Report of the Association Between Multisystem Inflammatory Syndrome and Severe Myocarditis

Introduction: The people worldwide have been affected by severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) infection since its appearance in December, 2019. Kawasaki disease-like hyperinflammatory shock associated with SARS-CoV-2 infection in previously healthy children has been reported in the literature, which is now referred to as a multisystem inflammatory syndrome in children (MIS-C). Some aspects of MIS-C are similar to those of Kawasaki disease, toxic shock syndrome, secondary hemophagocytic syndrome, and macrophage activation syndrome. Case Presentation: This study reported an 11-year-old boy with MIS-C presented with periorbital and peripheral edema, abdominal pain, elevated liver enzymes, severe right pleural effusion, moderate ascites, and severe failure of right and left ventricles. Conclusion(s): Due to the increasing number of reported cases of critically ill patients afflicted with MIS-C and its life-threatening complications, it was recommended that further studies should be carried out in order to provide screening tests for myocardial dysfunction. Adopting a multidisciplinary approach was found inevitable.Copyright © 2023, Author(s). This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/) which permits copy and redistribute the material just in noncommercial usages, provided the original work is properly cited.

Blood Pressure, Proteases and Inhibitors

Blood pressure is controlled through a complex network of interacting peptide systems, principally involving the angiotensin, natriuretic peptide, endothelin and apelin families. The most complex and thoroughly investigated is the renin-angiotensin system (RAS) in which selective and potent inhibitors of the key biosynthetic proteolytic enzymes, renin and angiotensin-converting enzyme (ACE), have proved to be valuable drugs for the effective treatment of hypertension and heart failure, as well as other cardiovascular and renal disorders. Some of the other proteases in these pathways, e.g.neprilysin and ACE2, are also being explored as potential drug targets. © 2023 Elsevier Inc. All rights reserved.

SARS-CoV-2 induces cardiomyocyte apoptosis and inflammation but can be ameliorated by ACE inhibitor Captopril.

Although the clinical manifestation of COVID-19 is mainly respiratory symptoms, approximately 20% of patients suffer from cardiac complications. COVID-19 patients with cardiovascular disease have higher severity of myocardial injury and poor outcomes. The underlying mechanism of myocardial injury caused by SARS-CoV-2 infection remains unclear. Using a non-transgenic mouse model infected with Beta variant (B.1.351), we found that the viral RNA could be detected in lungs and hearts of infected mice. Pathological analysis showed thinner ventricular wall, disorganized and ruptured myocardial fiber, mild inflammatory infiltration, and mild epicardia or interstitial fibrosis in hearts of infected mice. We also found that SARS-CoV-2 could infect cardiomyocytes and produce infectious progeny viruses in human pluripotent stem cell-derived cardiomyocyte-like cells (hPSC-CMs). SARS-CoV-2 infection caused apoptosis, reduction of mitochondrial integrity and quantity, and cessation of beating in hPSC-CMs. In order to dissect the mechanism of myocardial injury caused by SARS-CoV-2 infection, we employed transcriptome sequencing of hPSC-CMs at different time points after viral infection. Transcriptome analysis showed robust induction of inflammatory cytokines and chemokines, up-regulation of MHC class I molecules, activation of apoptosis signaling and cell cycle arresting. These may cause aggravate inflammation, immune cell infiltration, and cell death. Furthermore, we found that Captopril (hypotensive drugs targeting ACE) treatment could alleviate SARS-CoV-2 induced inflammatory response and apoptosis in cardiomyocytes via inactivating TNF signaling pathways, suggesting Captopril may be beneficial for reducing COVID-19 associated cardiomyopathy. These findings preliminarily explain the molecular mechanism of pathological cardiac injury caused by SARS-CoV-2 infection, providing new perspectives for the discovery of antiviral therapeutics.

Angioedema induced by angiotensin-converting enzyme inhibitors: An analysis of hospitalizations during the covid-19 pandemic.

