Influencia de la obesidad en la severidad de la infección por SARS-CoV-2

La obesidad es una enfermedad metabólica crónica asociada a un incremento de la morbimortalidad cuya prevalencia se ha incrementado a niveles pandémicos lo que la constituye como un factor de riesgo clínico típico de peor pronóstico en pacientes con COVID-19. El propósito de esta revisión fue categorizar los principales factores fisiopatológicos que influyen en la gravedad de COVID-19 en pacientes con obesidad, mediante la búsqueda sistemática de artículos publicados hasta el 11 de marzo de 2022 usando diferentes bases de datos (Scopus, Cochrane, PubMed, Web of Science y Medline). Los resultados indican que la presencia de angiotensina II permite el ingreso del virus SARS-CoV-2 en las células del tejido adiposo convirtiéndolo en un depósito importante del virus lo que causa una diseminación más rápida a órganos vecinos. Estos valores incrementados de angiotensina II en el pulmón pueden inducir a vasoconstricción que a su vez conduce a un desajuste de ventilación/perfusión e hipoxemia, así como a inflamación y daño oxidativo. El incremento de la angiotensina II en pacientes con obesidad puede exacerbar el aumento del nivel de angiotensina II inducido por COVID-19, lo que lleva a una lesión pulmonar más grave, además de la formación de microcoágulos que colapsan la irrigación a nivel capilar, sobre todo la del alveolo, causando fallo a este nivel con extravasación de líquidos y neumonía fulminante. Además, la obesidad produce una alteración del sistema inmune comprometiendo así su capacidad de respuesta ante la infección respiratoria y propiciando un empeoramiento de la enfermedad.

Obesity is a chronic metabolic disease associated with increased morbidity and mortality whose prevalence has increased to pandemic levels, making it a typical clinical risk factor for worse prognosis in patients with COVID-19. The purpose of this review was to categorize the main pathophysiological factors that influence the severity of COVID-19 in patients with obesity, through a systematic search for articles published up to March 11, 2022 using different databases (Scopus, Cochrane, PubMed, Web of Science and Medline). The results indicate that the presence of angiotensin II allows the SARS-CoV-2 virus to enter the adipose tissue cells, making it an important reservoir for the virus, which causes faster dissemination to neighboring organs. These increased values of angiotensin II in the lung can induce vasoconstriction which in turn leads to ventilation/perfusion mismatch and hypoxemia, as well as inflammation and oxidative damage. The increase in angiotensin II in the obese can exacerbate the increase in the level of angiotensin II induced by COVID-19, leading to more severe lung injury, in addition to the formation of microclots that collapse the irrigation at the capillary level, especially in the alveolus, causing failure at this level with fluid extravasation and fulminant pneumonia. In addition, obesity produces an alteration of the immune system, thus compromising its ability to respond to respiratory infection and leading to a worsening of the disease.

Efficacy and Safety of Fixed-Dose Combination of Efonidipine and Telmisartan in Stage II Hypertensive Patients: Results from Randomized Clinical Trial

Aim: The aim of this study was to evaluate the anti-hypertensive efficacy of a fixed-dose combination (FDC) of Efonidipine 40 mg and Telmisartan 40 mg in Stage II hypertensive patients. Study Design: Multicentric, randomized, double-blind, parallel, comparative Phase III clinical trial. Methodology: This clinical trial was conducted at six geographically distributed sites across India and enrolled 240 Stage II hypertensive patients. They were randomized into two groups in a ratio of 1:1 using computer-generated block randomization to receive E+T (FDC of Efonidipine 40 mg + Telmisartan 40mg) or C+T (FDC of Cilnidipine 10 mg + Telmisartan 40 mg) group intervention once daily for a period of 90 days. The study site staff, investigator and patients were blinded to the treatment allocation. The primary endpoint of the study evaluated the mean reduction in sitting systolic BP (SBP) and diastolic BP (DBP) from baseline to day 90 whereas the secondary endpoints assessed were mean reduction in BP from baseline to day 30 & 60, patients achieving target BP (<140/90 mmHg) and the safety and tolerability of the investigational products based on the incidences of adverse events (AEs) reported. Results: A total of 118 subjects were randomized to the E+T group wherein the mean (±SD) SBP and DBP at baseline was 167.25 ± 4.68/107.26 ± 5.19 mmHg. After 30 days of treatment with the E+T group, the mean reduction in SBP/DBP of 29.37/18.06 mmHg was observed whereas at Day 60 reduction of 38.55/22.69 mmHg was seen from the baseline. At Day 90, SBP/DBP decreased to 119.41±14.99/81.67±4.29 mmHg with a mean reduction of 47.94/25.89 mmHg in the E+T group. During the study period, the difference in systolic blood pressure between the treatments with E+T and C+T was -0.48 mmHg, with the two-sided 95% confidence interval (CI) ranging from -4.54 to 3.58?mmHg. The corresponding difference in diastolic blood pressure was -0.77 (95% CI: -2.60 to 1.06) mm?Hg. The upper boundary of the 95% CI was below the margin of 10?mmHg, confirming the non-inferiority of E+T to C+T. A total of 92% of patients who had been assigned to E+T treatment achieved their target BP goal. Only one patient reported an adverse event with E+T treatment. No unexpected AEs were reported in the E+T group suggesting its good safety and tolerability. Overall, the E+T treatment was effective, safe and well-tolerated by the patients for 90 days. Conclusion: It was concluded that the FDC of Efonidipine 40 mg and Telmisartan 40 mg was efficacious in the management of Stage II hypertension.

