-
Molecular Pharmacology Oct 2023Englerin A (EA) is a potent agonist of tetrameric transient receptor potential canonical (TRPC) ion channels containing TRPC4 and TRPC5 subunits. TRPC proteins form...
Englerin A (EA) is a potent agonist of tetrameric transient receptor potential canonical (TRPC) ion channels containing TRPC4 and TRPC5 subunits. TRPC proteins form cation channels that are activated by plasma membrane receptors. They convert extracellular signals such as angiotensin II into cellular responses, whereupon Na and Ca influx and depolarization of the plasma membrane occur. Via depolarization, voltage-gated Ca (CaV) channels can be activated, further increasing Ca influx. We investigated the extent to which EA also affects the functions of CaV channels using the high-voltage-activated L-type Ca channel CaV1.2 and the low-voltage-activated T-type Ca channels CaV3.1, CaV3.2, and CaV3.3. After expression of cDNAs in human embryonic kidney (HEK293) cells, EA inhibited currents through all T-type channels at half-maximal inhibitory concentrations (IC) of 7.5 to 10.3 M. In zona glomerulosa cells of the adrenal gland, angiotensin II-induced elevation of cytoplasmic Ca concentration leads to aldosterone release. We identified transcripts of low- and high-voltage-activated CaV channels and of TRPC1 and TRPC5 in the human adrenocortical (HAC15) zona glomerulosa cell line. Although no EA-induced TRPC activity was measurable, Ca channel blockers distinguished T- and L-type Ca currents. EA blocked 60% of the CaV current in HAC15 cells and T- and L-type channels analyzed at -30 mV and 10 mV were inhibited with IC values of 2.3 and 2.6 M, respectively. Although the T-type blocker Z944 reduced basal and angiotensin II-induced 24-hour aldosterone release, EA was not effective. In summary, we show here that EA blocks CaV1.2 and T-type CaV channels at low-micromolar concentrations. SIGNIFICANCE STATEMENT: In this study we showed that englerin A (EA), a potent agonist of tetrameric transient receptor potential canonical (TRPC)4- or TRPC5-containing channels and currently under investigation to treat certain types of cancer, also inhibits the L-type voltage-gated Ca (CaV) channel CaV1.2 and the T-type CaV channels CaV3.1, CaV3.2, and CaV3.3 channels at low micromolar concentrations.
Topics: Humans; Calcium Channels, T-Type; Angiotensin II; Aldosterone; HEK293 Cells; Transient Receptor Potential Channels; TRPC Cation Channels; Calcium
PubMed: 37399325
DOI: 10.1124/molpharm.122.000651 -
Journal of Clinical Hypertension... Aug 2023Studies have shown that angiotensin converting enzyme inhibitors (ACEIs) are superior in primary and secondary prevention for cardiac mortality and morbidity to... (Meta-Analysis)
Meta-Analysis
Studies have shown that angiotensin converting enzyme inhibitors (ACEIs) are superior in primary and secondary prevention for cardiac mortality and morbidity to angiotensin receptor blocker (ARBs). One of the common side effects from ACEI is dry cough. The aims of this systematic review, and network meta-analysis are to rank the risk of cough induced by different ACEIs and between ACEI and placebo, ARB or calcium channel blockers (CCB). We performed a systematic review, and network meta-analysis of randomized controlled trials to rank the risk of cough induced by each ACEI and between ACEI and placebo, ARB or CCB. A total of 135 RCTs with 45,420 patients treated with eleven ACEIs were included in the analyses. The pooled estimated relative risk (RR) between ACEI and placebo was 2.21 (95% CI: 2.05-2.39). ACEI had more incidences of cough than ARB (RR 3.2; 95% CI: 2.91, 3.51), and pooled estimated of RR between ACEI and CCB was 5.30 (95% CI: 4.32-6.50) Moexipril ranked as number one for inducing cough (SUCRA 80.4%) and spirapril ranked the least (SUCRA 12.3%). The order for the rest of the ACEIs are as follows: ramipril (SUCRA 76.4%), fosinopril (SUCRA 72.5%), lisinopril (SUCRA 64.7%), benazepril (SUCRA 58.6%), quinapril (SUCRA 56.5%), perindopril (SUCRA 54.1%), enalapril (SUCRA 49.7%), trandolapril (SUCRA 44.6%) and, captopril (SUCRA 13.7%). All ACEI has the similar risk of developing a cough. ACEI should be avoided in patients who have risk of developing cough, and an ARB or CCB is an alternative based on the patient's comorbidity.
