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1.
Int J Mol Sci ; 23(3)2022 Feb 04.
Article in English | MEDLINE | ID: covidwho-1745038

ABSTRACT

This review article is focused on antihypertensive drugs, namely angiotensin converting enzyme inhibitors (ACEI) and angiotensin II receptor blockers (ARB), and their immunomodulatory properties reported in hypertensive patients as well as in experimental settings involving studies on animal models and cell lines. The immune regulatory action of ACEI and ARB is mainly connected with the inhibition of proinflammatory cytokine secretion, diminished expression of adhesion molecules, and normalization of CRP concentration in the blood plasma. The topic has significant importance in future medical practice in the therapy of patients with comorbidities with underlying chronic inflammatory responses. Thus, this additional effect of immune regulatory action of ACEI and ARB may also benefit the treatment of patients with metabolic syndrome, allergies, or autoimmune disorders.


Subject(s)
Angiotensin Receptor Antagonists/pharmacology , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Immunomodulation/drug effects , Animals , Antihypertensive Agents/pharmacology , COVID-19 , Humans
2.
Life Sci ; 291: 120267, 2022 Feb 15.
Article in English | MEDLINE | ID: covidwho-1587054

ABSTRACT

Tauopathy is a term that has been used to represent a pathological condition in which hyperphosphorylated tau protein aggregates in neurons and glia which results in neurodegeneration, synapse loss and dysfunction and cognitive impairments. Recently, drug repositioning strategy (DRS) becomes a promising field and an alternative approach to advancing new treatments from actually developed and FDA approved drugs for an indication other than the indication it was originally intended for. This paradigm provides an advantage because the safety of the candidate compound has already been established, which abolishes the need for further preclinical safety testing and thus substantially reduces the time and cost involved in progressing of clinical trials. In the present review, we focused on correlation between tauopathy and common diseases as type 2 diabetes mellitus and the global virus COVID-19 and how tau pathology can aggravate development of these diseases in addition to how these diseases can be a risk factor for development of tauopathy. Moreover, correlation between COVID-19 and type 2 diabetes mellitus was also discussed. Therefore, repositioning of a drug in the daily clinical practice of patients to manage or prevent two or more diseases at the same time with lower side effects and drug-drug interactions is a promising idea. This review concluded the results of pre-clinical and clinical studies applied on antidiabetics, COVID-19 medications, antihypertensives, antidepressants and cholesterol lowering drugs for possible drug repositioning for management of tauopathy.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/physiopathology , Drug Repositioning , Hypoglycemic Agents/pharmacology , Tauopathies/drug therapy , Antidepressive Agents/pharmacology , Antihypertensive Agents/pharmacology , Apoptosis/drug effects , COVID-19/drug therapy , Diabetes Mellitus, Type 2/physiopathology , Glycogen Synthase Kinase 3 beta/antagonists & inhibitors , Humans , Molecular Targeted Therapy/methods , Proto-Oncogene Proteins c-akt/metabolism , Tauopathies/physiopathology
4.
Front Cell Infect Microbiol ; 11: 639177, 2021.
Article in English | MEDLINE | ID: covidwho-1389152

ABSTRACT

Several comorbidities, including hypertension, have been associated with an increased risk of developing severe disease during SARS-CoV-2 infection. Angiotensin II receptor blockers (ARBs) are currently some of the most widely-used drugs to control blood pressure by acting on the angiotensin II type 1 receptor (AT1R). ARBs have been reported to trigger the modulation of the angiotensin I converting enzyme 2 (ACE2), the receptor used by the virus to penetrate susceptible cells, raising concern that such treatments may promote virus capture and increase their viral load in patients receiving ARBs therapy. In this in vitro study, we reviewed the effect of ARBs on ACE2 and AT1R expression and investigated whether treatment of permissive ACE2+/AT1R+ Vero E6 cells with ARBs alters SARS-CoV-2 replication in vitro in an angiotensin II-free system. After treating the cells with the ARBs, we observed an approximate 50% relative increase in SARS-CoV-2 production in infected Vero E6 cells that correlates with the ARBs-induced up-regulation of ACE2 expression. From this data, we believe that the use of ARBs in hypertensive patients infected by SARS-CoV-2 should be carefully evaluated.