Protective Effect and Mechanism of Kuntai Capsule on Angiotensin II -Induced Hypertension in Ovariectomized Rats / 中国结合医学杂志

OBJECTIVE@#To explore the protective effect and mechanism of Kuntai (KT) Capsule on angiotensin II (Ang II)-induced hypertension in ovariectomized (OVX) rats.@*METHODS@#Fifty-four rats were randomly divided into 6 groups according to a random number table, 9 in each group: control, OVX sham+Ang II, OVX, OVX+Ang II, OVX+Ang II +E2, and OVX+Ang II +KT. OVX rats model was constructed by retroperitoneal bilateral ovariectomy. After 4 weeks of pretreatment with KT Capsule [0.8 g/(kg·d) and 17- β -estradiol (E2, 1.2 mg/(kg·d)] respectively, Ang II was injected into a micro-osmotic pump with a syringe to establish a hypertensive rat model. Blood pressure of rat tail artery was measured in a wake state of rats using a non-invasive sphygmomanometer. Blood pressure changes were compared between the intervention groups (OVX+Ang II +KT, OVX+Ang II +E2) and the negative control group (OVX+Ang II). Serum malondialdehyde (MDA) level and superoxide dismutase (SOD) activity were detected respectively. The expressions of oxidative stress-related protein superoxide dismutase2 (SOD2) and anti-thioredoxin (TRX), autophagy marker protein [beclin1, light chain (LC) 3 II/I ratio and autophagy canonical pathway protein phosphatidylinositol 3-kinase (PI3K)/serine/threonine kinase (AKT)-mammalian target of rapamycin (mTOR)] were evaluated by Western blotting.@*RESULTS@#Compared with the OVX+Ang II group, the systolic blood pressure of OVX+Ang II +KT group was significantly lowered (P<0.05) but not the diastolic blood pressure. Besides, SOD2 and TRX protein levels in mycardial tissues were significantly reduced in the OVX+Ang II +KT group compared with the OVX+Ang II group (P<0.05). Oxidative stress serum markers MDA and SOD were down- and up-regulated in the OVX+Ang II +KT group, respectively (P<0.05). Compared with OVX+Ang II group, the levels of cardiac proteins beclin-1 and LC3II/LC3 I in OVX+Ang II +KT group were also up-regulated (P<0.05), and the expression levels of p-PI3K, p-AKT and mTOR protein were down-regulated (P<0.05).@*CONCLUSION@#KT could protect blood pressure of Ang II-induced OVX rats by inhibiting oxidative stress and up-regulating protective autophagy.

Mental stress induces endothelial dysfunction by AT1R-mediated redox imbalance in overweight/obese men

The main goal of this study was to determine whether oxidative imbalance mediated by AT1 receptor (AT1R) is responsible for deleterious endothelial responses to mental stress (MS) in overweight/obese class I men. Fifteen overweight/obese men (27±7 years old; 29.8±2.6 kg/m2) participated in three randomized experimental sessions with oral administration of the AT1R blocker olmesartan (40 mg; AT1R blockade) or ascorbic acid (AA; 3g) infusion or placebo [both intravenously (0.9% NaCl) and orally]. After two hours, endothelial function was determined by flow-mediated dilation (FMD) before (baseline), 30 min (30MS), and 60 min (60MS) after a five-minute acute MS session (Stroop Color Word Test). Blood was collected before (baseline), during MS, and 60 min after MS for redox homeostasis profiling: lipid peroxidation (TBARS; thiobarbituric acid reactive species), protein carbonylation, and catalase activity by colorimetry and superoxide dismutase (SOD) activity by an ELISA kit. At the placebo session, FMD significantly decreased 30MS (P=0.05). When compared to baseline, TBARS (P<0.02), protein carbonylation (P<0.01), catalase (P<0.01), and SOD (P<0.01) increased during the placebo session. During AT1R blockade, FMD increased 30 min after MS (P=0.01 vs baseline; P<0.01 vs placebo), while AA infusion increased FMD only 60 min after MS. No differences were observed during MS with the AT1R blockade and AA regarding TBARS, protein carbonylation, catalase, and SOD. AT1R-mediated redox imbalances played an important role in endothelial dysfunction to mental stress.

P2X7 receptor antagonist improves gastrointestinal disorders in spontaneously hypertensive rats

The purinergic system participates in the control of blood pressure. Hypertension promotes the occurrence of gastrointestinal disorders such as intestinal inflammation and gastric emptying delay. This study aimed i) to investigate the participation of the P2X7 receptor blocker Brilliant Blue G (BBG) on gastric emptying of solids and changes in oxidative stress in the gastric fundus, duodenum, and colon of spontaneously hypertensive rats (SHR) and ii) to study the putative relationship of this effect with the renin-angiotensin system. Rats were divided into five groups: Control, SHR, SHR+BBG, SHR+BBG+ATP, and SHR+BBG+ANG II. In the gastrointestinal tract, we assessed gastric emptying (GE) and oxidative stress markers (NOx, MPO, GSH, SOD). We observed a decrease in the GE rate (P<0.05) in SHR vs control rats (21.8±2.0% vs 42.8±3.5%). The decrease in GE was returned (P<0.05) to control levels by BBG in SHR rats (21.8±2.0% vs 41.6±3.2%). Co-administration of ATP or ANG II together with BBG bypassed the effect of the P2X7 antagonist on GE in SHR (P<0.05) (21.9±5.0% vs 25.6±3.0% vs 41.6±3.2%). The MPO activity increased (P<0.05) in the gastric fundus of SHR compared to control rats (6.12±2.26 vs 0.077±0.02 UMPO/mg tissue); this effect was prevented (P<0.05) by BBG (0.55±0.15 vs 6.12±2.26 UMPO/mg tissue). Data demonstrated that blockage of P2X7 receptors with BBG can improve the GE delay and oxidative stress biomarkers in SHR animals. This preventive effect of BBG on GE delay was abrogated by ANG II and ATP, thus prompting crosstalk between renin-angiotensin and the purinergic signaling systems underlying this phenomenon.

