Angiotensin II type 2 receptor signalling as a pain target: Bench, bedside and back-translation.

Translating promising preclinical pain relief data for novel molecules from drug discovery to positive clinical trial outcomes is challenging. The angiotensin II type 2 (AT2) receptor is a clinically-validated target based upon positive proof-of-concept clinical trial data in patients with post-herpetic neuralgia. This trial was conducted because AT2 receptor antagonists evoked pain relief in rodent models of neuropathic pain. EMA401 was selected as the drug candidate based upon its suitable preclinical toxicity and safety profile and good pharmacokinetics. Herein, we provide an overview of the discovery, preclinical and clinical development of EMA401, for the alleviation of peripheral neuropathic pain.

Synthesis, Characterization and Application of a MIP-polyHIPE for Selective Extraction of Angiotensin II Receptor Antagonists Residues in Natural Waters.

Polymers via high internal phase emulsion (polyHIPEs) were molecularly imprinted with Irbesartan, an antihypertensive drug belonging to the class of angiotensin II receptor antagonists (sartan drugs), chosen for the proof-of-concept extraction of hazardous emerging contaminants from water. Different analyte-functional monomer molar ratios (1:100, 1:30 and 1:15) were investigated, and the MIP polyHIPEs have been characterized, parallel to the not imprinted polymer (NIP), by batch sorption experiments. The material with the highest template-functional monomer ratio was the best for Irbesartan removal, showing a sorption capacity fivefold higher than the NIP. Regarding the adsorption kinetics, the analyte-sorbent equilibrium was reached after about 3 h, and the film diffusion model best fitted the kinetic profile. Selectivity was further demonstrated by testing Losartan, another sartan drug, observing a fourfold lower sorption capacity, but still higher than that of NIP. The polymers were also synthesized in cartridges for solid-phase extraction (SPE), which was helpful for evaluating the breakthrough curves and performing pre-concentrations. These have been done in tap and river water samples (100-250 mL, 15-500 µg L-1 Irbesartan), obtaining quantitative sorption/desorption on the MIP-polyHIPE (RSD < 14%, n = 3). The NIP provided a recovery of just around 30%, evidence of partial uptake of the target from water.

The effects of losartan or angiotensin II receptor antagonists on cartilage: a systematic review.

OBJECTIVE: The aim of this study is to analyze the latest evidence on the effects of losartan or Ang II receptor antagonists on cartilage repair, with a focus on their clinical relevance. DESIGN: The PubMed, Embase, and Cochrane Library databases were searched up to November 12th 2021 to evaluate the effects of losartan or Ang II receptor antagonists on cartilage repair in in vitro studies and in vivo animal studies. Study design, sample characteristics, treatment type, duration, and outcomes were analyzed. The risk of bias and the quality of the eligible studies were assessed using the Systematic Review Centre for Laboratory Animal Experimentation (SYRCLE) risk of bias assessment tool and Collaborative Approach to Meta-Analysis and Review of Animal Data from Experimental Studies (CAMARADES). RESULTS: A total of 12 studies were included in this systematic review. Of the 12 eligible studies, two studies were in vitro human studies, three studies were in vitro animal studies, one study was an in vitro human and animal study, and six studies were in vivo animal studies. The risk bias and quality assessments were predominantly classified as moderate. Since meta-analysis was difficult due to differences in treatment type, dosage, route of administration, and method of outcome assessment among the eligible studies, qualitative evaluation was conducted for each study. CONCLUSIONS: Both in vitro and in vivo studies provide evidence to demonstrate beneficial effects of Ang II receptor antagonists on osteoarthritis and cartilage defect models across animal species.

Angiotensin type 2 receptor antagonism as a new target to manage gout.