Subject(s)
Angiotensin Receptor Antagonists , COVID-19 , Angiotensin Receptor Antagonists/pharmacology , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Antihypertensive Agents/pharmacology , Humans , Renin-Angiotensin System , SARS-CoV-2
6.
Stem Cell Reports ; 16(10): 2459-2472, 2021 10 12.
Article in English | MEDLINE | ID: covidwho-1377840

ABSTRACT

The pathogenicity of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has been attributed to its ability to enter through the membrane-bound angiotensin-converting enzyme 2 (ACE2) receptor. Therefore, it has been heavily speculated that angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) therapy may modulate SARS-CoV-2 infection. In this study, exposure of human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) and human endothelial cells (hECs) to SARS-CoV-2 identified significant differences in protein coding genes involved in immunity, viral response, and cardiomyocyte/endothelial structure. Specifically, transcriptome changes were identified in the tumor necrosis factor (TNF), interferon α/ß, and mitogen-activated protein kinase (MAPK) (hPSC-CMs) as well as nuclear factor kappa-B (NF-κB) (hECs) signaling pathways. However, pre-treatment of hPSC-CMs or hECs with two widely prescribed antihypertensive medications, losartan and lisinopril, did not affect the susceptibility of either cell type to SARS-CoV-2 infection. These findings demonstrate the toxic effects of SARS-CoV-2 in hPSC-CMs/hECs and, taken together with newly emerging multicenter trials, suggest that antihypertensive drug treatment alone does not alter SARS-CoV-2 infection.


Subject(s)
Antihypertensive Agents/pharmacology , COVID-19/drug therapy , Endothelial Cells/drug effects , Myocytes, Cardiac/drug effects , COVID-19/genetics , Cells, Cultured , Disease Susceptibility , Endothelial Cells/metabolism , Host-Pathogen Interactions/drug effects , Humans , Lisinopril/pharmacology , Losartan/pharmacology , Myocytes, Cardiac/metabolism , SARS-CoV-2/drug effects , SARS-CoV-2/physiology , Transcriptome/drug effects
7.
Bioorg Chem ; 116: 105272, 2021 11.
Article in English | MEDLINE | ID: covidwho-1370451

ABSTRACT

Hypertension has been recognized as one of the most frequent comorbidities and risk factors for the seriousness and adverse consequences in COVID-19 patients. 3,4-dihydropyrimidin-2(1H) ones have attracted researchers to be synthesized via Beginilli reaction and evaluate their antihypertensive activities as bioisosteres of nifedipine a well-known calcium channel blocker. In this study, we report synthesis of some bioisosteres of pyrimidines as novel CCBs with potential ACE2 inhibitory effect as antihypertensive agents with protective effect against COVID-19 infection by suppression of ACE2 binding to SARS-CoV-2 Spike RBD. All compounds were evaluated for their antihypertensive and calcium channel blocking activities using nifedipine as a reference standard. Furthermore, they were screened for their ACE2 inhibition potential in addition to their anti-inflammatory effects on LPS-stimulated THP-1 cells. Most of the tested compounds exhibited significant antihypertensive activity, where compounds 7a, 8a and 9a exhibited the highest activity compared to nifedipine. Moreover, compounds 4a,b, 5a,b, 7a,b, 8a,c and 9a showed promising ACE2:SARS-CoV-2 Spike RBD inhibitory effect. Finally, compounds 5a, 7b and 9a exerted a promising anti-inflammatory effect by inhibition of CRP and IL-6 production. Ultimately, compound 9a may be a promising antihypertensive candidate with anti-inflammatory and potential efficacy against COVID-19 via ACE2 receptor inhibition.


