Search Results (12)

Calcium channel blockers (CCBs), originally developed for cardiovascular indications, have gained attention for their therapeutic potential in neuropsychiatric, endocrine, and pain-related disorders. In neuropsychiatry, nimodipine and isradipine, both L-type CCBs, show mood-stabilizing and neuroprotective effects, with possible benefits in depression, bipolar disorder, and schizophrenia. In endocrinology, verapamil, a non-dihydropyridine L-type blocker, has been associated with the preservation of pancreatic β-cell function and reduced insulin dependence in diabetes. CCBs may also aid in managing primary aldosteronism and pheochromocytoma, particularly in patients with calcium signaling mutations. In pain medicine, α2δ ligands and selective blockers of N-type and T-type channels demonstrate efficacy in neuropathic and inflammatory pain. However, their broader use is limited by challenges in central nervous system (CNS) penetration, off-target effects, and heterogeneous trial outcomes. Future research should focus on pharmacogenetic stratification, novel delivery platforms, and combination strategies to optimize repurposing of CCBs across disciplines. Full article

Renal artery stenosis (RAS) is a vascular condition characterized by narrowing of one or both renal arteries, leading to reduced blood flow to the kidneys, activation of the renin–angiotensin–aldosterone system (RAAS), and subsequent renovascular hypertension. Overactivation of the same cascade potentiates the production of angiotensin II, which induces systemic vasoconstriction, increases sodium and water retention via aldosterone, and activates the sympathetic nervous system. Angiotensin II is also implicated in endothelial dysfunction, oxidative stress, and chronic inflammation, thus impairing vascular remodeling and arterial stiffness, all of which serve to accelerate cardiovascular complications, such as left ventricular hypertrophy, heart failure, and myocardial infarction. RAS is usually due in at least 90% of cases to atherosclerosis, which typically affects older people with diabetes and smoking as risk factors. There are two types of RAS: unilateral and bilateral. Bilateral RAS is commonly associated with flash pulmonary edema, a life-threatening emergency condition in which alveolar space flooding can occur within minutes. RAS typically remains asymptomatic until the late stage with complications of hypertension, ischemic nephropathy, or chronic kidney disease. FMD tends to create structural abnormalities of the artery, whereas atherosclerosis causes plaque formation and endothelial dysfunction of the artery. Epidemiological surveys have revealed that the prevalence of RAS ranges from 4% to 53% and is especially high among patients with hypertension, cardiovascular disease, or CKD. Diagnosis is based on clinical suspicion and supported by imaging studies, including Doppler ultrasound, computed tomography angiography, and magnetic resonance angiography. Early detection also relies on certain laboratory biomarkers, especially in identifying high-risk patients. These markers would include increased plasma renin activity, elevated aldosterone-renin ratio, and inflammatory markers, including C-reactive protein and endothelin-1. Treatment would also involve pharmacological approaches, including RAAS inhibitors, beta-blockers, and statins, and interventional treatments, including angioplasty and stenting in patients with severe forms of the disease. However, the Cardiovascular Outcomes in Renal Atherosclerotic Lesions (CORAL) Trial showed that most patients would likely require medical therapy, and that intervention should be reserved for those with uncontrolled hypertension, progressive renal dysfunction, or recurrent episodes of pulmonary edema. Other emerging therapies include drug-eluting balloons, bioresorbable stents, and gene-editing techniques, all of which have shown great promise in the few studies that have been conducted, although further evaluation is needed. Despite these advances, there are still gaps in knowledge regarding patient stratification, biomarker validation, and the development of personalized treatment strategies. This article reviews the complexities of RAAS and its systemic impact on cardiovascular and renal health. Future research can therefore focus on improving early diagnosis, optimizing patient selection for intervention, and developing new therapies to slow disease progression and mitigate complications. Full article

Cardiorenal syndrome (CRS) is a life-threatening disorder that involves a complex interplay between the two organs. Managing this multifaceted syndrome is challenging in the hospital and requires a multidisciplinary approach to tackle the many manifestations and complications. There is no universally accepted algorithm to treat patients, and therapeutic options vary from one patient to another. The mainstays of therapy involve the stabilization of hemodynamics, decongestion using diuretics or renal replacement therapy, improvement of cardiac output with inotropes, and goal-directed medical treatment with renin–angiotensin–aldosterone system inhibitors, beta-blockers, and other medications. Mechanical circulatory support is another viable option in the armamentarium of agents that improve symptoms in select patients. Full article