BACKGROUND: There is a growing search for therapeutic targets in the treatment of gout. The present study aimed to evaluate the analgesic and anti-inflammatory potential of angiotensin type 2 receptor (AT2R) antagonism in an acute gout attack mouse model. METHODS: Male wild-type (WT) C57BL/6 mice either with the AT2R antagonist, PD123319 (10 pmol/joint), or with vehicle injections, or AT2R KO mice, received intra-articular (IA) injection of monosodium urate (MSU) crystals (100 µg/joint), that induce the acute gout attack, and were tested for mechanical allodynia, thermal hyperalgesia, spontaneous nociception and ankle edema development at several times after the injections. To test an involvement of AT2R in joint pain, mice received an IA administration of angiotensin II (0.05-5 nmol/joint) with or without PD123319, and were also evaluated for pain and edema development. Ankle joint tissue samples from mice undergoing the above treatments were assessed for myeloperoxidase activity, IL-1ß release, mRNA expression analyses and nitrite/nitrate levels, 4 h after injections. RESULTS: AT2R antagonism has robust antinociceptive effects on mechanical allodynia (44% reduction) and spontaneous nociception (56%), as well as anti-inflammatory effects preventing edema formation (45%), reducing myeloperoxidase activity (54%) and IL-1ß levels (32%). Additionally, Agtr2tm1a mutant mice have largely reduced painful signs of gout. Angiotensin II administration causes pain and inflammation, which was prevented by AT2R antagonism, as observed in mechanical allodynia 4 h (100%), spontaneous nociception (46%), cold nociceptive response (54%), edema formation (83%), myeloperoxidase activity (48%), and IL-1ß levels (89%). PD123319 treatment also reduces NO concentrations (74%) and AT2R mRNA levels in comparison with MSU untreated mice. CONCLUSION: Our findings show that AT2R activation contributes to acute pain in experimental mouse models of gout. Therefore, the antagonism of AT2R may be a potential therapeutic option to manage gout arthritis.

Inhibition of the angiotensin II type 2 receptor AT2R is a novel therapeutic strategy for glioblastoma.

Glioblastoma (GBM) is an aggressive malignant primary brain tumor with limited therapeutic options. We show that the angiotensin II (AngII) type 2 receptor (AT2R) is a therapeutic target for GBM and that AngII, endogenously produced in GBM cells, promotes proliferation through AT2R. We repurposed EMA401, an AT2R antagonist originally developed as a peripherally restricted analgesic, for GBM and showed that it inhibits the proliferation of AT2R-expressing GBM spheroids and blocks their invasiveness and angiogenic capacity. The crystal structure of AT2R bound to EMA401 was determined and revealed the receptor to be in an active-like conformation with helix-VIII blocking G-protein or ß-arrestin recruitment. The architecture and interactions of EMA401 in AT2R differ drastically from complexes of AT2R with other relevant compounds. To enhance central nervous system (CNS) penetration of EMA401, we exploited the crystal structure to design an angiopep-2-tethered EMA401 derivative, A3E. A3E exhibited enhanced CNS penetration, leading to reduced tumor volume, inhibition of proliferation, and increased levels of apoptosis in an orthotopic xenograft model of GBM.

Impact of angiotensin II receptor antagonism on the sex-selective dysregulation of cardiovascular function induced by in utero dexamethasone exposure.