Subject(s)
Angiotensin-Converting Enzyme Inhibitors/pharmacology , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Antihypertensive Agents/pharmacology , Antiviral Agents/pharmacology , COVID-19/drug therapy , Calcium Channel Blockers/pharmacology , Angiotensin-Converting Enzyme Inhibitors/chemical synthesis , Angiotensin-Converting Enzyme Inhibitors/chemistry , Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Antihypertensive Agents/chemical synthesis , Antihypertensive Agents/chemistry , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , Calcium Channel Blockers/chemical synthesis , Calcium Channel Blockers/chemistry , Humans , SARS-CoV-2/drug effects
8.
Zool Res ; 42(5): 633-636, 2021 Sep 18.
Article in English | MEDLINE | ID: covidwho-1369995

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the etiologic agent responsible for the global coronavirus disease 2019 (COVID-19) pandemic. Numerous studies have demonstrated that cardiovascular disease may affect COVID-19 progression. In the present study, we investigated the effect of hypertension on viral replication and COVID-19 progression using a hypertensive mouse model infected with SARS-CoV-2. Results revealed that SARS-CoV-2 replication was delayed in hypertensive mouse lungs. In contrast, SARS-CoV-2 replication in hypertensive mice treated with the antihypertensive drug captopril demonstrated similar virus replication as SARS-CoV-2-infected normotensive mice. Furthermore, antihypertensive treatment alleviated lung inflammation induced by SARS-CoV-2 replication (interleukin (IL)-1ß up-regulation and increased immune cell infiltration). No differences in lung inflammation were observed between the SARS-CoV-2-infected normotensive mice and hypertensive mice. Our findings suggest that captopril treatment may alleviate COVID-19 progression but not affect viral replication.


Subject(s)
Antihypertensive Agents/therapeutic use , COVID-19/complications , Captopril/therapeutic use , Hypertension/complications , Lung Diseases/drug therapy , SARS-CoV-2 , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Animals , Antihypertensive Agents/pharmacology , Captopril/pharmacology , Gene Expression Regulation/drug effects , Inflammation/complications , Inflammation/drug therapy , Interleukin-1beta/genetics , Interleukin-1beta/metabolism , Lung Diseases/etiology , Lung Diseases/virology , Mice , Virus Replication/drug effects
9.
Hipertens Riesgo Vasc ; 37(4): 169-175, 2020.
Article in Spanish | MEDLINE | ID: covidwho-1322115

ABSTRACT

The first case of COVID-19 was reported on 31 December 2019 in Wuhan, China. Ever since there has been unprecedented and growing interest in learning about all aspects of this new disease. Debate has been generated as to the association between antihypertensive therapy with renin-angiotensin-aldosterone system (RAAS) inhibitors and SARS-CoV-2 infection. While many questions as yet remain unanswered, the aim of this report is to inform health professionals about the current state of knowledge. Because this is an ever-evolving topic, the recommendation is that it be updated as new evidence becomes available. Below, we provide a review of pre-clinical and clinical studies that link coronavirus to the RAAS.


Subject(s)
Betacoronavirus , Coronavirus Infections/physiopathology , Pandemics , Pneumonia, Viral/physiopathology , Renin-Angiotensin System/physiology , ADAM17 Protein/physiology , Angiotensin II/physiology , Angiotensin Receptor Antagonists/adverse effects , Angiotensin Receptor Antagonists/pharmacology , Angiotensin Receptor Antagonists/therapeutic use , Angiotensin-Converting Enzyme 2 , Angiotensin-Converting Enzyme Inhibitors/adverse effects , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Antihypertensive Agents/adverse effects , Antihypertensive Agents/pharmacology , Antihypertensive Agents/therapeutic use , COVID-19 , COVID-19 Vaccines , Coronavirus Infections/complications , Coronavirus Infections/immunology , Coronavirus Infections/prevention & control , Humans , Hypertension/complications , Hypertension/physiopathology , Lung/physiopathology , Models, Biological , Pandemics/prevention & control , Peptidyl-Dipeptidase A/drug effects , Peptidyl-Dipeptidase A/physiology , Pneumonia, Viral/complications , Pneumonia, Viral/immunology , Pneumonia, Viral/prevention & control , Receptors, Virus/drug effects , Renin-Angiotensin System/drug effects , Respiratory Distress Syndrome/etiology , Respiratory Distress Syndrome/physiopathology , SARS-CoV-2 , Serine Endopeptidases/physiology , Viral Vaccines , Virus Internalization/drug effects
10.
Medicina (Kaunas) ; 57(6)2021 Jun 18.
Article in English | MEDLINE | ID: covidwho-1273483

ABSTRACT

BACKGROUND: The association of coronavirus disease 2019 (COVID-19) with hypertension has been one of the frequently discussed topics in current studies since hypertension was identified as a risk factor for coronavirus disease. However, no studies seem to be focused on the BP (blood pressure) in patients with hypertension after COVID-19. REPORT: This report presents the cases of five frail geriatric patients (avg. age 78.3 (±6.4) years) with sarcopenia and controlled hypertension (office BP < 140 mmHg) who were diagnosed with SARS-CoV-2. FINDINGS: Control ABPM performed after COVID-19 showed that these hypertensive patients were hypotensive and that the previously well-established therapy was suddenly too intensive for them. CONCLUSIONS: These findings suggest that BP control after COVID-19 is needed and that ABPM is, particularly in frail geriatric patients, by no means a luxury but a necessity.