The most common type of alopecia in women is female androgenetic alopecia (FAGA), characterized by progressive hair loss in a patterned distribution. Many oral therapies, including spironolactone (an aldosterone antagonist), androgen receptor blockers (e.g., flutamide/bicalutamide), 5-alpha-reductase inhibitors (e.g., finasteride/dutasteride), and oral contraceptives, target the mechanism of androgen conversion and binding to its respective receptor and therefore could be administered for the treatment of FAGA. Despite significant advances in the oral treatment of FAGA, its management in patients with a history of gynecological malignancies, the most common cancers in women worldwide, may still be a concern. In this review, we focus on the safety of antiandrogens for the treatment of FAGA patients. For this purpose, a targeted literature review was conducted on PubMed, utilizing the relevant search terms. To sum up, spironolactone seems to be safe for the systemic treatment of FAGA, even in high-risk populations. However, a general uncertainty remains regarding the safety of other medications in patients with a history of gynecologic malignancies, and further studies are needed to evaluate their long-term safety in patients with FAGA and risk factors to establish an optimal risk assessment and treatment selection protocol. Full article

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. In this retrospective review article, we aimed to present a selection of chemical compounds or medications that have long been recognized as interfering with the RAAS. It is noteworthy that these substances may also exhibit regulatory effects in different types of ionic currents. Apocynin, known to attenuate the angiotensin II-induced activation of epithelial Na⁺ channels, was shown to stimulate peak and late components of voltage-gated Na⁺ current (I_Na). Esaxerenone, an antagonist of the mineralocorticoid receptor, can exert an inhibitory effect on peak and late I_Na directly. Dexamethasone, a synthetic glucocorticoid, can directly enhance the open probability of large-conductance Ca²⁺-activated K⁺ channels. Sparsentan, a dual-acting antagonist of the angiotensin II receptor and endothelin type A receptors, was found to suppress the amplitude of peak and late I_Na effectively. However, telmisartan, a blocker of the angiotensin II receptor, was effective in stimulating the peak and late I_Na along with a slowing of the inactivation time course of the current. However, telmisartan’s presence can also suppress the erg-mediated K⁺ current. Moreover, tolvaptan, recognized as an aquaretic agent that can block the vasopressin receptor, was noted to suppress the amplitude of the delayed-rectifier K⁺ current and the M-type K⁺ current directly. The above results indicate that these substances not only have an interference effect on the RAAS but also exert regulatory effects on different types of ionic currents. Therefore, to determine their mechanisms of action, it is necessary to gain a deeper understanding. Full article

As some of the renin–angiotensin–aldosterone system (RAAS)-dependent mechanisms underlying the cognitive performance modulation could include oxidative balance alterations, in this study we aimed to describe some of the potential interactions between RAAS modulators (Losartan and Ramipril) and oxidative stress in a typical model of memory impairment. In this study, 48 white male Swiss mice were divided into six groups and received RAAS modulators (oral administration Ramipril 4 mg/kg, Losartan 20 mg/kg) and a muscarinic receptors inhibitor (intraperitoneal injection scopolamine, 0.5 mg/kg) for 8 consecutive days. Then, 24 h after the last administration, the animals were euthanized and whole blood and brain tissues were collected. Biological samples were then processed, and biochemical analysis was carried out to assess superoxide dismutase and glutathione activities and malondialdehyde concentrations. In the present experimental conditions, we showed that RAAS modulation via the angiotensin-converting enzyme inhibition (Ramipril) and via the angiotensin II receptor blockage (Losartan) chronic treatments could lead to oxidative stress modulation in a non-selective muscarinic receptors blocker (scopolamine) animal model. Our results showed that Losartan could exhibit a significant systemic antioxidant potential partly preventing the negative oxidative effects of scopolamine and a brain antioxidant potential, mainly by inhibiting the oxidative-stress-mediated cellular damage and apoptosis. Ramipril could also minimize the oxidative-mediated damage to the lipid components of brain tissue resulting from scopolamine administration. Both blood serum and brain changes in oxidative stress status were observed following 8-day treatments with Ramipril, Losartan, scopolamine, and combinations. While the serum oxidative stress modulation observed in this study could suggest the potential effect of RAAS modulation and scopolamine administration on the circulatory system, blood vessels endothelia, and arterial tension modulation, the observed brain tissues oxidative stress modulation could lead to important information on the complex interaction between renin–angiotensin and cholinergic systems. Full article