BACKGROUND: The pathogenesis of angioedema induced by angiotensin-converting enzyme inhibitors is based on the accumulation of bradykinin as a result of angiotensin-converting enzyme blockade. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) binds to the angiotensin-converting enzyme 2 receptor, which may inhibit its production and thereby lead to an increase in bradykinin levels. Thus, SARS-CoV-2 infection may be a likely trigger for the development of angioedema. AIMS: This study aimed to analyze cases of hospitalizations of patients with angioedema associated with the use of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers during the coronavirus disease 2019 (COVID-19) pandemic. MATERIALS AND METHODS: This study retrospectively analyzed medical records of patients admitted to the Vitebsk Regional Clinical Hospital between May 2020 and December 2020 with isolated (without urticaria) angioedema while receiving angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. In all patients, smears from the naso and oropharynx for COVID-19 were analyzed by polymerase chain reaction. RESULT(S): Fifteen inpatients (9 men and 6 women) aged 44-72 years were admitted because of emergent events, of which 53.6% had isolated angioedema. In two cases, a concomitant diagnosis of mild COVID-19 infection was established with predominant symptoms of angioedema, including edema localized in the face, tongue, sublingual area, and soft palate. All patients had favorable disease outcomes. CONCLUSION(S): Patients with angiotensin-converting enzyme inhibitor-induced angioedema may require hospitalization to monitor upper respiratory tract patency. There were cases of a combination of angiotensin-converting enzyme inhibitor-induced angioedema and mild COVID-19. Issues requiring additional research include the effect of SARS- CoV-2 infection on the levels of bradykinin and its metabolites, the triggering role of COVID-19 in the development of angioedema in patients receiving angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, recommendations for the management of patients with angiotensin-converting enzyme inhibitor-induced angioedema, and a positive result for COVID-19.Copyright © 2020 Pharmarus Print Media All rights reserved.

Case report of congenital disorder of glycosylation type Ia combined with dilated cardiomyopathy.

Clinical data and follow-up of a case of congenital disorder of glycosylation type Ia (CDG-Ia) combined with dilated cardiomyopathy admitted to the Department of Cardiology, Children's Hospital of Nanjing Medical University were analyzed retrospectively.The 5-year-old female patient was admitted in December 2016 due to recu-rrent shortness of breath for 2 months.Clinical symptoms and signs included repeated attacks of shortness of breath, physical retardation, malnutrition, binocular esotropia, multiple episodes of hypoglycemia, hepatosplenomegaly, hypotonia and other multi-system damages.Cardiac echocardiography suggested the feature of dilated cardiomyopathy, including the significant enlargement of the left ventricle, and decreased systolic function.Genetic testing revealed a compound heterozygous mutation in the PMM2 gene, and as a result, the patient was diagnosed as CDG-Ia.The patient's condition improved after symptomatic treatments such as Cedilanid, Dopamine, Dobutamine, Furosemide, as well as support treatments like myocardium nutrition, blood sugar maintenance, liver protection, etc.After discharge, the patient was given oral Digoxin, Betaloc, Captopril and diuretics, and hypoglycemia-controlling agents.The patient was followed up every 3-6 months.After more than 2 years of follow-up, the heart function and heart enlargement gradually returned to normal.During the Corona Virus Disease 2019 outbreak, self-withdrawal continued for 2 months.Re-examinations showed decreased cardiac function and enlarged left ventricle again.Medications were resumed again, and the patient was followed up closely.This case report suggested that CDG-Ia may be associated with dilated cardiomyopathy, and the cardiac phenotype may be improved by symptomatic supportive treatment.Copyright © 2021 by the Chinese Medical Association.