Topics: Humans; Antihypertensive Agents; Angiotensin-Converting Enzyme Inhibitors; Angiotensin Receptor Antagonists; Network Meta-Analysis; Cough; Hypertension; Calcium Channel Blockers
PubMed: 37417783
DOI: 10.1111/jch.14695 -
Acta Physiologica (Oxford, England) May 2024The renin-angiotensin system (RAS) plays a key role in blood pressure regulation. The RAS is a complex interconnected system composed of two axes with opposite effects.... (Review)
Review
The renin-angiotensin system (RAS) plays a key role in blood pressure regulation. The RAS is a complex interconnected system composed of two axes with opposite effects. The pressor arm, represented by angiotensin (Ang) II and the AT receptor (ATR), mediates the vasoconstrictor, proliferative, hypertensive, oxidative, and pro-inflammatory effects of the RAS, while the depressor/protective arm, represented by Ang-(1-7), its Mas receptor (MasR) and the AT receptor (ATR), opposes the actions elicited by the pressor arm. The ATR, ATR, and MasR belong to the G-protein-coupled receptor (GPCR) family. GPCRs operate not only as monomers, but they can also function in dimeric (homo and hetero) or higher-order oligomeric states. Due to the interaction with other receptors, GPCR properties may change: receptor affinity, trafficking, signaling, and its biological function may be altered. Thus, heteromerization provides a newly recognized means of modulation of receptor function, as well as crosstalk between GPCRs. This review is focused on angiotensin receptors, and how their properties are influenced by crosstalk with other receptors, adding more complexity to an already complex system and potentially opening up new therapeutic approaches.
Topics: Humans; Renin-Angiotensin System; Animals; Receptors, G-Protein-Coupled; Signal Transduction; Receptor Cross-Talk; Receptors, Angiotensin; Receptor, Angiotensin, Type 1; Blood Pressure; Receptor, Angiotensin, Type 2
PubMed: 38488216
DOI: 10.1111/apha.14134 -
The Journal of the Association of... Nov 2023Overactivity of the renin-angiotensin-aldosterone system (RAAS) is a consistent feature of COVID-19 as indicated by high concentrations of angiotensin II (Ang II) in... (Review)
Review
Overactivity of the renin-angiotensin-aldosterone system (RAAS) is a consistent feature of COVID-19 as indicated by high concentrations of angiotensin II (Ang II) in lungs and other tissues. Virus-induced downregulation of angiotensin-converting enzyme-2 (ACE2) explains the raised Ang II levels. Available evidence points to the crucial role of Ang II in the pathogenesis of coronavirus disease. The proinflammatory, immune stimulant, and procoagulant effects exhibited by the peptide at high tissue levels explain lung injury, a characteristic feature of severe COVID-19. Angiotensin II (Ang II) inhibitors [both the angiotensin-converting enzyme inhibitors (ACEIs) and the angiotensin receptor blockers (ARBs)] constitute the logical therapy for established COVID-19 infection. While ACEIs help to lower Ang II levels in the tissues, ARBs antagonize the effects of the peptide on the target tissues. Of the two, ARBs offer a better choice because of the minimal adverse effects of dry cough and angioedema. The effectiveness of Ang II inhibitors in COVID-19 is well supported by their protective effect against lung injury in animals induced by the virus spike protein as well as the clinical improvement of shortened hospital stay and reduced mortality in observational studies in humans. A unique feature of these agents is that mutations of the coronavirus 2 (CoV-2) would have little impact on their effectiveness since they do not interfere with the host cell entry of the virus or its replication. Expectedly, the agents might retain their usefulness against variant strains, including "ο" and its subvariants. The overall safety of Ang II inhibitors has been well established beyond doubt since they have been in use for years in the management of cardiovascular (CV) diseases, diabetes mellitus, and chronic kidney disease (CKD). Regular use of ARBs in all patients who are COVID-19 positive and symptomatic (mild, moderate, or severe) offers a good option worth serious consideration. : S HT. COVID-19 Therapeutics Why Not Angiotensin Receptor Blockers (ARBs)? J Assoc Physicians India 2023;71(11):71-75.