Podocytes are highly specialized cells that play a pivotal role in the blood filtration process in the glomeruli of the kidney, and their dysfunction leads to renal diseases. For this reason, the study and application of this cell type is of great importance in the field of regenerative medicine. Hypertension is mainly regulated by the renin–angiotensin–aldosterone system (RAAS), with its main mediator being angiotensin II (ANG II). Elevated ANG II levels lead to a pro-fibrotic, inflammatory, and hypertrophic milieu that induces apoptosis in podocytes. The activation of RAAS is critical for the pathogenesis of podocyte injury; as such, to prevent podocyte damage, patients with hypertension are administered drugs that modulate RAAS signaling. A prime example is the orally active, non-peptide, selective angiotensin-II-type I receptor (AGTR1) blocker losartan. Here, we demonstrate that SIX2-positive urine-derived renal progenitor cells (UdRPCs) and their immortalized counterpart (UM51-hTERT) can be directly differentiated into mature podocytes. These podocytes show activation of RAAS after stimulation with ANG II, resulting in ANG II-dependent upregulation of the expression of the angiotensin-II-type I receptor, AGTR1, and the downregulated expression of the angiotensin-II-type II receptor 2 (AGTR2). The stimulation of podocytes with losartan counteracts ANG II-dependent changes, resulting in a dependent favoring of the specific receptor from AGTR1 to AGTR2. Transcriptome analysis revealed 94 losartan-induced genes associated with diverse biological processes and pathways such as vascular smooth muscle contraction, the oxytocin signaling pathway, renin secretion, and ECM-receptor interaction. Co-stimulation with losartan and ANG II induced the exclusive expression of 106 genes associated with DNA methylation or demethylation, cell differentiation, the developmental process, response to muscle stretch, and calcium ion transmembrane transport. These findings highlight the usefulness of UdRPC-derived podocytes in studying the RAAS pathway and nephrotoxicity in various kidney diseases. Full article

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), responsible for the coronavirus disease of 2019 (COVID-19) pandemic, has affected and continues to affect millions of people across the world. Patients with essential arterial hypertension and renal complications are at particular risk of the fatal course of this infection. In our study, we have modeled the selected processes in a patient with essential hypertension and chronic kidney disease (CKD) suffering from COVID-19, emphasizing the function of the renin-angiotensin-aldosterone (RAA) system. The model has been built in the language of Petri nets theory. Using the systems approach, we have analyzed how COVID-19 may affect the studied organism, and we have checked whether the administration of selected anti-hypertensive drugs (angiotensin-converting enzyme inhibitors (ACEIs) and/or angiotensin receptor blockers (ARBs)) may impact the severity of the infection. Besides, we have assessed whether these drugs effectively lower blood pressure in the case of SARS-CoV-2 infection affecting essential hypertensive patients. Our research has shown that neither the ACEIs nor the ARBs worsens the course infection. However, when assessing the treatment of hypertension in the active SARS-CoV-2 infection, we have observed that ARBs might not effectively reduce blood pressure; they may even have the slightly opposite effect. On the other hand, we have confirmed the effectiveness of arterial hypertension treatment in patients receiving ACEIs. Moreover, we have found that the simultaneous use of ARBs and ACEIs averages the effects of taking both drugs, thus leading to only a slight decrease in blood pressure. We are a way from suggesting that ARBs in all hypertensive patients with COVID-19 are ineffective, but we have shown that research in this area should still be continued. Full article

Mutated channelopathy could play important roles in the pathogenesis of aldosterone-producing adenoma (APA). In this study, we identified a somatic mutation, KCNJ5 157-159delITE, and reported its immunohistological, pathophysiological and pharmacological characteristics. We conducted patch-clamp experiments on HEK293T cells and experiments on expression of aldosterone synthase (CYP11B2) and aldosterone secretion in HAC15 cells to evaluate electrophysiological and functional properties of this mutated KCNJ5. Immunohistochemistry was conducted to identify expressions of several steroidogenic enzymes. Macrolide antibiotics and a calcium channel blocker were administrated to evaluate the functional attenuation of mutated KCNJ5 channel in transfected HAC15 cells. The interaction between macrolides and KCNJ5 protein was evaluated via molecular docking and molecular dynamics simulation analysis. The immunohistochemistry analysis showed strong CYP11B2 immunoreactivity in the APA harboring KCNJ5 157-159delITE mutation. Whole-cell patch-clamp data revealed that mutated KCNJ5 157-159delITE channel exhibited loss of potassium ion selectivity. The mutant-transfected HAC15 cells increased the expression of CYP11B2 and aldosterone secretion, which was partially suppressed by clarithromycin and nifedipine but not roxithromycin treatment. The docking analysis and molecular dynamics simulation disclosed that roxithromycin had strong interaction with KCNJ5 L168R mutant channel but not with this KCNJ5 157-159delITE mutant channel. We showed comprehensive evaluations of the KCNJ5 157-159delITE mutation which revealed that it disrupted potassium channel selectivity and aggravated autonomous aldosterone production. We further demonstrated that macrolide antibiotics, roxithromycin, could not interfere the aberrant electrophysiological properties and gain-of-function aldosterone secretion induced by KCNJ5 157-159delITE mutation. Full article

