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The Canadian Journal of Cardiology Dec 2023Despite the availability of various therapeutic classes of antihypertensive drugs, hypertension remains poorly controlled, in part because of poor adherence. Hence,... (Review)
Review
Despite the availability of various therapeutic classes of antihypertensive drugs, hypertension remains poorly controlled, in part because of poor adherence. Hence, there is a need for the development of antihypertensive drugs acting on new targets to improve control of blood pressure. This review discusses novel insights (including the data of recent clinical trials) with regard to interference with the renin-angiotensin system, focusing on the enzymes aminopeptidase A and angiotensin-converting enzyme 2 (ACE2) in the brain, as well as the substrate of renin- angiotensinogen-in the liver. It raises the possibility that centrally acting amino peptidase A inhibitors (eg, firibastat), preventing the conversion of angiotensin II to angiotensin III in the brain, might be particularly useful in African Americans and patients with obesity. Firibastat additionally upregulates brain ACE2, allowing the conversion of angiotensin II to its protective metabolite angiotensin-(1-7). Furthermore, antisense oligonucleotides or small interfering ribonucleic acids suppress hepatic angiotensinogen for weeks to months after 1 injection and thus could potentially overcome adherence issues. Finally, interference with ACE2 ubiquitination is emerging as a future option for the treatment of neurogenic hypertension, given that ubiquitination resistance might upregulate ACE2 activity.
Topics: Humans; Renin-Angiotensin System; Antihypertensive Agents; Glutamyl Aminopeptidase; Angiotensin-Converting Enzyme 2; Angiotensinogen; Angiotensin II; Hypertension; Brain
PubMed: 37348757
DOI: 10.1016/j.cjca.2023.06.013 -
Systematic Reviews Sep 2021Conflicting findings and the analysis of unpublished and retracted data have led to controversy on the safety of angiotensin-converting enzyme inhibitors and angiotensin... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Conflicting findings and the analysis of unpublished and retracted data have led to controversy on the safety of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in people with COVID-19 infection. This meta-analysis examined the association of prescription of angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB) with the outcome from COVID-19.
METHODS
A systematic search was conducted to find published studies that reported the outcome of COVID-19 in relation to prescription of ACEI or ARB. Two authors (MF and AD) independently screened and extracted data and assessed study quality and strength of association using standardised tools. The endpoints for the meta-analyses were severe or critical disease outcome and mortality based on standardised criteria.
RESULTS
Twenty-six studies including 8389 people prescribed ACEI or ARB and 20,989 people not prescribed these medications were included. The quality of studies varied, and the overall strength of association was poor with a high risk of confounding bias. Patients prescribed ACEI or ARB had a greater prevalence of risk factors. Meta-analysis found an association between prescription of ACEI or ARB with severe or critical disease outcome (risk ratio, RR, 1.23, 95% confidence interval, CI, 1.06 to 1.42, p = 0.006, I = 88%) but this association was lost in sensitivity analyses. There was no association between ACEI or ARB prescription and mortality (RR 1.18, 95% CI 0.92 to 1.50, p = 0.19, I = 82%).
CONCLUSIONS
This meta-analysis suggests that people prescribed ACEI or ARB more commonly had severe or critical disease outcome, but not mortality, in published cohorts of patients diagnosed with COVID-19. This finding is most likely due to a greater prevalence of risk factors in these patients rather than due to exposure to angiotensin pathway inhibitors.
Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Angiotensins; COVID-19; Humans; SARS-CoV-2
PubMed: 34488897
DOI: 10.1186/s13643-021-01802-6 -
The Journals of Gerontology. Series A,... Aug 2021The physiopathological mechanisms that regulate menopausal and sex differences in colonic transit, inflammatory processes, and efficacy of treatments have not been...
