II. Here, they have been docked into the cavity to evaluate their effect on the BOS ligand via docking and molecular dynamics simulations. A consistent binding of sartans within the cavity during the simulation was found, suggesting that they could act as furin inhibitors. Finally, sartans interact with the same amino acids as W254, leading to a competitive binding that may influence the pharmacological efficacy and potential drug interactions of sartans. Full article

Chronic wound treatments pose a challenge for healthcare worldwide, particularly for the people in developed countries. Chronic wounds significantly impair quality of life, especially among the elderly. Current research is devoted to novel approaches to wound care by repositioning cardiovascular agents for topical wound treatment. The emerging field of medicinal products’ repurposing, which involves redirecting existing pharmaceuticals to new therapeutic uses, is a promising strategy. Recent studies suggest that medicinal products such as sartans, beta-blockers, and statins have unexplored potential, exhibiting multifaceted pharmacological properties that extend beyond their primary indications. The purpose of this review is to analyze the current state of knowledge on the repositioning of cardiovascular agents’ use and their molecular mechanisms in the context of wound healing. Full article

The N-terminal portion of the octapeptide angiotensin II (DRVYIHPF; AngII), a vasopressor peptide that favorably binds to, and activates, AngII type 1 receptor (AT₁R), has an important role in maintaining bioactive conformation. It involves all three charged groups, namely (i) the N-terminal amino group cation, (ii) the Asp sidechain anion and (iii) the Arg guanidino cation. Neutralization of any one of these three charged groups results in a substantial reduction (<5%) in bioactivity, implicating a specialized function for this cluster. In contrast, angiotensin A (ARVYIHPF; AngA) has reduced bioactivity at AT₁R; however, replacement of Asp in AngII with sarcosine (N-methyl-glycine) not only restores bioactivity but increases the activity of agonist, antagonist, and inverse agonist analogues. A bend produced at the N-terminus by the introduction of the secondary amino acid sarcosine is thought to realign the functional groups that chaperone the C-terminal portion of AngII, allowing transfer of the negative charge originating at the C-terminus to be transferred to the Tyr hydroxyl-forming tyrosinate anion, which is required to activate the receptor and desensitizes the receptor (tachyphylaxis). Peptide (sarilesin) and nonpeptide (sartans) moieties, which are long-acting inverse agonists, appear to desensitize the receptor by a mechanism analogous to tachyphylaxis. Sartans/bisartans were found to bind to alpha adrenergic receptors resulting in structure-dependent desensitization or resensitization. These considerations have provided information on the mechanisms of receptor desensitization/tolerance and insights into possible avenues for treating addiction. In this regard sartans, which appear to cross the blood–brain barrier more readily than bisartans, are the preferred drug candidates. Full article

Echolucency, a measure of plaque instability associated with increased cardiovascular risk, can be assessed in both the carotid plaque and the plaque-free common carotid intima–media (IM) complex as a gray-scale median (plaque-GSM and IM-GSM, respectively). The impact of specific vascular risk factors on these two phenotypes remains uncertain, including the nature and extent of their influence. This study aims to seek the determinants of plaque-GSM and IM-GSM. Plaque-GSM and IM-GSM were measured in subjects from the IMPROVE study cohort (aged 54–79, 46% men) recruited in five European countries. Plaque-GSM was measured in subjects who had at least one IMT_max ≥ 1.5 mm (n = 2138), whereas IM-GSM was measured in all subjects included in the study (n = 3188). Multiple regression with internal cross-validation was used to find independent predictors of plaque-GSM and IM-GSM. Plaque-GSM determinants were plaque-size (IMT_max), and diastolic blood pressure. IM-GSM determinants were the thickness of plaque-free common carotid intima–media complex (PF CC-IMTmean), height, systolic blood pressure, waist/hip ratio, treatment with fibrates, mean corpuscular volume, treatment with alpha-2 inhibitors (sartans), educational level, and creatinine. Latitude, and pack-years_code were determinants of both plaque-GSM and IM-GSM. The overall models explain 12.0% of plaque-GSM variability and 19.7% of IM-GSM variability. A significant correlation (r = 0.51) was found between plaque-GSM and IM-GSM. Our results indicate that IM-GSM is a weighty risk marker alternative to plaque-GSM, offering the advantage of being readily measurable in all subjects, including those in the early phases of atherosclerosis where plaque occurrence is relatively infrequent. Full article

Quantum pharmacology introduces theoretical models to describe the possibility of ultra-high dilutions to produce biological effects, which may help to explain the placebo effect observed in hypertensive clinical trials. To determine this within physiology and to evaluate novel ARBs, we tested the ability of known angiotensin II receptor blockers (ARBs) (candesartan and telmisartan) used to treat hypertension and other cardiovascular diseases, as well as novel ARBs (benzimidazole-N-biphenyl tetrazole (ACC519T), benzimidazole-bis-N,N′-biphenyl tetrazole (ACC519T(2)) and 4-butyl-N,N0-bis[[20-2Htetrazol-5-yl)biphenyl-4-yl]methyl)imidazolium bromide (BV6(K⁺)₂), and nirmatrelvir (the active ingredient in Paxlovid) to modulate vascular contraction in iliac rings from healthy male New Zealand White rabbits in responses to various vasopressors (angiotensin A, angiotensin II and phenylephrine). Additionally, the hemodynamic effect of ACC519T and telmisartan on mean arterial pressure in conscious rabbits was determined, while the ex vivo ability of BV6(K⁺)₂ to activate angiotensin-converting enzyme-2 (ACE2) was also investigated. We show that commercially available and novel ARBs can modulate contraction responses at ultra-high dilutions to different vasopressors. ACC519T produced a dose-dependent reduction in rabbit mean arterial pressure while BV6(K⁺)₂ significantly increased ACE2 metabolism. The ability of ARBs to inhibit contraction responses even at ultra-low concentrations provides evidence of the existence of quantum pharmacology. Furthermore, the ability of ACC519T and BV6(K⁺)₂ to modulate blood pressure and ACE2 activity, respectively, indicates their therapeutic potential against hypertension. Full article

ACE inhibitors, sartans, and sacubitril are among the most important drugs for the prevention of cardiovascular mortality and morbidity. At the same time, they are known to cause non-allergic bradykinin-mediated angioedema, a potentially fatal swelling of the mucosa and/or submucosa and deeper skin without signs of urticaria or pruritus, occurring mainly in the head and neck region. In contrast with hereditary angioedema, which is also mediated by bradykinin, angioedema triggered by these drugs is by far the most common subtype of non-allergic angioedema. The molecular mechanisms underlying this type of angioedema, which are discussed here, are not yet sufficiently understood. There are a number of approved drugs for the prevention and treatment of acute attacks of hereditary angioedema. These include inhibitors of bradykinin synthesis that act as kallkrein inhibitors, such as the parenterally applied plasma pool, and recombinant C1 esterase inhibitor, ecallantide, lanadelumab, and the orally available berotralstat, as well as the bradykinin receptor type 2 antagonist icatibant. In contrast, no diagnostic tools, guidelines, or treatments have yet been approved for the diagnosis and treatment of acute non-allergic drug-induced angioedema, although it is more common and can take life-threatening courses. Approved specific drugs and a structured diagnostic workflow are needed for this emergency diagnosis. Full article