Molecularly imprinted polymer-modified carbon paste electrodes (MIP-CPE): A review on sensitive electrochemical sensors for pharmaceutical determinations

Recent years have been associated with the development of various sensor-based technologies in response to the undeniable need for the rapid and precise analysis of an immense variety of pharmaceuticals. In this regard, special attention has been paid to the design and fabrication of sensing platforms based on electrochemical detection methods as they can offer many advantages, such as portability, ease of use, relatively cheap instruments, and fast response times. Carbon paste electrodes (CPEs) are among the most promising conductive electrodes due to their beneficial properties, including ease of electrode modification, facile surface renewability, low background currents, and the ability to modify with different analytes. However, their widespread use is affected by the lack of sufficient selectivity of CPEs. Molecularly imprinted polymers (MIPs) composed of tailor-made cavities for specific target molecules are appealing complementary additives that can overcome this limitation. Accordingly, adding MIP to the carbon paste matrix can contribute to the required selectivity of sensing platforms. This review aims to present a categorized report on the recent research and the outcomes in the combinatory fields of MIPs and CPEs for determining pharmaceuticals in complex and simple matrices. CPEs modified with MIPs of various pharmaceutical compounds, including analgesic drugs, antibiotics, antivirals, cardiovascular drugs, as well as therapeutic agents affecting the central nervous system (CNS), will be addressed in detail.Copyright © 2023 Elsevier B.V.

Clinical features and treatment of mixed cardiogenic and distributive shock in patients with multisystem inflammatory syndrome in children (MIS-C)

Background and Aim: Mixed shock in multisystem inflammatory syndrome in children (MIS-C) associated with COVID-19 is con-sequence of acute heart failure, inflammation-induced vasodilation and potential volume loss. Method(s): Retrospective analysis included 25 patients (7 girls) with MIS-C-related combined shock, treated in period from April 2020 to December 2021. Result(s): Mean age of patients was 12.6 +/- 4.0 years. Admission was 6.1 +/- 1.6 days after symptoms onset. Systemic inflammatory response was manifested with neutrophilia (10.7 +/- 4.2 x109/), lymphopenia (1.1 +/- 0.7 x109/L), elevated CRP (220.9 +/- 86.1 mg/L), ferritin (684.5 +/- 549.5 mug/L) and D-dimer (1528 +/- 1254 ng/mL). One third of patients had acute kidney injury with glomerular filtration rate of 64 +/- 22 mL/min/1.73 m2 and urea level of 16.0 +/- 8.4 mmol/L. All patients had acute heart failure with ejection fraction 47.2% +/- 7.7% and fractional shortening 23.6% +/- 4.9%, 92% of patients had NTproBNP gt;1500 pg/mL and 58% had elevated troponin I (1.34 +/- 1.47 ng/mL). Z-scores for end-diastolic left ventricle, interventricular septum and pos-terior wall diameters were 0.7 +/- 1.1, 1.7 +/- 1.3 and 0.6 +/- 0.7 respectively. All patients had mild/moderate mitral regurgitation, and 60% had mild pericardial effusion. Inotropes, administered during first 3.7 +/- 1.6 days, were divided in three groups: 1) dop-amine (n = 14), 2) dobutamine + dopamine (n = 5), 3) milrinone +/- dopamine (n = 6). Additional treatment included diuretics and captopril. Total fluid balance (including insensible loss of 300 mL/m2/day) through days 1-7 was +860 mL/m2, +128 mL/m2,-108 mL/m2,-36 mL/m2,-306 mL/m2,-335 ml/m2,-298 ml/m2 (total-95 ml/m2). Methylprednisolone/intravenous immuno-globulin and low-molecular-weight heparin/acetylsalicylic acid were administered and fever persisted 1.2 days averagely. Oxygen supplementation was needed in 71% of patients. Transitory bradycardia was noticed and there was no difference in heart rate between treatment groups. Profound hypotension was revealed on admission and correction differed regarding treat-ment (p lt;0.05) (Figure 1). All patient survived with clinical improvement (one had mechanical ventilation, and one had stroke). Conclusion(s): Mixed shock is the most severe manifestation of MIS-C, and treatment of heart failure should be combined with cau-tious fluid resuscitation.