Subject(s)
COVID-19 , Hypertension , Hypotension , Aged , Antihypertensive Agents/pharmacology , Antihypertensive Agents/therapeutic use , Blood Pressure , Blood Pressure Monitoring, Ambulatory , Frail Elderly , Humans , Hypertension/complications , Hypertension/drug therapy , Hypotension/complications , SARS-CoV-2
11.
Med Hypotheses ; 152: 110609, 2021 Jul.
Article in English | MEDLINE | ID: covidwho-1225346

ABSTRACT

Preexisting hypertension is a known risk factor for severe COVID-19. Abnormal activation of RAS upregulates angiotensin II (Ang-II) and contributes to severe manifestations of COVID-19. Although RAS inhibitors (RASi) are a mainstay of antihypertensive therapy, they have been associated (in some animal studies) with an increase in angiotensin converting enzyme 2 (ACE2) receptors that facilitate cellular entry of the SARS-CoV-2 virus. Nonetheless, current medical practice does not recommend curtailing RASi to protect hypertensive patients from COVID. On the contrary, there is clinical evidence to support a beneficial effect of RASi for hypertensive patients in the midst of a COVID-19 pandemic, although the precise mechanism for this is unclear. In this paper, we hypothesize that RASi reduces the severity of COVID-19 by promoting ACE2-AT1R complex formation at the cell surface, where AT1R mediates the major vasopressor effects of Ang-II. Furthermore, we propose that the interaction between ACE2 and AT1R impedes binding of SARS-CoV-2 to ACE2, thereby allowing ACE2 to convert Ang-II to the more beneficial Ang(1-7), that has vasodilator and anti-inflammatory activity. Evidence for ACE2-AT1R complex formation during reduced Ang-II comes from receptor colocalization studies in isolated HEK293 cells, but this has not been confirmed in cells having endogenous expression of ACE2 and AT1R. Since the SARS-CoV-2 virus attacks the kidney, as well as the heart and lung, our hypothesis for the effect of RASi on COVID-19 could be tested in vitro using human proximal tubule cells (HK-2), having ACE2 and AT1 receptors. Specifically, colocalization of fluorescent labelled: SARS-CoV-2 spike protein, ACE2, and AT1R in HK-2 cells can be used to clarify the mechanism of RASi action in renal and lung epithelia, which could lead to protocols for reducing the severity of COVID-19 in both hypertensive and normotensive patients.


Subject(s)
COVID-19 , Pandemics , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Animals , Antihypertensive Agents/pharmacology , HEK293 Cells , Humans , Peptidyl-Dipeptidase A/metabolism , Renin , Renin-Angiotensin System , SARS-CoV-2 , Spike Glycoprotein, Coronavirus
12.
Circ Res ; 128(7): 1062-1079, 2021 04 02.
Article in English | MEDLINE | ID: covidwho-1166630