Eucommia ulmoides extract attenuates angiotensin II-induced cardiac microvascular endothelial cell dysfunction by inactivating p53

Abstract Angiotensin II (AngII) causes endothelial dysfunction. Eucommia ulmoides extract (EUE) is documented to manipulate AngII, but its impact on cardiac microvascular endothelial cell (CMVEC) function remains unknown. This study determines the effects of EUE on AngII-treated CMVECs. CMVECs were treated with different concentrations of AngII or EUE alone and/or the p53 protein activator, WR-1065, before AngII treatment, followed by examinations of the apoptotic, migratory, proliferative, and angiogenic capacities and nitric oxide (NO), p53, von Willebrand factor (vWF), endothelin (ET)-1, endothelial NO synthase (eNOS), manganese superoxide dismutase (MnSOD), hypoxia-inducible factor (HIF)-1α, and vascular endothelial growth factor (VEGF) levels. AngII induced CMVEC dysfunction in a concentration-dependent manner. EUE enhanced the proliferative, migratory, and angiogenic capacities and NO, MnSOD, and eNOS levels but repressed apoptosis and vWF and ET-1 levels in AngII-induced dysfunctional CMVECs. Moreover, AngII increased p53 mRNA levels, p-p53 levels in the nucleus, and p53 protein levels in the cytoplasm and diminishes HIF-1α and VEGF levels in CMVECs; however, these effects were counteracted by EUE treatment. Moreover, WR-1065 abrogated the mitigating effects of EUE on AngII-induced CMVEC dysfunction by activating p53 and decreasing HIF-1α and VEGF expression. In conclusion, EUE attenuates AngII-induced CMVEC dysfunction by upregulating HIF-1α and VEGF levels via p53 inactivation

Angiotensin II and human obesity. A narrative review of the pathogenesis / Angiotensina II y obesidad humana. Revisión narrativa de la patogénesis

Abstract Angiotensin II (Ang II) is a hormone and the main effector of the renin-angiotensin system (RAS). This peptide has crucial pathophysiological effects on hypertension, cardiac hypertrophy, endothelial proliferation, inflammation and tissue remodelling through G protein-coupled receptors. The pro-inflammatory role of Ang II has been reported in various inflammatory processes. Obesity is linked to a chronic inflammatory process which in turn is the cause of some of its morbidities. Ang II is related to the comorbidities related to the comorbidities of obesity, which include alterations in the heart, kidney, hypertension and coagulation. In this regard, activation of AT1 receptors by Ang II can induce an inflammatory process mediated by the transcription factor NF-kB, triggering inflammation in various systems that are related to the comorbidities observed in obesity. The aim of this review was to highlight the pro-inflammatory effects of Ang II and the alterations induced by this hormone in various organs and systems in obesity. The search was done since 1990 through Medline, EMBASE and PubMed, using the keywords: angiotensin II; angiotensin II, obesity; angiotensin II, kidney, obesity; angiotensin II, coagulation, obesity; angiotensin II, inflammation, obesity; angiotensin II, adipose tissue, obesity; angiotensin II, hypertension, obesity; angiotensin II, insulin resistance, obesity; angiotensin II, adiponectin, leptin, obesity; angiotensin II, COVID-19, obesity. Angiotensin II through its interaction with its AT1 receptor, can induce alterations in diverse systems that are related to the comorbidities observed in obesity. Therapeutic strategies to decrease the production and action of Ang II could improve the clinical conditions in individuals with obesity.

Resumen La angiotensina II (Ang II) es una hormona y el principal efector del sistema renina-angiotensina (SRA). Este péptido tiene importantes efectos fisiopatológicos en la hipertensión, la hipertrofia cardíaca, la proliferación endotelial, la inflamación y la remodelación tisular a través de receptores acoplados a la proteína G. El papel pro-inflamatorio de la Ang II se ha reportado en diversos procesos inflamatorios. La obesidad está ligada a un proceso inflamatorio crónico que a su vez es causa de algunas de sus morbilidades. Se ha demostrado que la Ang II está relacionada con las comorbilidades de la obesidad, que incluyen alteraciones en el corazón, el riñón, la hipertensión y la coagulación. En este sentido, la activación de los receptores AT1 por la Ang II puede inducir un proceso inflamatorio mediado por el factor de transcripción NFkB desencadenado inflamación en diversos sistemas que se relacionan con las co-morbilidades observadas en la obesidad. El propósito de esta revisión fue destacar el efecto pro-inflamatorio de la Ang II y las alteraciones inducidas por esta hormona en diversos órganos y sistemas en la obesidad. La búsqueda se hizo desde 1990 a través de Medline, EMBASE and PubMed, utilizando las palabras clave: angiotensina II; angiotensina II, obesidad; angiotensina II, riñón, obesidad; angiotensina II, coagulación, obesidad; angiotensina II, inflamación, obesidad; angiotensin II, adipose tissue, obesidad; angiotensin II, hipertensión, obesidad; angiotensin II, resistencia a la insulina, obesidad; angiotensin II, adiponectina, leptina, obesidad; angiotensina II, COVID-19, obesidad. La angiotensina II a través de su interacción con su receptor AT1 puede inducir alteraciones en diversos sistemas que están relacionados con las comorbilidades observadas en la obesidad. Estrategias terapeúticas para disminuir su producción y la acción de la AngII pudieran mejorar las condiciones clínicas en individuos con obesidad.