In utero exposure to glucocorticoids in late gestation programs changes in cardiovascular function. The objective of this study was to determine the degree to which angiotensin II mediates sex-biased changes in autonomic function as well as basal and stress-responsive cardiovascular function following in utero glucocorticoid exposure. Pregnant rats were administered the synthetic glucocorticoid dexamethasone (Dex; 0.4 mg/kg/day sc) or vehicle on gestation days 18-21. Mean arterial pressure, heart rate, and heart rate variability (HRV) were measured via radiotelemetry in freely moving, conscious adult rats. To evaluate the impact of stress, rats were placed in a restraint tube for 20 min. In a separate cohort of rats, restraint stress was performed before and after chronic treatment with the angiotensin type 1 receptor antagonist, losartan (30 mg/kg/day ip). Frequency domain analysis of HRV was evaluated, and data were integrated into low-frequency (LF, 0.20-0.75 Hz) and high-frequency (HF, 0.75-2.00 Hz) bands. Prenatal Dex resulted in an exaggerated pressor and heart rate response to restraint in female offspring that was attenuated by prior losartan treatment. HF power was higher in vehicle-exposed female rats compared with Dex females. Following losartan, HF power was equivalent between female vehicle and Dex-exposed rats. In utero exposure to Dex produced female-biased alterations in stress-responsive cardiovascular function, which may be indicative of a reduction in parasympathetic activity. Moreover, these findings suggest this autonomic dysregulation may be mediated, in part, by long-term changes in renin-angiotensin signaling.NEW & NOTEWORTHY Our findings reveal the involvement of angiotensin II on sex-selective cardiovascular function and autonomic changes in adult offspring exposed to dexamethasone during the last 4 days of gestation. We show that angiotensin II receptor blockade reverses the exaggerated pressor and heart rate response to acute restraint stress and the autonomic dysregulation observed in female, but not male, offspring exposed to dexamethasone in utero.

Association of angiotensin-converting enzyme inhibitors or angiotensin II receptor antagonists use with risk of atrial fibrillation after pacemaker implantation among very old patients.

It remains unknown whether and to what extend the angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) can play a role in the development of atrial fibrillation (AF) after pacemaker implantation in very old patients. Therefore, we aimed to investigate the association between oral ACEIs or ARBs and the risk of developing AF in very old patients after pacemaker implantation. Patients above 80 years old with pacemaker implantation and without baseline history of AF were included and their real-world information about ACEIs or ARBs use was extracted from electronic medical records. New AF cases were confirmed via the records of outpatient visits. The multivariable Cox proportional-hazards model was used to evaluate the associations between oral ACEIs or ARBs and risk of AF after pacemaker implantation. Among a total of 388 identified patients aged 80 to 98 years, 118 used ACEIs, 174 had ARBs therapy, and 115 AF were identified after pacemaker implantation during a median follow-up time of 3.1 years. After adjustment for potential confounders, patients with daily use of ARBs had a relatively lower risk of AF after pacemaker implantation (HR: 0.627, 95% CI: 0.425, 0.926; P = 0.019) compared with those non-users, whereas ACEIs therapy didn't show a significant relation with AF risk (HR: 1.335, 95% CI: 0.894, 1.995; P = 0.157). In conclusion, for very old patients with a permanent pacemaker, daily use of oral ARBs was associated with a relative lower risk of AF after pacemaker implantation, however, daily use of ACEIs was not related with AF risk.

Angiotensin-converting enzyme inhibitors, angiotensin-II-receptor antagonists and angiotensin-receptor blocker/neprilysin inhibitor utilization in heart failure patients: Sub-analysis of a nation-wide population-based study in the Czech Republic.