The physiopathological mechanisms that regulate menopausal and sex differences in colonic transit, inflammatory processes, and efficacy of treatments have not been clarified. The dopaminergic system and renin-angiotensin system coexist in the gut and regulate different processes such as motility, absorption/secretion, and inflammation. We investigated the changes in expression of major angiotensin and dopamine receptors in the colon of male, female, and ovariectomized female mice. Possible interaction between both systems was investigated using male and female mice deficient (ko) for major angiotensin and dopamine receptors. In wild-type mice, colonic tissue from females showed lower angiotensin type 1/angiotensin type 2 ratio (an index of pro-inflammatory/anti-inflammatory renin-angiotensin system balance), lower dopamine D1 and D2 receptor expression, and lower levels of pro-inflammatory and pro-oxidative markers relative to males. Interestingly, ovariectomy increased the expression of pro-inflammatory angiotensin type 1 receptor expression and decreased anti-inflammatory angiotensin type 2 receptor expression, increased D1 and D2 receptor expression, and increased the levels of pro-inflammatory and pro-oxidative markers. Ovariectomy-induced changes were blocked by estrogen replacement. The present results suggest a mutual regulation between colonic angiotensin and dopamine receptors and sex differences in this mutual regulation. Estrogen regulates changes in both angiotensin and dopamine receptor expression, which may be involved in sex- and surgical menopause-related effects on gut motility, permeability, and vulnerability to inflammatory processes.
Topics: Angiotensins; Animals; Colon; Estrogens; Female; Male; Menopause; Mice; Ovariectomy; Receptors, Dopamine; Sex Characteristics
PubMed: 32991714
DOI: 10.1093/gerona/glaa244 -
Peptides Jun 2022Vascular aging is a complex and multifaceted process that provokes profound molecular, structural, and functional changes in the vasculature. Eventually, these profound...
Vascular aging is a complex and multifaceted process that provokes profound molecular, structural, and functional changes in the vasculature. Eventually, these profound aging alterations make arteries more prone to vascular disease, including hypertension, atherosclerosis and other arterial complications that impact the organism beyond the cardiovascular system and accelerate frailty. For these reasons, preventing or delaying the hallmarks of vascular aging is nowadays a major health goal, especially in our aged societies. In this context, angiotensin(Ang)-(1-7), a major player of the protective branch of the renin-angiotensin system, has gained relevance over recent years as growing knowledge on its anti-aging properties is being unveiled. Here, we briefly review the main actions of Ang-(1-7) against vascular aging. These include protection against vascular cell senescence, anti-inflammatory and antioxidant effects together with the induction of cytoprotective systems. Ang-(1-7) further ameliorates endothelial dysfunction, a hallmark of vascular aging and disease, attenuates fibrosis and calcification and promotes protective angiogenesis and repair. Although further research is needed to better understand the anti-aging properties of Ang-(1-7) on the vasculature, this heptapeptide arises as a promising pharmacological tool for preventing vascular aging and frailty.
Topics: Aged; Aging; Angiotensin I; Angiotensin II; Frailty; Humans; Peptide Fragments; Renin-Angiotensin System
PubMed: 35231551
DOI: 10.1016/j.peptides.2022.170775 -
International Journal of Clinical... 2022The present study aims to investigate the relationship between vitamin D deficiency and renin-angiotensin-aldosterone levels in patients with essential hypertension.
OBJECTIVE
The present study aims to investigate the relationship between vitamin D deficiency and renin-angiotensin-aldosterone levels in patients with essential hypertension.
METHODS
The present study observed two groups of patients from Urumqi, Xinjiang, China, from April 2017 to March 2018. There were two subject groups: the hypertension group (80 patients with essential hypertension selected by random cluster sampling) and the control group (76 healthy adults). The 25-hydroxyvitamin D (25(OH)D or vitamin D) levels were measured through electrolytes; fasting blood glucose, blood lipids, and other biochemical indicators were detected using immune chemiluminescence; and plasma renin activity and angiotensin II concentrations were detected with radio-immunity.
RESULTS
Comparison between the hypertension group and control group showed statistically significant differences in the systolic pressure and levels of 25(OH)D, renin, and triglycerides ( < 0.05). The correlation analysis showed that 25(OH)D was negatively correlated with renin ( = -0.185; =0.021) and positively correlated with systolic pressure ( = -0.105; =0.035). There were no statistically significant differences in diastolic pressure, fasting blood glucose, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglycerides between the two groups.
CONCLUSIONS
The results of the present study show that vitamin D deficiency is common in Urumqi, Xinjiang, China and vitamin D levels are negatively correlated with renin levels. Vitamin D plays an important role in regulating blood pressure by affecting renin levels through the renin-angiotensin-aldosterone system.