Uso de anticorpos monoclonais por pacientes com covid-19 interfere na concentração sérica de angiotensina II? / Does the use of monoclonal drugs by patients with COVID-19 interfere with the serum concentration of angiotensin II? / ¿El uso de fármacos monoclonales por pacientes con COVID-19 interfiere con la concentración sérica de angiotensina II?

Introdução:uma vez conhecidos os mecanismos de patogênese do SARS-CoV-2, vários métodos de tratamento para a COVID-19 foram desenvolvidos, dentre eles destaca-se o uso dos anticorpos monoclonais para o contexto de pacientes em estágios graves da doença. Objetivo: compreender se o uso dos anticorpos monoclonais para tratamento da COVID-19 grave interfere nos níveis séricos da angiotensina II. Metodologia:Para a realização dessa pesquisa foram selecionados através do DeCS e MeSH os descritores "COVID-19", "Angiotensin II" e "Antibodies, Monoclonal" e seus respectivos "entry terms" sugeridos pela base MeSH. Posteriormente,utilizando-se os operadores booleanos OR e AND, foi montada uma estratégia de busca, a qual foi utilizada nas bases de dados PUBMED, EMBASE, Web of Science, Cochrane Library e Scopus, sem restrição dedata de publicação ou idioma. Resultados:ao final do processo de seleção dos artigos, 29 foram selecionados para a leitura e análise completa. Nesta revisão, foram abordados diferentes tipos de anticorpos monoclonais, os quais foram oportunamente agrupados de acordo com o seu mecanismo de ação. Conclusão: foi possível concluir que das cinco classes de anticorpos monoclonais tratadas neste trabalho, três potencialmente podem causar alterações nos níveis séricos de angiotensina II (AU).

Introduction:once the mechanisms of pathogenesis of SARS-CoV-2 are known, several methods of treatment for COVID-19 have been developed, among them the use of monoclonal antibodies for the context of patients in severe stages of the disease. Purpose:to understand whether the use of monoclonal antibodies for the treatment of severe COVID-19 interferes with serum angiotensin II levels. Methodology:For this research were selected through DeCS and MeSH the descriptors "COVID-19", "Angiotensin II" and "Antibodies, Monoclonal" and their respective entry "Terms" suggested by the MeSH database. Subsequently, using the boolean operators OR and AND, a search strategy was set up, which was used in the databases PUBMED, EMBASE, Web of Science, Cochrane Library and Scopus, without restriction of publication date or language. Results:at the end of the article selection process, 29 were selected for reading and full analysis. In this review, different types of monoclonal antibodies were addressed, which were opportunely grouped according to their mechanism of action. Conclusion:it was possible to conclude that of the five classes of monoclonal antibodies treated in this study, three potentially can cause changes in serum levels of angiotensin II (AU).

Introducción:Una vez conocidos los mecanismos de patogénesis del SARSCoV-2, se desarrollaron variosmétodos de tratamiento para el COVID-19, entre ellos, el uso de anticuerpos monoclonales para el contexto de pacientes en fases graves de la enfermedad. Objetivo:Comprender si el uso de anticuerpos monoclonales para el tratamiento de la COVID-19 grave interfiere en los niveles séricos de angiotensina II. Metodología:Los descriptores "COVID-19", "Angiotensina II", "Anticuerpos, Monoclonales" y sus respectivos "entry terms" (términos de entrada) sugeridos por el MeSH fueron seleccionados a través de DeCS yMeSH. Posteriormente, utilizando los operadores booleanos OR y AND, se estableció una estrategia de búsqueda que se utilizó en las bases de datos PUBMED, EMBASE, Web of Science, Cochrane Library y Scopus, sin restricción de fecha de publicación ni de idioma. Resultados:Al final del proceso de selección de artículos, se seleccionaron 29 artículos para su lectura y análisis completos. En esta revisión se han abordado diferentes tipos de anticuerpos monoclonales, que se han agrupado oportunamente según su mecanismo de acción. Conclusión:Se pudo concluir que de las cinco clases de anticuerpos monoclonales tratados en este trabajo, tres pueden potencialmente causar alteraciones en los niveles séricos de angiotensina II (AU).