Topics: Humans; Angiotensin Receptor Antagonists; COVID-19 Drug Treatment; COVID-19; Angiotensin-Converting Enzyme Inhibitors; Renin-Angiotensin System; SARS-CoV-2
PubMed: 38720500
DOI: 10.59556/japi.71.0393 -
European Journal of Internal Medicine Feb 2024More than 90 % of patients developing heart failure (HF) have hypertension. The most frequent concomitant conditions are type-2 diabetes mellitus, obesity, atrial... (Review)
Review
More than 90 % of patients developing heart failure (HF) have hypertension. The most frequent concomitant conditions are type-2 diabetes mellitus, obesity, atrial fibrillation, and coronary disease. HF outcome research focuses on decreasing mortality and preventing hospitalization for worsening HF syndrome. All drugs that decrease these HF endpoints lower blood pressure. Current drug treatments for HF are (i) angiotensin-converting enzyme inhibitors, angiotensin receptor blockers or angiotensin receptor neprilysin inhibitors, (ii) selected beta-blockers, (iii) steroidal and non-steroidal mineralocorticoid receptor antagonists, and (iv) sodium-glucose cotransporter 2 inhibitors. For various reasons, these drug treatments were first studied in HF patients with a reduced ejection fraction (HFrEF). Subsequently, they have been investigated in HF patients with a preserved left ventricular ejection fraction (LVEF, HFpEF) of mostly hypertensive etiology, and with modest benefits largely assessed on top of background treatment with the drugs already proven effective in HFrEF. Additionally, diuretics are given on symptomatic indications. Patients with HFpEF may have diastolic dysfunction but also systolic dysfunction visualized by lack of longitudinal shortening. Considering the totality of evidence and the overall need for antihypertensive treatment and/or treatment of hypertensive complications in almost all HF patients, the principal drug treatment of HF appears to be the same regardless of LVEF. Rather than LVEF-guided treatment of HF, treatment of HF should be directed by symptoms (related to the level of fluid retention), signs (tachycardia), severity (NYHA functional class), and concomitant diseases and conditions. All HF patients should be given all the drug classes mentioned above if well tolerated.
Topics: Humans; Heart Failure; Stroke Volume; Ventricular Function, Left; Angiotensin-Converting Enzyme Inhibitors; Angiotensin Receptor Antagonists; Hypertension
PubMed: 37865559
DOI: 10.1016/j.ejim.2023.10.008 -
Diagnostics (Basel, Switzerland) Nov 2023Autoimmune dermatological diseases (AIDD) encompass a diverse group of disorders characterized by aberrant immune responses targeting the skin and its associated... (Review)
Review
Autoimmune dermatological diseases (AIDD) encompass a diverse group of disorders characterized by aberrant immune responses targeting the skin and its associated structures. In recent years, emerging evidence suggests a potential involvement of the renin-angiotensin system (RAS) in the pathogenesis and progression of these conditions. RAS is a multicomponent cascade, primarily known for its role in regulating blood pressure and fluid balance. All of the RAS components play an important role in controlling inflammation and other immune responses. Angiotensin II, the main effector, acts on two essential receptors: Angiotensin Receptor 1 and 2 (AT1R and AT2R). A disturbance in the axis can lead to many pathological processes, including autoimmune (AI) diseases. AT1R activation triggers diverse signaling cascades involved in inflammation, fibrosis and tissue remodeling. Experimental studies have demonstrated the presence of AT1R in various cutaneous cells and immune cells, further emphasizing its potential contribution to the AI processes in the skin. Furthermore, recent investigations have highlighted the role of other RAS components, beyond angiotensin-converting enzyme (ACE) and Ang II, that may contribute to the pathophysiology of AIDD. Alternative pathways involving ACE2, Ang receptors and Ang-(1-7) have been implicated in regulating immune responses and tissue homeostasis within the skin microenvironment. Understanding the intricate involvement of the RAS in AIDD may provide novel therapeutic opportunities. Targeting specific components of the RAS, such as angiotensin receptor blockers (ARBs), ACE inhibitors (ACEIs) or alternative RAS pathway modulators, could potentially ameliorate inflammatory responses, reduce tissue damage and lessen disease manifestations. Further research is warranted to outline the exact mechanisms underlying RAS-mediated immune dysregulation in AIDD. This abstract aims to provide a concise overview of the intricate interplay between the RAS and AIDD. Therefore, we elaborate a systematic review of the potential challenge of RAS in the AIDD, including psoriasis, systemic sclerosis, vitiligo, lupus erythematosus and many more.