Two unknown impurities were observed during the process development for multigram-scale synthesis of eplerenone (Inspra^®). The new process-related impurities were identified and fully characterized as the corresponding (7β,11α,17α)-11-hydroxy- and (7α,11β,17α)-9,11-dichloroeplerenone derivatives 12a and 13. Seven other known but poorly described in the literature eplerenone impurities, including four impurities A, B, C and E listed in the European Pharmacopoeia 8.4 were also detected, identified and fully characterized. All these contaminants result from side reactions taking place on the steroid ring C of the starting 11α-hydroxy-7α-(methoxycarbonyl)-3-oxo-17α-pregn-4-ene-21,17-carbolactone (12) and the key intermediate (7α,17α)-9(11)-enester 7, including epimerization of the C-7 asymmetric center, oxidation, dehydration, chlorination and lactonization. The impurities were isolated and/or synthesized and fully characterized by infrared spectroscopy (IR), nuclear magnetic resonance spectroscopy (NMR) and high-resolution mass spectrometry/electrospray ionization (HRMS/ESI). Their ¹H- and ¹³C-NMR signals were fully assigned. The molecular structures of the eight impurities, including the new (7β,11α,17α)-11-hydroxy- and (7α,11β,17α)-9,11-dichloroeplerenone related substances 12a and 13, were solved and refined using single-crystal X-ray diffraction (SCXRD). The full identification and characterization of these impurities should be useful for the quality control and the validation of the analytical methods in the manufacture of eplerenone. Full article

The epithelial sodium channel (ENaC) plays critical roles in maintaining fluid and electrolyte homeostasis and is located in the aldosterone-sensitive distal nephron (ASDN). We previously found that Nedd4-2 C2 knockout (KO) mice showed salt-sensitive hypertension with paradoxically enhanced ENaC gene expression in ASDN under high oral salt intake. Eplerenone (EPL), a selective aldosterone blocker, is a promising therapeutic option for resistant or/and salt-sensitive hypertension. We examined the effect of EPL on Nedd4-2 C2 KO mice with respect to blood pressure, metabolic parameters, and molecular level changes in ASDN under high oral salt intake. We found that EPL failed to reduce blood pressure in KO mice with high oral salt intake and upregulated ENaC expression in ASDN. Thus, salt-sensitive hypertension in Nedd4-2 C2 KO was EPL-resistant. Gene expression analyses of laser-captured specimens in ASDN suggested the presence of non-aldosterone-dependent activation of ENaC transcription in ASDN of Nedd4-2 C2 KO mice, which was abolished by amiloride treatment. Our results from Nedd4-2 C2 KO mice suggest that enhanced ENaC gene expression is critically involved in salt-sensitive hypertension under certain conditions of specific enzyme isoforms for their ubiquitination. Full article

Although chronic sympathetic activation provides inotropic and chronotropic support to the failing heart, such activation may also have deleterious effects, including the direct cardiotoxic effects of catecholamines, activation of the renin-angiotensin-aldosterone system and an increase in myocardial oxygen demand. These observations indicate that β-blockade might be beneficial in the treatment of heart failure resulting from dilated cardiomyopathy or ischaemic heart disease. Carvedilol is a non-selective β-blocker acting on β1-, β2-, and α1-adrenoceptors. It possesses potent anti-oxidant and anti-apoptotic properties, along with neuroprotective, vasculoprotective, cardioprotective effects, and it has reduced overall mortality in patients with heart failure in controlled clinical trials. Its role in treating cardiomyopathy requires focus. The fact that anthracyclines are cardiotoxic seriously narrows their therapeutic index in cancer therapy. The cardiotoxic risk increases with the cumulative dose and may lead to congestive heart failure and dilated cardiomyopathy in adults and in children. This review focuses on recent research regarding the beneficial effects of carvedilol in the treatment of dilated cardiomyopathy and to revisit the available evidence on the cardioprotection of carvedilol when associated with anthracycline and to explain the mechanisms underlying the benefits of their co-administration. Full article