Clinical Significance of HSCARG for Atherosclerotic Coronary Heart Disease and Reduced ROS-Oxidative Stress in in Vivo and in Vitro Models via p47phox by NF-κB Activity

ABSTRACT Introduction: Coronary heart disease (CHD) is a dynamic process in which there are interactions between endothelial dysfunction, oxidative stress, and inflammatory responses. The aim of the present study was to investigate the function and mechanism of HSCARG in the treatment of CHD. Methods: Male apolipoprotein E/low-density lipoprotein receptor-deficient mice were given a high-fat diet with 21% fat and 0.15% cholesterol for the in vivo model. Human umbilical vein endothelial cells were incubated with angiotensin II for the in vitro model. HSCARG expression was inhibited in patients or mice with CHD. Results: HSCARG reduced oxidative stress in mice with CHD. HSCARG also reduced reactive oxygen species (ROS)-oxidative stress in the in vitro model. HSCARG induced p47phox expression in the in vitro model by NF-κB activity. The regulation of nuclear factor kappa B (NF-κB) activity or p47phox expression participates in the effects of HSCARG in CHD. Conclusion: Altogether, our data indicate that HSCARG reduced ROS-oxidative stress in in vivo and in vitro models of CHD via p47phox by NF-κB activity and may be a clinical target for CHD.

Outcomes Following the Use of Angiotensin II in Patients with Postoperative Vasoplegic Syndrome: A Case Series

Catecholamine?resistant postoperative vasoplegic syndrome (PVS) lacks effective treatment modalities. Synthetic angiotensin II was recently approved for the treatment of vasodilatory shock; however, its use in PVS is not well described. We report outcomes in six patients receiving angiotensin II for the treatment of isolated PVS. All patients achieved their MAP goal and the majority showed improvement in lactate and background catecholamine dose; however, variables of perfusion changed discordantly. Three of six patients survived to hospital discharge.

Bloqueadores do Receptor de Angiotensina Avaliados por Medida de Consultório e Residencial da Pressão Arterial. Estudo TeleMRPA / Angiotensin Receptor Blockers Evaluated by Office and Home Blood Pressure Measurements. TeleHBPM Study

Resumo Fundamento O tratamento adequado e a obtenção das metas na hipertensão arterial são importantes na redução dos desfechos cardiovasculares. Objetivos Descrever os bloqueadores do receptor de angiotensina (BRA) em monoterapia ou combinação dupla e a taxa de controle da hipertensão arterial. Métodos Estudo transversal que avaliou pacientes em uso de BRA entre 2017 e 2020. Foram excluídos aqueles em uso de três ou mais anti-hipertensivos. As variáveis analisadas foram: sexo, idade, índice de massa corporal, medidas válidas da medida residencial da pressão arterial (MRPA); pressão arterial sistólica (PAS) e diastólica (PAD) obtidas pela MRPA e de forma casual; variabilidade pressórica; classe dos anti-hipertensivos e dos BRAs. Foram utilizados testes de t pareado, qui-quadrado e Fisher, além de sobreposição dos intervalos de confiança de 95% com nível de significância de 5% (p < 0,05). Resultados Foram selecionados 17.013 pacientes; destes, 12.813 preencheram os critérios, dos quais 62,1% eram do sexo feminino. O número médio de medidas válidas foi de 23,3 (±2,0), com médias para a PAS de 126,8±15,8 mmHg e 133,5±20,1 mmHg (p < 0,001) e para a PAD de 79,1±9,7 mmHg e 83,6±11,9 mmHg (p < 0,001) pela MRPA e medida casual, respectivamente. Losartana foi o BRA mais utilizado e o que apresentou comportamentos mais elevados da pressão arterial. As combinações de BRA com diuréticos ou com antagonistas de canal de cálcio tiveram menores valores de pressão arterial. Conclusões Losartana foi utilizada em mais da metade dos pacientes, apesar de ser a menos eficiente na redução e no controle da pressão arterial.

Abstract Background Adequate treatment of arterial hypertension and achieving arterial hypertension goals in are important in reducing cardiovascular outcomes. Objectives To describe angiotensin receptor blockers in monotherapy or double combination therapy and the rate of arterial hypertension control. Methods This cross-sectional study evaluated patients who were using angiotensin receptor blockers between 2017 and 2020. Those using three or more antihypertensive drugs were excluded. The analyzed variables included sex, age, body mass index, valid home blood pressure monitoring (HBPM) measurements, casual and HBPM systolic and diastolic blood pressure measurements, blood pressure variability, and antihypertensive and angiotensin receptor blocker class. Paired t, chi-square, and Fisher's exact tests were used, as well as overlapping 95% confidence intervals and a significance level of 5% (p < 0.05). Results Of 17,013 patients, 12,813 met the inclusion criteria, 62.1% of whom were female. The mean number of valid measurements was 23.3 (SD, 2.0). The mean HBPM and casual measurements for systolic blood pressure were 126.8 (SD, 15.8) mmHg and 133.5 (SD, 20.1) mmHg (p <0.001), respectively, while those for diastolic blood pressure were 79.1 (SD, 9.7 mmHg) and 83.6 (SD, 11.9) mmHg (p <0.001), respectively. Losartan was the most common angiotensin receptor blocker and resulted in the highest blood pressure values. Combinations of angiotensin receptor blockers with diuretics or calcium channel antagonists resulted in lower blood pressure values. Conclusions More than half of the patients used losartan, although it was the least efficient drug for reducing and controlling blood pressure.