Topics: Adult; Aldosterone; Angiotensins; Asian People; Blood Pressure; Essential Hypertension; Female; Humans; Male; Middle Aged; Renin; Vitamin D Deficiency
PubMed: 35814306
DOI: 10.1155/2022/8975396 -
JACC. Clinical Electrophysiology Aug 2023Electrical stimulation of the left stellate ganglion (LSG) can evoke ventricular arrhythmias (VAs) that originate from the right ventricular outflow tract (RVOT). The...
BACKGROUND
Electrical stimulation of the left stellate ganglion (LSG) can evoke ventricular arrhythmias (VAs) that originate from the right ventricular outflow tract (RVOT). The involvement of pulmonary artery innervation is unclear.
OBJECTIVES
This study investigated the effects of selective pulmonary artery denervation (PADN) on blood pressure (BP), sympathetic activity, ventricular effective refractory period (ERP), and the incidence of VAs induced by LSG stimulation in canines.
METHODS
Radiofrequency ablation with basic anesthetic monitoring was used to induce PADN in canines. In Protocol 1 (n = 11), heart rate variability, serum norepinephrine and angiotensin-II levels, BP changes and ventricular ERP in response to LSG stimulation were measured before and after PADN. In Protocol 2 (n = 8), the incidence of VAs induced by LSG stimulation was calculated before and after PADN in a canine model of complete atrioventricular block. In addition, sympathetic nerves in the excised pulmonary arteries were immunohistochemically stained with tyrosine hydroxylase.
RESULTS
The low-frequency components of heart rate variability, serum norepinephrine and angiotensin-II levels were remarkably decreased post-PADN. Systolic BP elevation and RVOT ERP shortening induced by LSG stimulation were mitigated by PADN. The number of RVOT-premature ventricular contractions as well as RVOT tachycardia episodes and duration induced by LSG stimulation were significantly reduced after PADN. In addition, a large number of tyrosine hydroxylase-immunoreactive nerve fibers were located in the anterior wall of the pulmonary artery.
CONCLUSIONS
PADN ameliorated RVOT ERP shortening, and RVOT-VAs induced by LSG stimulation by inhibiting cardiac sympathetic nerve activity.
Topics: Animals; Dogs; Pulmonary Artery; Stellate Ganglion; Tyrosine 3-Monooxygenase; Arrhythmias, Cardiac; Norepinephrine; Denervation; Angiotensins
PubMed: 37086230
DOI: 10.1016/j.jacep.2023.02.009 -
The Journal of Allergy and Clinical... Mar 2021
Topics: Administration, Inhalation; Adrenal Cortex Hormones; Angiotensin-Converting Enzyme 2; Angiotensins; Humans; Pulmonary Disease, Chronic Obstructive
PubMed: 33388167
DOI: 10.1016/j.jaci.2020.11.018 -
Journal of the... 2022The SARS-CoV-2 virus is spreading around the world, and its clinical manifestation COVID-19 is challenging medical, economic, and social systems. With more and more... (Review)
Review
The SARS-CoV-2 virus is spreading around the world, and its clinical manifestation COVID-19 is challenging medical, economic, and social systems. With more and more scientific and social media reports on the COVID-19 pandemic appearing, differences in geographical presentations and clinical management occur. Since ACE2 (angiotensin-converting enzyme 2) is the gatekeeper receptor for the SARS-CoV-2 virus in the upper bronchial system, we here focus on the central role of the renin-angiotensin aldosterone system (RAAS) in the SARS-CoV-2 virus infection, the role of pharmacological RAAS inhibitors, and specific genetic aspects, i.e., single nucleotide polymorphisms (SNP) for the clinical outcome of COVID-19. We aimed to bring together clinical, epidemiological, molecular, and pathophysiological and pharmacological data/observations on cardiovascular aspects in the actual SARS-CoV-2 virus pandemic. In detail, we will report controversies about the Yin-Yan between ACE2 and ACE1 and potential implications for the treatment of hypertension, coronary artery disease, and heart failure. Here, we summarize the encouraging and dynamic global effort of multiple biomedical disciplines resulted in astonishing fight against COVID-19 targeting the renin-angiotensin-aldosterone system, yet the race for ACE just begun.