AIMS: Sub-analysis of a retrospective nation-wide observational analysis of heart failure (HF) epidemiology reported to the Czech National Registry of Reimbursed Health Services between 2012 and 2018 aimed at angiotensin-converting enzyme inhibitors (ACEI), angiotensin-II-receptor antagonists (ARB) and angiotensin receptor blocker/neprilysin inhibitor (ARNI) use. METHODS AND RESULTS: ACEi and ARBs were generally used in 87.6% of all HF patients in 2012 (n=154 627); 84.5% in 2013 (n=170 861); 83.5% in 2014 (n=186 963); 81.6% in 2015 (n=198 844); 80.1% in 2016 (n=205 793); 78.0% in 2017 (n=212 152) and in 76.7% in 2018 (n=219 235). In a sub-analysis of patients with a medical procedure and/or examination using an I50.x ICD code accounted for in the given year, ACEi and ARBs were generally used in 99.3% in 2012 (n=63 250); 96% in 2013 (n=62 241); 95.2% in 2014 (n=64 414); 93.3% in 2015 (n=65 217); 91.8% in 2016 (n=65 236); 90.1% in 2017 (n=65 761) and in 88.6% in 2018 (n=66 332). In 2018, the majority of patients with HF were prescribed ramipril (n=49 909; 17.5%) and perindopril (n=44 332; 15.5%). The mostly prescribed ARBs in 2018 were telmisartan (n=18 669; 6.5%); losartan (n=13 935; 4.9%) and valsartan (n=4 849; 1.7%). In 24.5% of cases, ACEIs and ARBs were prescribed in a fixed combination with another drug. ARNI became gradually more prescribed from 2018 (n=9 659 in November 2020). CONCLUSION: In an analysis of ACEIs, ARBs and ARNIs utilization in all patients treated for heart failure in the given year in the whole country, we found a comparable rate of drug prescription in comparison with specific heart failure registries. This indicates a good translation of current standard of care into common clinical practice. Ramipril and perindopril remained the mostly prescribed ACEIs and telmisartan became the mostly prescribed ARB. Since 2018, ARNIs began to be widely prescribed.

ARB might be superior to ACEI for treatment of hypertensive COVID-19 patients.

The administration of ACEI/ARB (angiotensin-converting enzyme inhibitors/Angiotension II receptor blockers) in COVID-19 (coronavirus disease 2019) patients with hypertension exhibits a lower risk of mortality compared with ACEI/ARB non-users. In this context, an important question arises: is ACEI or ARB more suitable for the treatment of hypertensive COVID-19 patients? Taken into consideration the following four rationales, ARB may offer a more significant benefit than ACEI for the short-term treatment of hypertensive COVID-19 patients: 1. ACEI has no inhibition on non-ACE-mediated Ang II production under infection conditions, whereas ARB can function properly regardless of how Ang II is produced; 2. ACEI-induced bradykinin accumulation may instigate severe ARDS while ARB has no effects on kinin metabolism; 3. ARB alleviates viscous sputa production and inflammatory reaction significantly in contrast to ACEI; 4. ARB may attenuate the lung fibrosis induced by mechanical ventilation in severe patients and improve their prognosis significantly compared with ACEI. To examine the advantages of ARB over ACEI on hypertensive COVID-19 patients, retrospective case-control studies comparing the clinical outcomes for COVID-19 patients receiving ARB or ACEI treatment is strikingly needed in order to provide guidance for the clinical application.

The Protective Effects of AT2R Agonist, CGP42112A, Against Angiotensin II-Induced Oxidative Stress and Inflammatory Response in Astrocytes: Role of AT2R/PP2A/NFκB/ROS Signaling.

Angiotensin II receptor type 2 (AT2R) agonists have been known to promote neuroprotection by limiting ischemic insult, neuronal proliferation, and differentiation. Further, AT2R agonists have also been associated with the suppression of neuroinflammation and neurodegeneration. Of note, brain astrocytes play a critical role in these neuroinflammatory and neurodegenerative processes. However, the role of AT2R in astrocytic activation remains elusive. Therefore, this study evaluated the role and molecular mechanism of AT2R agonist CGP42112A (CGP) against Angiotensin II (Ang II)-induced astrocytic activation in primary astrocytes, and in a rat model of hypertension. Here, we demonstrated that AT2R activation by CGP abrogated Ang II-induced astrocytic activation, by mitigating the ROS production, mitochondrial dysfunction, IκB-α degradation, NFκB nuclear translocation, and release of TNF-α in astrocytes. However, AT2R-mediated anti-inflammatory effects were reversed by AT2R antagonist, PD123319 (PD), in both in vitro and in vivo conditions. Mechanistically, AT2R via protein phosphatase-2A (PP2A) abrogated the Ang II-induced NFκB activation, ROS generation, and subsequent astrocytic activation. Importantly, PP2A antagonist, okadaic acid, reversed the anti-inflammatory effects of AT2R in Ang II-stimulated primary astrocytes and in the cortex of hypertensive rats. Thus, the present study suggests that AT2R by activating PP2A inhibits oxidative stress and NFκB activation, thereby preventing the astrocytic pro-inflammatory activation. Therefore, AT2R might be advantageous therapeutic target for neuroinflammatory/neurodegenerative diseases perpetuated by astrocytic activation.