Zofenopril antitumor activity in mice bearing Ehrlich solid carcinoma: Modulation of PI3K/AKT signaling pathway

Angiotensin-II (AgII) is thought to be crucial for tumor growth and progression. Moreover, hydrogen sulfide (H2S) performs a controversial action in cancer pathology. Zofenopril (ZF) is an angiotensin-converting enzyme (ACE) inhibitor with H2S donating properties. Hence, this study aims at investigating the tumor suppressor activity of ZF and elucidating the involved trajectories in Ehrlich's solid tumor (EST)-bearing mice. EST was induced by the intradermal injection of Ehrlich's ascites carcinoma cells into femoral region. All parameters were assessed after 28 days post-inoculation or one-week thereafter. ZF treatment resulted in significant reduction of tumor weights with marked decrease in IL-6 and VEGF levels in serum, and tumor Ag II and CEA contents. Additionally, the administration of ZF downregulated the tumor gene expression of cyclin-D, ACE-1, and Bcl2 and upregulated the proapoptotic gene, BAX. Moreover, ZF increased CBS gene expression, which is a major contributor to cellular H2S production. In addition, ZF was able to reduce the protein expression of PI3K, pAKT, pGSK-3ß, and NFκB. Our study has provided novel insights into the possible mechanisms by which ZF may produce its tumor defeating properties. These intersecting trajectories involve the interference between PI3K/Akt and CBS signaling pathways

O uso de inibidores do Sistema Renina-Angiotensina pode aumentar a suscetibilidade à infecção pelo SARS-CoV-2 (COVID-19)? / Can the use of Renin-Angiotensin System inhibitors increase the susceptibility to SARSCoV-2 infection (COVID-19)?

Diante do contexto pandêmico da COVID-19, esforços têm sido direcionados ao desenvolvimento de medidas terapêuticas seguras e eficazes no combate à doença. Entretanto, divergências entre as condutas adotadas nesses pacientes tem sido frequentes. Em especial, fármacos inibidores do Sistema Renina-Angiotensina, como os Inibidores da Enzima Conversora de Angiotensina e Bloqueadores do Receptor da Angiotensina, são foco de grande discussão. Diversos autores questionam uma possível relação de risco aumentado entre o uso de tais medicações e o desenvolvimento de formas mais graves da doença, ao correlacionar a regulação positiva da Enzima Conversora de Angiotensina 2 induzida por esses fármacos com o fato do SARS-CoV-2 usar essa enzima como receptor celular. Enquanto isso, outros autores defendem que essa modulação atue como fator protetor à gravidade da infecção, levando em consideração a promoção de efeitos vasodepressores, anti-fibróticos e anti-inflamatórios. Dada a alta prevalência do uso desses anti-hipertensivos, a presente revisão analisa o funcionamento do Sistema Renina-Angiotensina; aspectos moleculares do novo coronavírus; e a inibição da Angiotensina 2 no contexto dessa infecção, para discutir qual conduta seria mais adequada no manejo da hipertensão arterial e doenças cardiovasculares, dada a pandemia da COVID-19.

In the face of the pandemic context of the COVID-19, efforts have been directed to the development of safe and effective therapeutic actions in combating the disease. However, divergences between management of these patients have been frequent. Especially, Renin-Angiotensin System inhibitors, as Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers, are the focus of great discussion. Several authors question a possible increased risk relation between the use of that medication and the development of the most severe disease form, when correlating AngiotensinConverting Enzyme 2 upregulation induced by those drugs with the fact that SARS-CoV-2 uses this enzyme as its cellular receptor. Meanwhile, other authors defend that the referred modulation acts as a protective factor to infection severity, considering the induction of vasodepressor, antifibrotic and anti-inflammatory effects. Given the high prevalence of the use of those antihypertensive drugs, the present review analyses the Renin-Angiotensin System functionning; molecular aspects of the novel coronavirus; and the Angiotensin 2 inhibition in the context of this infection, in order to discuss which conduct would be more appropriate in the management of arterial hypertension and cardiovascular diseases, given the COVID-19 pandemic.

Inhibition of CXCR2 alleviates the development of abdominal aortic aneurysm in Apo E-/- mice

ABSTRACT Purpose To investigate the relationship between atherosclerotic abdominal aortic aneurysm (AAA) and CXC chemokine receptor type 2 (CXCR2). Methods Mouse AAA model was established by embedding angiotensin-II pump (1000 ng/kg/min) in ApoE-/- mice. Mice were received SB225002, a selective CXCR2 antagonist, for treatment. Blood pressure was recorded, and CXCR2+ macrophages were examined by flow cytometry analysis. Terminal-deoxynucleotidyl transferase mediated nick end labeling (TUNEL) staining was performed to detect cell apoptosis of abdominal aortic aneurysms. Macrophages were isolated from ApoE-/- mice and treated with Ang II and/or SB225002. Dihydroethidium staining was carried out to determine reactive oxygen species (ROS) activity. Enzyme-linked immunosorbent assay (ELISA) was performed to determine the production of IL-1β and TNF-α. The corresponding gene expressions were measured using real-time polymerase chain reaction (PCR), western blot, and immunohistochemistry staining. Results We found that Ang II activated the expression of CXCR2 in monocytes during the formation of AAA. Inhibition of CXCR2 significantly reduced the size of AAA, attenuated inflammation and phenotypic changes in blood vessels. Ang II-induced macrophages exhibited elevated ROS activity, and elevated levels of 1β and TNF-α, which were then partly abolished by SB225002. Conclusions CXCR2 plays an important role in AAA, suggesting that inhibiting CXCR2 may be a new treatment for AAA.