Dysgeusia and Appetite Loss: Thinking Beyond MDD and COVID-19

Background: Dysgeusia is a distortion of taste sensation. Etiologies can include medications and Covid-19, among others. Dysgeusia may lead to appetite loss which is nonspecific and can have multiple causes, including major depressive disorder (MDD) (Coulter, 1988). Although post-marketing data revealed no association between nifedipine and dysgeusia (Ackerman, 1997), case reports of dysgeusia from nifedipine exist (Ackerman, 1997). We present a case of nifedipine-induced dysgeusia mistaken for depression. Case Report: A 42-year-old man with hypertension and diabetes was admitted to the hospital following right thalamocapsular and intraventricular hemorrhages. Hypertension was managed with metoprolol, lisinopril, nifedipine, and chlorthalidone. Levetiracetam was started for seizure prophylaxis. Medications included pantoprazole, simethicone, transdermal lidocaine, insulin, metformin, docusate, senna, and subcutaneous heparin. Psychiatric consultation was requested out of concern that appetite loss indicated depression. The day before psychiatric evaluation, mirtazapine 15 mg at bedtime for mood and appetite was started. Nifedipine 90 mg daily had been started 9 days prior to his first complaint of decreased appetite. The patient reported feeling disconnected from his family and “sad" for ∼10 years, complaining that family members “talk behind his back.” He was otherwise without paranoia. He denied insomnia, anhedonia, hopelessness, poor concentration, suicidal ideation, homicidal ideation, guilt, mania, or hallucinations. He reported poor appetite due to epigastric discomfort and bad taste to foods. Covid-19 testing was not yet widely available. No other signs or symptoms suggestive of Covid-19 were present. Although alert and fully oriented, concentration was impaired with sometimes tangential thought processes. Affect was full without depression. A diagnosis of adjustment disorder was made. The psychiatry team suspected nifedipine-induced dysgeusia and advised discontinuing nifedipine. Appetite improved two days later. Discussion: This case highlights the importance of considering alternative causes of nonspecific symptoms of depression, including decreased appetite, that may have non-psychiatric causes. Dysgeusia is widely recognized as a symptom of Covid-19. Other causes, including medications may be underrecognized and amenable to intervention. Conclusion: It would be helpful to consider medication side-effects as potential causes for taste distortion alongside psychiatric diagnoses, and COVID-19. References: 1. Coulter DM: Eye pain with nifedipine and disturbance of taste with captopril: a mutually controlled study showing a method of post marketing surveillance BMJ 1988;296: 1086–8. 2. Ackerman BH, Kasbekar N: Disturbances of taste and smell induced by drugs. Pharmacotherapy 1997;17(3):482-96.

EFFECT OF CORONAVIRUS INFECTION ON PATIENTS WITH CONTROLLED AND UNCONTROLLED ARTERIAL HYPERTENSION

Objective: To assess the severity of coronavirus infection in patients with hypertension, including resistantand refractory hypertension, and to assess the effect of taking ACE inhibitors and ARBs on the course of COVID-19. Design and method: We called 252 people with an established diagnosis of hypertension, included in the database from November 2018 to July 2021, in order to identify patients who have recently undergone COVID-19. Initially, the patients were divided into groups depending on the number of drugs taken and the achievement of target blood pressure levels. Results: 21 (8.3%) of 252 people had a coronavirus infection. 10 out of 21 patients (48%) noted blood pressure destabilization. 6 (60%) of these 10 initially belonged to the group of uncontrolled hypertension (4 of 6 had refractory hypertension, 2 of 6 had uncontrolled resistant hypertension), however, all of them noted worsening blood pressure control and increased frequency of hypertensive crises compared with the period before COVID-19. In 4 out of 9 patients with initially controlled hypertension, BP was destabilized with subsequent normalization of BP during the recovery period. COVID-19 lasted no more than 14 days in all patients and hypertensive crises was treated by taking short-acting drugs, including an ACE inhibitor (Captopril) and an imidazoline receptor agonist (Moxonidine). 7 (33.3%) and 12 (57.1%) of 21 patients continued to take ACE inhibitors and ARBs, respectively, during coronavirus infection. In 2 (9.6%) of 21 patients, the target BP values were achieved during monotherapy with calcium channel antagonists. All patients with Covid-19 had mild or moderate disease;hospitalization was not required in any of the cases. Conclusions: COVID-19 can destabilize blood pressure in patients with hypertension. Taking an ACE inhibitor / ARB does not worsen the course of coronavirus infection in patients with both controlled and uncontrolled hypertension.