Another controller system for arterial pressure. AngII-vasopressin neural network of the parvocellular paraventricular nucleus may regulate arterial pressure during hypotension.

Angiotensin II (AngII) immunoreactive cells, fibers and receptors, were found in the parvocelluar region of paraventricular nucleus (PVNp) and AngII receptors are present on vasopressinergic neurons. However, the mechanism by which vasopressin (AVP) and AngII may interact to regulate arterial pressure is not known. Thus, we tested the cardiovascular effects of blockade of the AngII receptors on AVP neurons and blockade of vasopressin V1a receptors on AngII neurons. We also explored whether the PVNp vasopressin plays a regulatory role during hypotension in anesthetized rat or not. Hypovolemic-hypotension was induced by gradual bleeding from femoral venous catheter. Either AngII or AVP injected into the PVNp produced pressor and tachycardia responses. The responses to AngII were blocked by V1a receptor antagonist. The responses to AVP were partially attenuated by AT1 antagonist and greatly attenuated by AT2 antagonist. Hemorrhage augmented the pressor response to AVP, indicating that during hemorrhage, sensitivity of PVNp to vasopressin was increased. By hemorrhagic-hypotension and bilateral blockade of V1a receptors of the PVNp, we found that vasopressinergic neurons of the PVNp regulate arterial pressure towards normal during hypotension. Taken together these findings and our previous findings about angII (Khanmoradi and Nasimi, 2017a) for the first time, we found that a mutual cooperative system of angiotensinergic and vasopressinergic neurons in the PVNp is a major regulatory controller of the cardiovascular system during hypotension.

Colon adenocarcinoma-derived cells possessing stem cell function can be modulated using renin-angiotensin system inhibitors.

The cancer stem cell (CSC) concept proposes that cancer recurrence and metastasis are driven by CSCs. In this study, we investigated whether cells from colon adenocarcinoma (CA) with a CSC-like phenotype express renin-angiotensin system (RAS) components, and the effect of RAS inhibitors on CA-derived primary cell lines. Expression of RAS components was interrogated using immunohistochemical and immunofluorescence staining in 6 low-grade CA (LGCA) and 6 high-grade CA (HGCA) tissue samples and patient-matched normal colon samples. Primary cell lines derived from 4 HGCA tissues were treated with RAS inhibitors to investigate their effect on cellular metabolism, tumorsphere formation and transcription of pluripotency genes. Immunohistochemical and immunofluorescence staining showed expression of AT2R, ACE2, PRR, and cathepsins B and D by cells expressing pluripotency markers. ß-blockers and AT2R antagonists reduced cellular metabolism, pluripotency marker expression, and tumorsphere-forming capacity of CA-derived primary cell lines. This study suggests that the RAS is active in CSC-like cells in CA, and further investigation is warranted to determine whether RAS inhibition is a viable method of targeting CSCs.

Survival impact of angiotensin-converting enzyme inhibitors and angiotensin II receptor antagonists in head and neck cancer.