Topics: Angiotensin-Converting Enzyme 2; Angiotensin-Converting Enzyme Inhibitors; Angiotensins; Humans; Pandemics; Peptidyl-Dipeptidase A; SARS-CoV-2; COVID-19 Drug Treatment
PubMed: 35685188
DOI: 10.1155/2022/2549063 -
Basic & Clinical Pharmacology &... Sep 2021Inflammatory bowel diseases (IBDs) are chronic disorders of the gastrointestinal tract, which manifest in recurring gastrointestinal inflammation. The current treatment... (Review)
Review
Inflammatory bowel diseases (IBDs) are chronic disorders of the gastrointestinal tract, which manifest in recurring gastrointestinal inflammation. The current treatment options of IBD are not curative and are lacking in aspects like prevention of fibrosis. New treatment options are needed to fulfil the unmet needs and provide alternatives to drugs with resistances and side effects. Drugs targeting the renin-angiotensin system (RAS), besides being antihypertensive, also possess anti-inflammatory and antifibrotic properties and could offer an inexpensive alternative to control inflammation and fibrosis in the gut. RAS inhibitors have been effective in preventing and alleviating colitis in preclinical studies, but available human data are still sparse. This review outlines the pathophysiological functions of RAS in the gut and summarizes preclinical studies utilizing pharmacological RAS inhibitors in the treatment of experimental colitis. We discuss the alterations in intestinal RAS and the available evidence of the benefits of RAS inhibitors for IBD patients. Retrospective studies comparing IBD patients using ACE inhibitors or angiotensin II receptor blockers have provided optimistic results regarding a milder disease course and fewer hospitalizations and corticosteroid use in patients using RAS inhibitors. Prospective studies are needed to evaluate the effectiveness of these promising medications in the treatment of IBD.
Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Angiotensins; Animals; Antihypertensive Agents; Colitis; Drug Evaluation, Preclinical; Fibrosis; Humans; Hypertension; Inflammation; Inflammatory Bowel Diseases; Mice; Models, Animal; Renin-Angiotensin System; Retrospective Studies
PubMed: 34128327
DOI: 10.1111/bcpt.13624 -
Medicina (Kaunas, Lithuania) Nov 2022One of the essential regulators of arterial blood pressure, the renin-angiotensin-aldosterone system (RAAS) seems to be one of the most complex mechanisms in the human... (Review)
Review
One of the essential regulators of arterial blood pressure, the renin-angiotensin-aldosterone system (RAAS) seems to be one of the most complex mechanisms in the human body. Since the discovery of its key components and their actions, new substances and functions are still being unraveled. The main pathway begins with the secretion of renin in the kidney and culminates with the synthesis of angiotensin II (Ang II)-a strong vasoconstrictor-thanks to the angiotensin-converting enzyme (ACE). Research conducted in 2000 identified another enzyme, named ACE2, that converts Ang II into Ang-(1-7), a heptapeptide with opposing effects to those of Ang II: vasodilation and anti-inflammatory properties. This particular enzyme became of paramount importance during the last two decades, as a result of the confrontation of the human race with life-threatening epidemics. Multiple studies have been performed in order to uncover the link between ACE2 and human coronaviruses, the results of which we systemized in order to create an overview of the pathogenic mechanism. Human coronaviruses, such as SARS-CoV and SARS-CoV-2, attach to ACE2 via their spike proteins (S), causing the destruction of the enzyme. Because ACE2 limits the production of Ang II (by converting it into Ang-(1-7)), its destruction leads to a dysregulated inflammatory response. The purpose of this review is to decipher the complex pathophysiological mechanisms underlying the multiorgan complications (oral, cardiac, pulmonary, systemic) that appear as a result of the interaction of the SARS CoV-2 virus with the angiotensin-converting enzyme type 2.
Topics: Humans; Renin-Angiotensin System; SARS-CoV-2; Angiotensin-Converting Enzyme 2; COVID-19; Severe acute respiratory syndrome-related coronavirus; Angiotensins
PubMed: 36556919
DOI: 10.3390/medicina58121717