Angiotensin converting enzyme

Angiotensin converting enzyme (ACE) is well known for its dual actions to convert inactive Ang I to active Ang II, and degrades active bradykinin (BK), which plays an important role in controlling blood pressure. Because it is the bottleneck step for the production of pressor Ang II, it was targeted pharmacologically in the 1970s. Successful ACE inhibitors such as captopril were produced to treat hypertension. Studies on domain-specific ACE inhibitors are continuing to produce effective hypertension-controlling drugs with fewer side effects. ACE2 was discovered in 2000 and it converts Ang II into Ang(1-7), thereby reducing the concentration of Ang II as well as increasing that of Ang(1-7), an important enzyme for Ang(1-7)/Mas receptor signaling. ACE2 also acts as the receptor in the lung for the coronavirus, causing the infamous severe acute respiratory syndrome (SARS) in 2003. © 2021 Elsevier Inc. All rights reserved.

POS-009 CAPTOPRIL-INDUCED ACUTE INTERSTITIAL NEPHRITIS: A RARE ASSOCIATION

Introduction: Acute interstitial nephritis (AIN) is an important reversible cause of acute kidney injury (AKI). Its prevalence is about 6-8% in histologically proven AKI.Early diagnosis of drug-induced AKI is vital because the discontinuation of the causal treatment facilitates recovery of the renal function. Methods: We report a case of captopril-induced AIN. Results: We report the case of a 82-year-old woman with a history of untreated hypertension. She was admittedin our department for AKI. Two days before admission, Captopril was initiated for high blood pressure (BP) as well as vitamin therapy for suspicion of a sars covid 19 infection, which was ruled out by a negative pcr covid test and a normal thoracic scan. The initial physical examination showed asthenia and a BP of 160/90 mmHg. Urinary labstix was negative. The biological analysis showed AKI: creatinine rose from 80 to 230 and then to 530 µmol/l, anemia at 7 g/dl and moderate hyper eosinophilia at 700 elements/ml. A renal biopsy was not performed because of the presence of cysts, and the diagnosis of interstitial nephritis was suspected. The drug-induced origin was confirmed after having eliminated infectious and tumoral origin. The pharmacovigilance investigation incriminated captopril. Captopril was stopped and the patient was put on corticosteroids 0.5 mg/kg/d. The evolution was favorable with an improvement of the renal function (creatinine at 120 µmol/l one month later). Conclusions: Angiotensin-converting enzyme (ACE) inhibitors can cause an increase in serum creatinine or potassium levels in patients with renal failure, renal artery stenosis, heart failure, or hypovolemia, but are rarely reported to be involved as an etiology of AIN. We report one of the rare cases of captopril-induced AIN. No conflict of interest

An angiotensin receptor blocker in the presence of sars cov2 pseudovirus does not change protein expression of ace2 in human heart cell models