BACKGROUND: Preclinical evidence suggests a link between the renin-angiotensin system and oncogenesis. We aimed to explore the impact of angiotensin-converting enzyme inhibitors (ACEi) and angiotensin II receptor blockers (ARB) in head and neck cancer (HNC). METHODS: Over 5000 patients were identified from the Surveillance, Epidemiology, and End Results-Medicare linked dataset and categorized according to ACEi and ARB and diagnoses of chronic kidney disease (CKD) or hypertension (HTN). Overall survival (OS) and cancer-specific survival (CSS) were compared using Cox multivariable regression (MVA), expressed as hazard ratios (HR) with 95% confidence intervals (95%CI). RESULTS: No significant MVA associations for OS or CSS were found for ACEi. Compared to patients with CKD/HTN taking ARB, those with CKD/HTN not taking ARB experienced worse OS (HR 1.28, 95%CI 1.09-1.51, p = 0.003) and CSS (HR 1.23, 95%CI 1.00-1.50, p = 0.050). CONCLUSIONS: ARB usage is associated with improved OS and CSS among HNC patients with CKD or HTN.

Renin-angiotensin-aldosterone system inhibitors and SARS-CoV-2 infection: an analysis from the veteran's affairs healthcare system.

BACKGROUND: Angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB) are known to impact the functional receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The association between chronic therapy with these medications and infection risk remains unclear. OBJECTIVES: The objective was to determine the association between prior ACEI or ARB therapy and SARS-CoV-2 infection among patients with hypertension in the U.S. Veteran's Affairs health system. METHODS: We compared the odds of SARS-CoV-2 infection among three groups: patients treated with ACEI, treated with ARB, or treated with alternate first-line anti-hypertensives without ACEI/ARB. We excluded patients with alternate indications for ACEI or ARB therapy. We performed an augmented inverse propensity weighted analysis with adjustment for demographics, region, comorbidities, vitals, and laboratory values. RESULTS: Among 1,724,723 patients with treated hypertension, 659,180 were treated with ACEI, 310,651 with ARB, and 754,892 with neither. Before weighting, patients treated with ACEI or ARB were more likely to be diabetic and use more anti-hypertensives. There were 13,278 SARS-CoV-2 infections (0.8%) between February 12, 2020 and August 19, 2020. Patients treated with ACEI had lower odds of SARS-CoV-2 infection (odds ratio [OR] 0.93; 95% CI: 0.89-0.97) while those treated with ARB had similar odds (OR 1.02; 95% CI: 0.96-1.07) compared with patients treated with alternate first-line anti-hypertensives without ACEI/ARB. In falsification analyses, patients on ACEI did not have a difference in their odds of unrelated outcomes. CONCLUSIONS: Our results suggest the safety of continuing ACEI and ARB therapy. The association between ACEI therapy and lower odds of SARS-CoV-2 infection requires further investigation.

EMA401, an angiotensin II type 2 receptor antagonist blocks visceral hypersensitivity and colonic hyperpermeability in rat model of irritable bowel syndrome.

Visceral hypersensitivity and impaired gut barrier are crucial pathophysiology of irritable bowel syndrome (IBS), and injection of lipopolysaccharide or corticotropin-releasing factor, and repeated water avoidance stress simulate these gastrointestinal changes in rat (IBS models). We previously demonstrated that losartan, an angiotensin II type 1 (AT1) receptor antagonist prevented these changes, and we attempted to determine the effects of EMA401, an AT2 receptor antagonist in the current study. EMA401 blocked visceral hypersensitivity and colonic hyperpermeability in these models, and naloxone reversed the effects by EMA401. These results suggest that EMA401 may improve gut function via opioid signaling in IBS.

Tactics to prevent or slow progression of CKD in patients with diabetes.

Annual screening of urinary parameters, ongoing clinical vigilance, and proper medical therapy can help to keep declining renal function at bay.

Inhibitory efficiency of potential drugs against SARS-CoV-2 by blocking human angiotensin converting enzyme-2: Virtual screening and molecular dynamics study.