Low-intensity pulsed ultrasound ameliorates angiotensin II-induced cardiac fibrosis by alleviating inflammation via a caveolin-1-dependent pathway / 浙江大学学报（英文版）（B辑：生物医学和生物技术）

OBJECTIVES@#Cardiac hypertrophy and fibrosis are major pathological manifestations observed in left ventricular remodeling induced by angiotensin II (AngII). Low-intensity pulsed ultrasound (LIPUS) has been reported to ameliorate cardiac dysfunction and myocardial fibrosis in myocardial infarction (MI) through mechano-transduction and its downstream pathways. In this study, we aimed to investigate whether LIPUS could exert a protective effect by ameliorating AngII-induced cardiac hypertrophy and fibrosis and if so, to further elucidate the underlying molecular mechanisms.@*METHODS@#We used AngII to mimic animal and cell culture models of cardiac hypertrophy and fibrosis. LIPUS irradiation was applied in vivo for 20 min every 2 d from one week before mini-pump implantation to four weeks after mini-pump implantation, and in vitro for 20 min on each of two occasions 6 h apart. Cardiac hypertrophy and fibrosis levels were then evaluated by echocardiographic, histopathological, and molecular biological methods.@*RESULTS@#Our results showed that LIPUS could ameliorate left ventricular remodeling in vivo and cardiac fibrosis in vitro by reducing AngII-induced release of inflammatory cytokines, but the protective effects on cardiac hypertrophy were limited in vitro. Given that LIPUS increased the expression of caveolin-1 in response to mechanical stimulation, we inhibited caveolin-1 activity with pyrazolopyrimidine 2 (pp2) in vivo and in vitro. LIPUS-induced downregulation of inflammation was reversed and the anti-fibrotic effects of LIPUS were absent.@*CONCLUSIONS@#These results indicated that LIPUS could ameliorate AngII-induced cardiac fibrosis by alleviating inflammation via a caveolin-1-dependent pathway, providing new insights for the development of novel therapeutic apparatus in clinical practice.

TMEM16A inhibits angiotensin II-induced basilar artery smooth muscle cell migration in a WNK1-dependent manner

Vascular smooth muscle cell (VSMC) migration plays a critical role in the pathogenesis of many cardiovascular diseases. We recently showed that TMEM16A is involved in hypertension-induced cerebrovascular remodeling. However, it is unclear whether this effect is related to the regulation of VSMC migration. Here, we investigated whether and how TMEM16A contributes to migration in basilar artery smooth muscle cells (BASMCs). We observed that AngII increased the migration of cultured BASMCs, which was markedly inhibited by overexpression of TMEM16A. TMEM16A overexpression inhibited AngII-induced RhoA/ROCK2 activation, and myosin light chain phosphatase (MLCP) and myosin light chain (MLC20) phosphorylation. But AngII-induced myosin light chain kinase (MLCK) activation was not affected by TMEM16A. Furthermore, a suppressed activation of integrin

Parkinsonismo inducido por telmisartán: Reporte de caso / Induced parkinsonism for telmisartan: case report

RESUMEN INTRODUCCIÓN: El parkinsonismo es un síndrome clínico, caracterizado por temblor, rigidez y bradicinesia, debido a la alteración en el circuito dopaminérgico ganglio-basal, específicamente a nivel nigroestriatal. A continuación se presenta un caso de parkinsonismo inducido por telmisartán. PRESENTACIÓN DE CASO: Hombre de 78 años, con antecedentes de enfermedad de Parkinson de dos años de evolución, controlada con levodopa, pramipexol ER y amantadina, ingresa al servicio de urgencias por empeoramiento del parkinsonismo en las dos semanas previas a la consulta. Tenía antecedente de infarto cerebral en el territorio de la arteria cerebral posterior izquierda, hipertensión arterial crónica y diabetes mellitus tipo 2. Al examen neurológico presentaba bradicinesia y rigidez severa en las cuatro extremidades, con limitación significativa de la marcha, asociado a mioclonías. Se descartaron alteraciones infecciosas, metabólicas y lesiones agudas en la tomografía cerebral, por lo que se suspendió el telmisartán, posteriormente a lo cual los síntomas mejoraron. DISCUSIÓN: El parkinsonismo secundario a fármacos constituye la primera causa de este síndrome, en varios modelos farmacológicos se describe la acción que estos ejercen sobre los receptores dopaminérgicos. Así, el parkinsonismo inducido por telmisartán se considera desencadenado por disrupción dopaminérgica secundaria al antagonismo de los receptores de la angiotensina II a nivel de la sustancia gris periacueductal.

SUMMARY INTRODUCTION: Parkinsonism is a clinical syndrome characterized by tremor, rigidity, and bradykinesia due to alteration in the basal-ganglia dopaminergic circuit, specifically at the nigrostriatal level. The following is a case of parkinsonism induced by telmisartan. CASE PRESENTATION: A 78-year-old man with a 2-year history of Parkinson's disease of controlled evolution with levodopa, pramipexole ER, amantadine was admitted to the emergency department due to worsening of parkinsonism in the two weeks prior to consultation. He had a history of cerebral infarction in the territory of the left posterior cerebral artery, chronic arterial hypertension, and type 2 diabetes mellitus. On neurological examination, he presented bradykinesia and severe stiffness in all four limbs with significant limitation of gait, associated with myoclonus. Infectious and metabolic alterations and acute lesions were ruled out in the brain tomography, so telmisartan was suspended, after which the symptoms improved. DISCUSSION: Drug-induced parkinsonism is the first cause of this syndrome, and the action they exert on dopaminergic receptors has been described in several pharmacological models. Telmisartan-induced parkinsonism is considered triggered by dopaminergic disruption secondary to angiotensin II receptor antagonism at the periaqueductal gray substance level.