Introduction: ACE inhibitor (ACEI) or angiotensin receptor blocker (ARB) use in COVID-19 raised concern due to reported increases in ACE2, the cell receptor for SARS-CoV2. We tested the hypothesis that ARB (Losartan) and ACEI (Captopril) do not impact SARS-CoV2 associated ACE2 expression in cardiomyocytes (CMs). Methods: Beating monolayer ventricular CMs were generated from human iPSCs and grown as engineered heart tissue constructs (EHTs), which mimic a more mature phenotype than monolayer CMs. Drug treatments (24hrs) without pseudovirus were applied to EHTs: (A) Vehicle, 1μM Losartan (ARB), 1μM Angiotensin II (AngII), 1μM Losartan+1μM Ang II;(B) Vehicle, 1μM Captopril, 1μM Ang I, or 1μM AngI+1μM Captopril with 2-3 replicates for each combination and RNAseq as outcome. Drug treatment A only was repeated in monolayer CMs with a 5-6 day to rVSV-SARS-Cov2SpikeLuciferase-FLAG tagged pseudovirus (2-4 replicates) with immunoblotting for ACE2, Cathepsin B (CTSB) and Furin proteins. Results: Immunoblot densitometry showed abundant ACE2 protein in untreated CMs and EHTs. A focused mRNA analysis of 12 genes associated with SARS-Cov2 entry and processing (EHTs) revealed no significant changes in expression of ACE2, NRP1, CTSB, CTSL and FURIN due to Losartan or Captopril treatment. There was a nonsignificant trend towards Losartan-induced increase in AGTR1 with attenuation when AngII was administered, while ITGA5 trended upwards with Losartan+AngII. AGTRI also trended upwards with Captopril and AngI+Captopril. Upon pseudoviral challenge, CMs demonstrated increased ACE2 (55%) and slightly decreased Furin (24%) protein, with unchanged CTSB, although results were not statistically significant. Losartan addition, regardless of AngII, did not alter SARS-CoV2Spike pseudovirus mediated changes of ACE2, Furin or CTSB proteins. Conclusions: Losartan or Captopril did not substantially alter gene expression of ACE2, CTSB, CTSL, FURIN and NRP1 in EHTs without pseudovirus. Losartan did not show convincing evidence for pseudoviral mediated changes of proteins important for viral entry and processing in CM cell models.

SYNTHESIS OF FUSED PYRIMIDINES DERIVATIVES AND MANNICH BASES AND ASSESS OF THEIR ANTIBACTERIAL ACTIVITY, LASER EFFICACY AND MOLECULAR DOCKING

Fused pyrimidines gain an increasing interest as being a precursor for biologically active new compounds. The fused pyrimidine derivatives (1-5) were prepared by condensation of the 1,8-diamine naphthalene with some medical compounds in the presence of ammonium chloride as a dehydration agent for the water molecule and toluene as a solvent. Mannich base compounds (6-10) were prepared by reacting pyrimidines (1-5) with formaldehyde and 4-methoxyaniline. A microwave method was used in preparing the compounds. The prepared compounds were characterized by physical methods, through melting points and color, as well as by spectroscopic methods such as FT-IR and 1H-NMR. The purity of the prepared compounds was evaluated using TLC. The bioactivity of these compounds was tested against two types of bacteria, i.e. Escherichia coli and Staphylococcus aureus. The results of bioactivity showed an antibacterial activity compared to the standard drugs Cephalexin and Amoxicillin. The stability of selected compounds was evaluated by laser irradiation for (10, 20, 30, 40) seconds, and was found to be stable and did not decompose with a 30 seconds exposure. On the other hand, their color was changed at 40 seconds of exposure. Molecular docking studies were conducted to examine how some of the synthesized compounds bind to the putative target, SARS COV2 RNA-dependent RNA polymerase. The study concluded that some of the prepared compounds showed promising antibacterial and antiviral bioactivities. Further in vitro and in vivo toxicological and pharmacological studies are required to evaluate the possibility of using these compounds as a medicine.

Effect of Angiotensin-Converting-Enzyme Inhibitor and Angiotensin II Receptor Antagonist Treatment on ACE2 Expression and SARS-CoV-2 Replication in Primary Airway Epithelial Cells.