ABSTRACT

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) associates with a considerable high rate of mortality and represents currently the most important concern in global health. The risk of more severe clinical manifestation of COVID-19 is higher in males and steeply raised with age but also increased by the presence of chronic comorbidities. Among the latter, early reports suggested that arterial hypertension associates with higher susceptibility to SARS-CoV-2 infection, more severe course and increased COVID-19-related deaths. Furthermore, experimental studies suggested that key pathophysiological hypertension mechanisms, such as activation of the renin-angiotensin system (RAS), may play a role in COVID-19. In fact, ACE2 (angiotensin-converting-enzyme 2) is the pivotal receptor for SARS-CoV-2 to enter host cells and provides thus a link between COVID-19 and RAS. It was thus anticipated that drugs modulating the RAS including an upregulation of ACE2 may increase the risk for infection with SARS-CoV-2 and poorer outcomes in COVID-19. Since the use of RAS-blockers, ACE inhibitors or angiotensin receptor blockers, represents the backbone of recommended antihypertensive therapy and intense debate about their use in the COVID-19 pandemic has developed. Currently, a direct role of hypertension, independent of age and other comorbidities, as a risk factor for the SARS-COV-2 infection and COVID-19 outcome, particularly death, has not been established. Similarly, both current experimental and clinical studies do not support an unfavorable effect of RAS-blockers or other classes of first line blood pressure lowering drugs in COVID-19. Here, we review available data on the role of hypertension and its management on COVID-19. Conversely, some aspects as to how the COVID-19 affects hypertension management and impacts on future developments are also briefly discussed. COVID-19 has and continues to proof the critical importance of hypertension research to address questions that are important for global health.


Subject(s)
COVID-19/drug therapy , COVID-19/epidemiology , Hypertension/drug therapy , Hypertension/epidemiology , Angiotensin Receptor Antagonists/metabolism , Angiotensin Receptor Antagonists/pharmacology , Angiotensin Receptor Antagonists/therapeutic use , Angiotensin-Converting Enzyme 2/antagonists & inhibitors , Angiotensin-Converting Enzyme 2/metabolism , Angiotensin-Converting Enzyme Inhibitors/metabolism , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Antihypertensive Agents/metabolism , Antihypertensive Agents/pharmacology , Antihypertensive Agents/therapeutic use , COVID-19/metabolism , Humans , Hypertension/metabolism , Renin-Angiotensin System/drug effects , Renin-Angiotensin System/physiology , Risk Factors
13.
JAMA Netw Open ; 4(3): e213594, 2021 03 01.
Article in English | MEDLINE | ID: covidwho-1159048

ABSTRACT

Importance: The chronic receipt of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) has been assumed to exacerbate complications associated with COVID-19 and produce worse clinical outcomes. Objective: To conduct an updated and comprehensive systematic review and meta-analysis comparing mortality and severe adverse events (AEs) associated with receipt vs nonreceipt of ACEIs or ARBs among patients with COVID-19. Data Sources: PubMed and Embase databases were systematically searched from December 31, 2019, until September 1, 2020. Study Selection: The meta-analysis included any study design, with the exception of narrative reviews or opinion-based articles, in which COVID-19 was diagnosed through laboratory or radiological test results and in which clinical outcomes (unadjusted or adjusted) associated with COVID-19 were assessed among adult patients (≥18 years) receiving ACEIs or ARBs. Data Extraction and Synthesis: Three authors independently extracted data on mortality and severe AEs associated with COVID-19. Severe AEs were defined as intensive care unit admission or the need for assisted ventilation. For each outcome, a random-effects model was used to compare the odds ratio (OR) between patients receiving ACEIs or ARBs vs those not receiving ACEIs or ARBs. Main Outcomes and Measures: Unadjusted and adjusted ORs for mortality and severe AEs associated with COVID-19. Results: A total of 1788 records from the PubMed and Embase databases were identified; after removal of duplicates, 1664 records were screened, and 71 articles underwent full-text evaluation. Clinical data were pooled from 52 eligible studies (40 cohort studies, 6 case series, 4 case-control studies, 1 randomized clinical trial, and 1 cross-sectional study) enrolling 101 949 total patients, of whom 26 545 (26.0%) were receiving ACEIs or ARBs. When adjusted for covariates, significant reductions in the risk of death (adjusted OR [aOR], 0.57; 95% CI, 0.43-0.76; P < .001) and severe AEs (aOR, 0.68; 95% CI, 0.53-0.88; P < .001) were found. Unadjusted and adjusted analyses of a subgroup of patients with hypertension indicated decreases in the risk of death (unadjusted OR, 0.66 [95% CI, 0.49-0.91]; P = .01; aOR, 0.51 [95% CI, 0.32-0.84]; P = .008) and severe AEs (unadjusted OR, 0.70 [95% CI, 0.54-0.91]; P = .007; aOR, 0.55 [95% CI, 0.36-0.85]; P = .007). Conclusions and Relevance: In this systematic review and meta-analysis, receipt of ACEIs or ARBs was not associated with a higher risk of multivariable-adjusted mortality and severe AEs among patients with COVID-19 who had either hypertension or multiple comorbidities, supporting the recommendations of medical societies. On the contrary, ACEIs and ARBs may be associated with protective benefits, particularly among patients with hypertension. Future randomized clinical trials are warranted to establish causality.