PubMed: 37998534
DOI: 10.3390/diagnostics13223398 -
Journal of Diabetes and Its... Aug 2023In patients with chronic kidney disease (CKD) associated with type 2 diabetes mellitus (T2DM), slowing kidney disease progression is an important therapeutic goal. Many... (Review)
Review
In patients with chronic kidney disease (CKD) associated with type 2 diabetes mellitus (T2DM), slowing kidney disease progression is an important therapeutic goal. Many patients with T2DM and CKD also have cardiovascular (CV) comorbidities. Renin-angiotensin-aldosterone system inhibitors (RAASis), which include angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs), are drugs with known antihypertensive effects as well as CV and kidney protective effects in patients with CKD. Studies have shown that adding a sodium-glucose cotransporter-2 (SGLT2) inhibitor to ACEI or ARB therapy has additive benefits in terms of kidney and CV protection in patients with CKD (with/without T2DM). For patients with CKD associated with T2DM who have persistent albuminuria despite taking the maximum tolerated dose of a RAASi, adding a nonsteroidal mineralocorticoid receptor antagonist (finerenone) has demonstrated CV and kidney benefits in clinical trials. In this article, we review the use of ACEIs and ARBs for their kidney and CV protective effects when used alone or in combination with a drug with a different mechanism of action. From reviewing the available evidence, it seems clear that a multimodal drug effort is needed to achieve maximum kidney and CV protective effects for patients with CKD associated with T2DM.
Topics: Humans; Diabetes Mellitus, Type 2; Angiotensin-Converting Enzyme Inhibitors; Angiotensin Receptor Antagonists; Renal Insufficiency, Chronic; Antihypertensive Agents; Renin-Angiotensin System
PubMed: 37356235
DOI: 10.1016/j.jdiacomp.2023.108515 -
Journal of the American Geriatrics... Oct 2023Frail older adults may be less likely to receive guideline-directed medical therapy (GDMT)-renin-angiotensin blockers, beta-blockers, and mineralocorticoid receptor...
BACKGROUND
Frail older adults may be less likely to receive guideline-directed medical therapy (GDMT)-renin-angiotensin blockers, beta-blockers, and mineralocorticoid receptor antagonists-for heart failure with reduced ejection fraction (HFrEF). We aimed to examine the uptake of angiotensin receptor neprilysin inhibitor (ARNI) and GDMT in frail older adults with HFrEF.
METHODS
Using 2015-2019 Medicare data, we estimated the proportion of beneficiaries with HFrEF receiving ARNI and GDMT each year by frailty status, defined by a claims-based frailty index. Logistic regression was used to identify clinical characteristics associated with ARNI initiation. Cox proportional hazards regression was used to examine the association of GDMT use in 2015 and death or heart failure hospitalization in 2016-2019.
RESULTS
Among 147,506-180,386 beneficiaries with HFrEF (mean age: 77 years; 27% women; 42.6-49.1% frail) in 2015-2019, the proportion of patients receiving ARNI increased in both non-frail (0.4%-16.4%) and frail (0.3%-13.7%) patients (p for yearly-trend-by-frailty = 0.970). Among those not receiving a renin-angiotensin system blocker, patients with age ≥ 85 years (odds ratio [95% CI], 0.89 [0.80-0.99]), dementia (0.88 [0.81-0.96]), and frailty (0.87 [0.81-0.94]) were less likely to initiate ARNI. The proportion of patients receiving all 3 GDMT classes increased in non-frail patients (22.0%-27.0%) but changed minimally in frail patients (19.6%-21.8%). Regardless of frailty status, treatment with at least 1 class of GDMT was associated with lower death or heart failure hospitalization than no GDMT medications (hazard ratio [95% CI], 0.94 [0.91-0.97], 0.92 [0.89-0.94], 0.94 [0.91-0.97] for 1, 2, and 3 classes, respectively).
CONCLUSIONS
Our results suggest an evidence-practice gap in the use of ARNI and GDMT in Medicare beneficiaries with HFrEF, particularly those with frailty. Efforts to narrow this gap are needed to reduce the burden of HFrEF in older adults.