Bloqueio de Receptores AT1 Melhora o Desempenho Funcional Miocárdico na Obesidade / AT1Receptor Blockade Improves Myocardial Functional Performance in Obesity

Resumo Fundamento A obesidade tem sido associada com ativação crônica do sistema renina-angiotensina-aldosterona e importantes alterações no desempenho cardíaco. Objetivo Avaliar a influência do bloqueio de receptores de angiotensina-II do tipo 1 (AT1) sobre a morfologia e desempenho cardíaco de ratos obesos por dieta Métodos Ratos Wistar (n=48) foram submetidos a dieta controle (2,9 kcal/g) ou hiperlipídica (3,6 kcal/g) durante 20 semanas. Após a 16ª semana, foram distribuídos em quatro grupos: Controle (CO), Obeso (OB), Controle Losartan (CL) e Obeso Losartan (OL). CL e OL receberam losartan (30 mg/kg/dia) na água durante quatro semanas. Posteriormente, foram analisadas composição corporal, pressão arterial sistólica (PAS) e ecocardiograma. A função de músculos papilares foi avaliada em situação basal com concentração de cálcio ([Ca2+]o) de 2,50 mM e após manobras inotrópicas: potencial pós-pausa (PPP), elevação da [Ca2+]o e durante estimulação beta-adrenérgica com isoproterenol. A análise dos resultados foi feita por meio de Two-Way ANOVA e teste de comparações apropriado. O nível de significância considerado foi de 5%. Resultados Embora a alteração da PAS não tenha se mantido ao final do experimento, a obesidade se associou com hipertrofia cardíaca e maior velocidade de encurtamento da parede posterior do ventrículo esquerdo.No estudo de músculos papilares em condição basal, CL mostrou menor velocidade máxima de variação negativa da tensão desenvolvida (-dT/dt) do que CO. O PPP de 60s promoveu menor -dT/dt e pico de tensão desenvolvida (TD) em OB e CL, comparados ao CO, e maior variação relativa de TD e velocidade máxima de variação positiva (+dT/dt) no OL em relação a CL e OB. Sob 1,5, 2,0 e 2,5mM de [Ca2+]o, o grupo OL exibiu maior -dT/dt do que CL. Conclusão Losartan melhora a função miocárdica de ratos com obesidade induzida por dieta. (Arq Bras Cardiol. 2020; 115(1):17-28)

Abstract Background Obesity has been associated with chronic activation of the renin-angiotensin-aldosterone system and with significant changes in cardiac performance. Objective To assess the impact of a blockade of angiotensin-II receptor type 1 (AT1receptor) on morphology and on myocardial functional performance in rats with high-fat diet- induced obesity. Methods Wistar rats (n=48) were submitted to control (2.9 kcal/g) or high-fat (3.6 kcal/g) diet for 20 weeks. After the 16thweek they were divided into four groups: Control (CO), Obese (OB), Control Losartan (CL) and Obese Losartan (OL). CL and OL received losartan (30 mg/kg/day) in drinking water for four weeks. Subsequently, body composition, systolic blood pressure (SBP) and echocardiographic variables were analyzed. Papillary muscle function was assessed at baseline with 2.50 mM calcium concentration ([Ca2+]o) and after inotropic maneuvers: post-pause potentiation (PPP), [Ca2+]oelevation, and during beta-adrenergic stimulation with isoproterenol. Analysis of the results was performed by the Two-Way ANOVA and by the appropriate comparison test. The level of significance was set at 5%. Results Although SBP change had been not maintained at the end of the experiment, obesity was associated with cardiac hypertrophy and with increased left ventricle posterior wall shortening velocity. In the study of papillary muscles in basal condition, CL showed lower developed tension maximum negative variation velocity (-dT/dt) than CO. The 60s PPP promoted lower -dT/dt and maximum developed tension (DT) in OB and CL compared with CO, and higher relative DT variation and maximum positive variation velocity (+dT/dt) in OL compared with CL and OB. Under 1.5, 2.0, and 2.5mM [Ca2+]o, the OL group showed higher -dT/dt than CL. Conclusion Losartan improves myocardial function in high-fat diet-induced obesity. (Arq Bras Cardiol. 2020;115(1):17-28)

Azilsartan causing metabolic encephalopathy

Angiotensin II receptor blockers (ARBs) are the antihypertensive drugs associated with side effects, majorly such ascough and electrolyte disturbance. Azilsartan is a newly marketed ARB in India, not even having a well-establishedadverse effect profile. Here, we present a 58-year-old female who was admitted to the emergency department showingsigns and symptoms of delirium, disorientation, and vomiting for 4 days. The patient is known to have coronaryartery disease so that she underwent coronary artery bypass grafting. She was recently started on azilsartan for herchronic hypertension, along with other drugs. The presence of electrolyte imbalance in laboratory reports and currentsymptoms suggested azilsartan-induced encephalopathy. The patient was recovered after discontinuation of azilsartan.This case enlightens the clinical characteristics, possible mechanism, and treatment strategy opted to correct thecondition.