Rationale: SARS-CoV-2 gains entrance to airway epithelial cells (AECs) through binding of the viral spike protein to the angiotensin-converting enzyme 2 (ACE2) on the cell surface. However, ACE2 also converts angiotensin II into angiotensin-(1-7) and counterbalances the renin-angiotensin-aldosterone system, with resultant protective effects in the cardiovascular system. Some data suggest that two common antihypertension medications (angiotensin II receptor antagonists, ARBs; and angiotensin-converting-enzyme inhibitors, ACEIs) may increase ACE2 expression in heart and kidney cells, fueling debate about how these widely used medications may modulate SARS-CoV-2 infectivity and risk of COVID-19. Aim: Determine whether exposure of bronchial AECs to the ARB losartan or the ACEI captopril modulate expression of ACE2 by AECs, SARS CoV2 replication, or expression of proinflammatory cytokines and type I and III interferon (IFN) responses. Methods: Primary bronchial AECs from children and adults (n = 19; Ages 8-75 yrs) were differentiated ex vivo at an air-liquid interface to generate organotypic cultures. Cultures were treated with captopril (1 µM) or losartan (2 µM) with culture media changes starting 72 h before infection with SARS-CoV-2. In a biosafety level 3 (BSL-3) facility, cultures were infected with SARS-CoV-2 isolate USA-WA1/2020 at a multiplicity of infection (MOI) of 0.5. At 96 h following infection, RNA and protein were isolated. SARS-CoV-2 replication in cultures was assessed with quantitative PCR (qPCR). ACE2, IL-6, IL-1B, IFNB1, and IFNL2 expression were assessed by qPCR. Results: Neither captopril nor losartan treatment significantly changed ACE2, IL-6, IL-1B, IFNB1, or IFNL2 expression by AECs as compared to SARS-CoV-2 infected AEC cultures without captopril or losartan treatment. At 96 h following infection, SARS-CoV-2 copy number/ng RNA was not significantly different between untreated AEC cultures, cultures treated with captopril, or cultures treated with losartan. Conclusion: These findings suggest that at the level of the airway epithelium neither the ACEI captopril or ARB losartan significantly modify expression of the SARS-CoV-2 entry factor ACE2, nor does either medication increase replication SARS-CoV-2 replication. This ex vivo data is reassuring and is consistent with evolving clinical data suggesting ACEIs and ARBs do not increase the risk for poor prognosis with COVID-19 and may actually reduce the risk of COVID-19 disease.

Captopril alleviates lung inflammation in SARS-CoV-2-infected hypertensive mice.

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.

Cardiovascular medications and regulation of COVID-19 receptors expression.

INTRODUCTION: Emerging epidemiological studies suggested that Renin-Angiotensin-Aldosterone system (RAAS) inhibitors may increase infectivity and severity of COVID-19 by modulating the expression of ACE2. METHODS: In silico analysis was conducted to compare the blood expression levels of SARS-CoV-2 entry genes between age and gender matched cohort of hypertensive patients versus control, and to determine the effect of common cardiovascular medications on the expression of COVID-19 receptors in vitro using primary human hepatocytes. RESULTS: The transcriptomic analysis revealed a significant increase of ACE2 and TMPRSS2 in the blood of patients with hypertension. Treatment of primary human hepatocytes with captopril, but not enalapril, significantly increased ACE2 expression. A similar pattern of ACE2 expression was found following the in vitro treatments of rat primary cells with captopril and enalapril. Telmisartan, a second class RAAS inhibitors, did not affect ACE2 levels. We have also tested other cardiovascular medications that may be used alone, or in combination with RAAS inhibitors. Some of these medications increased TMPRSS2, while others, like furosemide, significantly reduced COVID-19 receptors. CONCLUSIONS: The increase in ACE2 expression levels could be due to chronic use of RAAS inhibitors or alternatively caused by other hypertension-related factors or presence of other comorbidities. Treatment of common co-morbidities often require chronic use of multiple medications, which may result in an additive increase in the expression of ACE2 and TMPRSS2. Our data suggest that more research is needed to determine the effect of different medications, as well as medication combinations, on COVID-19 receptors.