Subject(s)
Angiotensin Receptor Antagonists/pharmacology , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Antihypertensive Agents/pharmacology , COVID-19/mortality , Hypertension/drug therapy , Renin-Angiotensin System , Severity of Illness Index , Adult , Aged , Aged, 80 and over , Angiotensin Receptor Antagonists/adverse effects , Angiotensin Receptor Antagonists/therapeutic use , Angiotensin-Converting Enzyme Inhibitors/adverse effects , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Antihypertensive Agents/adverse effects , Antihypertensive Agents/therapeutic use , COVID-19/epidemiology , Comorbidity , Female , Humans , Hypertension/epidemiology , Male , Middle Aged , SARS-CoV-2
14.
Kidney Blood Press Res ; 46(2): 245-249, 2021.
Article in English | MEDLINE | ID: covidwho-1146805

ABSTRACT

BACKGROUND: Preclinical studies suggested that pharmacological inhibition of the renin-angiotensin-aldosterone system (RAAS) by ACE inhibitors (ACEis) or angiotensin II receptor blockers (ARBs) may increase local angiotensin-converting enzyme 2 (ACE2) expression. METHODS: In this study, we evaluated the effect of ACEi or ARB treatment on expression of ACE2, ACE, and AGTR1 in 3-month protocol kidney allograft biopsies of stable patients using RT-qPCR (n = 48). Protein ACE2 expression was assessed using immunohistochemistry from paraffin sections. RESULTS: The therapy with RAAS blockers was not associated with increased ACE2, ACE, or ATGR1 expression in kidney allografts and also ACE2 protein immunohistochemistry did not reveal differences among groups. CONCLUSIONS: ACEis or ARBs in kidney transplant recipients do not affect local ACE2 expression. This observation supports long-term RAAS treatment in kidney transplant recipients, despite acute complications such as COVID-19 where ACE2 serves as the entry protein for infection.


Subject(s)
Allografts/drug effects , Angiotensin Receptor Antagonists/therapeutic use , Angiotensin-Converting Enzyme 2/genetics , Antihypertensive Agents/therapeutic use , Gene Expression/drug effects , Kidney/drug effects , Adult , Aged , Allografts/metabolism , Angiotensin Receptor Antagonists/pharmacology , Angiotensin-Converting Enzyme 2/analysis , Angiotensin-Converting Enzyme 2/antagonists & inhibitors , Antihypertensive Agents/pharmacology , COVID-19/complications , COVID-19/genetics , Female , Humans , Kidney/metabolism , Kidney Transplantation , Male , Middle Aged , RNA, Messenger/analysis , RNA, Messenger/genetics , Renin-Angiotensin System/drug effects
15.
Hypertens Res ; 44(8): 955-968, 2021 08.
Article in English | MEDLINE | ID: covidwho-1139738

ABSTRACT

Angiotensin-converting enzyme 2 (ACE2) protects against organ damage in hypertension and cardiovascular diseases by counter regulating the renin-angiotensin system (RAS). ACE2 is also the receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Based on the claim that RAS inhibitors (RASIs) cause ACE2 overexpression in some animal experiments, concerns have arisen that RASIs may aggravate SARS-CoV-2 infection and coronavirus disease-2019 severity in RASI-treated patients. To achieve a comprehensive review, a systematic search of MEDLINE/PubMed was conducted regarding the effects of RASIs on tissue ACE2 mRNA/protein expression in healthy animals and animal models of human diseases. We identified 88 eligible articles involving 168 experiments in the heart, kidneys, lungs, and other organs. Three of 38 experiments involving healthy animals showed ACE2 expression greater than twice that of the control (overexpression). Among 102 disease models (130 experiments), baseline ACE2 was overexpressed in 16 models (18 experiments) and less than half the control level (repression) in 28 models (40 experiments). In 72 experiments, RASIs did not change ACE2 levels from the baseline levels of disease models. RASIs caused ACE2 overexpression compared to control levels in seven experiments, some of which were unsupported by other experiments under similar conditions. In 36 experiments, RASIs reversed or prevented disease-induced ACE2 repression, yielding no or marginal changes. Therefore, ACE2 overexpression appears to be a rare rather than common consequence of RASI treatment in healthy animals and disease models. Future studies should clarify the pathophysiological significance of RASI-induced reversal or prevention of ACE2 repression in disease models.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , Angiotensin-Converting Enzyme Inhibitors/adverse effects , Antihypertensive Agents/adverse effects , Gene Expression/drug effects , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Animals , Antihypertensive Agents/pharmacology , COVID-19 , Disease Models, Animal , MEDLINE , Renin-Angiotensin System/drug effects
16.
Cells ; 10(3)2021 03 03.
Article in English | MEDLINE | ID: covidwho-1129685