Topics: Humans; Female; Aged; United States; Aged, 80 and over; Male; Heart Failure; Neprilysin; Stroke Volume; Frailty; Receptors, Angiotensin; Medicare; Antihypertensive Agents; Adrenergic beta-Antagonists; Ventricular Dysfunction, Left; Angiotensin Receptor Antagonists
PubMed: 37345734
DOI: 10.1111/jgs.18481 -
Journal of the American Heart... Sep 2023Background The renin-angiotensin system plays a crucial role in human physiology, and its main hormone, angiotensin, activates 2 G-protein-coupled receptors, the...
Background The renin-angiotensin system plays a crucial role in human physiology, and its main hormone, angiotensin, activates 2 G-protein-coupled receptors, the angiotensin type-1 and type-2 receptors, in almost every organ. However, controversy exists about the location, distribution, and expression levels of these receptors. Concerns have been raised over the low sensitivity, low specificity, and large variability between lots of commercially available antibodies for angiotensin type-1 and type-2 receptors, which makes it difficult to reconciliate results of different studies. Here, we describe the first non-antibody-based sensitive and specific targeted quantitative mass spectrometry assay for angiotensin receptors. Methods and Results Using a technique that allows targeted analysis of multiple peptides across multiple samples in a single mass spectrometry analysis, known as TOMAHAQ (triggered by offset, multiplexed, accurate mass, high resolution, and absolute quantification), we have identified and validated specific human tryptic peptides that permit identification and quantification of angiotensin type-1 and type-2 receptors in biological samples. Several peptide sequences are conserved in rodents, making these mass spectrometry assays amenable to both preclinical and clinical studies. We have used this method to quantify angiotensin type-1 and type-2 receptors in postmortem frontal cortex samples of older adults (n=28) with Alzheimer dementia. We correlated levels of angiotensin receptors to biomarkers classically linked to renin-angiotensin system activation, including oxidative stress, inflammation, amyloid-β load, and paired helical filament-tau tangle burden. Conclusions These robust high-throughput assays will not only catalyze novel mechanistic studies in the angiotensin research field but may also help to identify patients with an unbalanced angiotensin receptor distribution who would benefit from angiotensin receptor blocker treatment.
Topics: Humans; Aged; Angiotensins; Receptors, Angiotensin; Renin-Angiotensin System; Angiotensin Receptor Antagonists; Antibodies
PubMed: 37681524
DOI: 10.1161/JAHA.123.030791 -
American Journal of Cardiovascular... Nov 2023Arterial hypertension is the main preventable cause of premature mortality worldwide. Across Latin America, hypertension has an estimated prevalence of 25.5-52.5%,... (Review)
Review
The Pivotal Role of Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers in Hypertension Management and Cardiovascular and Renal Protection: A Critical Appraisal and Comparison of International Guidelines.
Arterial hypertension is the main preventable cause of premature mortality worldwide. Across Latin America, hypertension has an estimated prevalence of 25.5-52.5%, although many hypertensive patients remain untreated. Appropriate treatment, started early and continued for the remaining lifespan, significantly reduces the risk of complications and mortality. All international and most regional guidelines emphasize a central role for renin-angiotensin-aldosterone system inhibitors (RAASis) in antihypertensive treatment. The two main RAASi options are angiotensin-converting enzyme inhibitors (ACEis) and angiotensin II receptor blockers (ARBs). Although equivalent in terms of blood pressure reduction, ACEis are preferably recommended by some guidelines to manage other cardiovascular comorbidities, with ARBs considered as an alternative when ACEis are not tolerated. This review summarizes the differences between ACEis and ARBs and their place in the international guidelines. It provides a critical appraisal of the guidelines based on available evidence from randomized controlled trials (RCTs) and meta-analyses, especially considering that hypertensive patients in daily practice often have other comorbidities. The observed differences in cardiovascular and renal outcomes in RCTs may be attributed to the different mechanisms of action of ACEis and ARBs, including increased bradykinin levels, potentiated bradykinin response, and stimulated nitric oxide production with ACEis. It may therefore be appropriate to consider ACEis and ARBs as different antihypertensive drugs classes within the same RAASi group. Although guideline recommendations only differentiate between ACEis and ARBs in patients with cardiovascular comorbidities, clinical evidence suggests that ACEis provide benefits in many hypertensive patients, as well as those with other cardiovascular conditions.
Topics: Humans; Angiotensin-Converting Enzyme Inhibitors; Angiotensin Receptor Antagonists; Bradykinin; Hypertension; Antihypertensive Agents; Renin-Angiotensin System
PubMed: 37668854
DOI: 10.1007/s40256-023-00605-5