ABSTRACT

(1) Background: Recently, influences of antihypertensive treatment on the renin-angiotensin-aldosterone system (RAAS) has gained attention, regarding a possible influence on inflammatory and anti-inflammatory pathways. We aimed to study the effects of newly initiated antihypertensive drugs on angiotensin (Ang) II and Ang (1-7) as representers of two counter-regulatory axes. (2) Methods: In this randomized, open-label trial investigating RAAS peptides after the initiation of perindopril, olmesartan, amlodipine, or hydrochlorothiazide, Ang II and Ang (1-7) equilibrium concentrations were measured at 8 a.m. and 12 a.m. at baseline and after four weeks of treatment. Eighty patients were randomized (1:1:1:1 fashion). (3) Results: Between the four substances, we found significant differences regarding the concentrations of Ang II (p < 0.0005 for 8 a.m., 12 a.m.) and Ang (1-7) (p = 0.019 for 8 a.m., <0.0005 for 12 a.m.) four weeks after treatment start. Ang II was decreased by perindopril (p = 0.002), and increased by olmesartan (p < 0.0005), amlodipine (p = 0.012), and hydrochlorothiazide (p = 0.001). Ang (1-7) was increased by perindopril and olmesartan (p = 0.008/0.002), but not measurably altered by amlodipine and hydrochlorothiazide (p = 0.317/ 0.109). (4) Conclusion: The initiation of all first line antihypertensive treatments causes early and distinct alterations of equilibrium angiotensin levels. Given the additional AT1R blocking action of olmesartan, RAAS peptides shift upon initiation of perindopril and olmesartan appear to work in favor of the anti-inflammatory axis compared to amlodipine and hydrochlorothiazide.


Subject(s)
Antihypertensive Agents/therapeutic use , Hypertension/drug therapy , Renin-Angiotensin System/drug effects , Antihypertensive Agents/pharmacology , Female , Humans , Hypertension/pathology , Male , Middle Aged
17.
Praxis (Bern 1994) ; 110(2): 60-64, 2021 Feb.
Article in German | MEDLINE | ID: covidwho-1084605

ABSTRACT

CME: Hypertension and the COVID-19 Pandemic: What to Consider in Medical Practice Abstract. The COVID-19 pandemic represents a major public health problem. A fraction of the population is at increased risk of developing complications of this disease, in particular older subjects as well as diabetic, obese and hypertensive patients. With regard to patients with high blood pressure, the existence of an increased risk remains to be confirmed in large controlled trials. So far the findings regarding this question are reassuring, whether these patients are treated or not. There seems to be no reason to worry when using blockers of the renin-angiotensin system. The observations available to date suggest that COVID-19 vaccine can be administered safely to hypertensive patients. In conclusion, there is no reason to implement changes in the care of hypertensive patients due to the pandemic.


Subject(s)
COVID-19 , Hypertension , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Antihypertensive Agents/pharmacology , Antihypertensive Agents/therapeutic use , COVID-19 Vaccines , Humans , Hypertension/drug therapy , Hypertension/epidemiology , Pandemics , Renin-Angiotensin System , SARS-CoV-2
18.
Acta Diabetol ; 58(7): 831-843, 2021 Jul.
Article in English | MEDLINE | ID: covidwho-1083870

ABSTRACT

The outbreak of coronavirus disease 2019 (COVID-19) caused by a novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a pandemic. The cellular receptor for SARS-CoV-2 entry is the angiotensin-converting enzyme 2, a membrane-bound homolog of angiotensin-converting enzyme. Henceforth, this has brought the attention of the scientific community to study the interaction between COVID-19 and the renin-angiotensin system (RAS), as well as RAS inhibitors. However, these inhibitors are commonly used to treat hypertension, chronic kidney disorder, and diabetes. Obesity is a known risk factor for heart disease, diabetes, and hypertension, whereas diabetes and hypertension may be indirectly related to each other through the effects of obesity. Furthermore, people with hypertension, obesity, diabetes, and other related complications like cardiovascular and kidney diseases have a higher risk of severe COVID-19 infection than the general population and usually exhibit poor prognosis. This severity could be due to systemic inflammation and compromised immune response and RAS associated with these comorbid conditions. Therefore, there is an urgent need to develop evidence-based treatment methods that do not affect the severity of COVID-19 infection and effectively manage these chronic diseases in people with COVID-19.


Subject(s)
COVID-19/mortality , Diabetes Mellitus/epidemiology , Hypertension/epidemiology , Obesity/epidemiology , Angiotensin-Converting Enzyme Inhibitors/adverse effects , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Antihypertensive Agents/pharmacology , Antihypertensive Agents/therapeutic use , COVID-19/complications , COVID-19/epidemiology , Comorbidity , Diabetes Complications/drug therapy , Diabetes Complications/epidemiology , Diabetes Complications/mortality , Diabetes Mellitus/drug therapy , Disease Progression , Heart Diseases/complications , Heart Diseases/drug therapy , Heart Diseases/epidemiology , Humans , Hypertension/complications , Hypertension/drug therapy , Obesity/complications , Pandemics , Peptidyl-Dipeptidase A/physiology , Renin-Angiotensin System/drug effects , Renin-Angiotensin System/physiology , Risk Factors , SARS-CoV-2/drug effects , SARS-CoV-2/physiology
20.
Eur Heart J ; 41(48): 4580-4588, 2020 12 21.
Article in English | MEDLINE | ID: covidwho-1066303

ABSTRACT

AIMS: Angiotensin-converting enzyme 2 (ACE2) is the cellular entry point for severe acute respiratory syndrome coronavirus (SARS-CoV-2)-the cause of coronavirus disease 2019 (COVID-19). However, the effect of renin-angiotensin system (RAS)-inhibition on ACE2 expression in human tissues of key relevance to blood pressure regulation and COVID-19 infection has not previously been reported. METHODS AND RESULTS: We examined how hypertension, its major metabolic co-phenotypes, and antihypertensive medications relate to ACE2 renal expression using information from up to 436 patients whose kidney transcriptomes were characterized by RNA-sequencing. We further validated some of the key observations in other human tissues and/or a controlled experimental model. Our data reveal increasing expression of ACE2 with age in both human lungs and the kidney. We show no association between renal expression of ACE2 and either hypertension or common types of RAS inhibiting drugs. We demonstrate that renal abundance of ACE2 is positively associated with a biochemical index of kidney function and show a strong enrichment for genes responsible for kidney health and disease in ACE2 co-expression analysis. CONCLUSION: Our results indicate that neither hypertension nor antihypertensive treatment is likely to alter the expression of the key entry receptor for SARS-CoV-2 in the human kidney. Our data further suggest that in the absence of SARS-CoV-2 infection, kidney ACE2 is most likely nephro-protective but the age-related increase in its expression within lungs and kidneys may be relevant to the risk of SARS-CoV-2 infection.


Subject(s)
Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/metabolism , Antihypertensive Agents/pharmacology , Hypertension , Kidney Tubules/metabolism , Lung/metabolism , Renin-Angiotensin System/drug effects , Adrenergic beta-Antagonists/pharmacology , Adult , Age Factors , Aged , Angiotensin Receptor Antagonists/pharmacology , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Animals , COVID-19/complications , Diuretics/pharmacology , Female , Gene Expression Profiling , Glomerular Filtration Rate , Humans , Hypertension/drug therapy , Hypertension/genetics , Kidney Tubules/physiopathology , Male , Middle Aged , Rats , Rats, Inbred SHR , SARS-CoV-2 , Sequence Analysis, RNA , Sex Factors , Transcriptome/drug effects
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