Till date millions of people are infected by SARS-CoV-2 throughout the world, while no potential therapeutics or vaccines are available to combat this deadly virus. Blocking of human angiotensin-converting enzyme 2 (ACE-2) receptor, the binding site of SARS-CoV-2 spike protein, an effective strategy to discover a drug for COVID-19. Herein we have selected 24 anti-bacterial and anti-viral drugs and made a comprehensive analysis by screened them virtually against ACE-2 receptor to find the best blocker by molecular docking and molecular dynamics studies. Analysis of results revealed that, Cefpiramide (CPM) showed the highest binding affinity of -9.1 kcal/mol. Furthermore, MD study for 10 ns and evaluation of parameters like RMSD, RMSF, radius of gyration, solvent accessible surface area analysis confirmed that CPM effectively binds and blocks ACE-2 receptor efficiently.

Clinical Characterization of Patients With COVID-19 in Primary Care in Catalonia: Retrospective Observational Study.

BACKGROUND: The country of Spain has one of the highest incidences of COVID-19, with more than 1,000,000 cases as of the end of October 2020. Patients with a history of chronic conditions, obesity, and cancer are at greater risk from COVID-19; moreover, concerns surrounding the use of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin type II receptor blockers (ARBs) and its relationship to COVID-19 susceptibility have increased since the beginning of the pandemic. OBJECTIVE: The objectives of this study were to compare the characteristics of patients diagnosed with COVID-19 to those of patients without COVID-19 in primary care; to determine the risk factors associated with the outcome of mortality; and to determine the potential influence of certain medications, such as ACEIs and ARBs, on the mortality of patients with COVID-19. METHODS: An observational retrospective study of patients diagnosed with COVID-19 in the Catalan Central Region of Spain between March 1 and August 17, 2020, was conducted. The data were obtained from the Primary Care Services Information Technologies System of the Catalan Institute of Health in Barcelona, Spain. RESULTS: The study population included 348,596 patients (aged >15 years) registered in the Primary Care Services Information Technologies System of the Catalan Central Region. The mean age of the patients was 49.53 years (SD 19.42), and 31.17% of the patients were aged ≥60 years. 175,484/348,596 patients (50.34%) were women. A total of 23,844/348,596 patients (6.84%) in the population studied were diagnosed with COVID-19 during the study period, and the most common clinical conditions of these patients were hypertension (5267 patients, 22.1%) and obesity (5181 patients, 21.7%). Overall, 2680/348,596 patients in the study population (0.77%) died during the study period. The number of deaths among patients without COVID-19 was 1825/324,752 (0.56%; mean age 80.6 years, SD 13.3), while among patients diagnosed with COVID-19, the number of deaths was 855/23,844 (3.58%; mean age 83.0 years, SD 10.80) with an OR of 6.58 (95% CI 6.06-7.15). CONCLUSIONS: We observed that women were more likely to contract COVID-19 than men. In addition, our study did not show that hypertension, obesity, or being treated with ACEIs or ARBs was linked to an increase in mortality in patients with COVID-19. Age is the main factor associated with mortality in patients infected with SARS-CoV-2.

Calcium channel blockers, angiotensin II receptor antagonists and alpha-blockers accentuate blood pressure reducing caused by dental local anesthesia.

OBJECTIVE: The primary aim of this study was to investigate the effect associated with patients' factor such as systemic disease on the blood pressure of patients in dental procedure. The secondary aim of this study was to investigate the effect associated with systemic disease and antihypertensive on the blood pressure changes with local anesthesia. METHODS: The blood pressure was measured before and after local anesthesia injection for dental treatment. The effect associated with patients' factor such as systemic disease on the blood pressure and the effect on blood pressure changes of the type of antihypertensive drugs and the systemic disease were analyzed using a multivariate analysis of variance test. RESULTS: We analyzed 1306 patients scheduled for the dental procedure. Age and some systemic diseases such as hypertension and angina pectoris affected blood pressure before local anesthesia. On the other hand, age and systemic diseases did not affect blood pressure changes. And, some antihypertensive affected systolic blood pressure changes. CONCLUSIONS: The blood pressure change with local anesthesia was not associated with systemic diseases and age but was associated with antihypertensive agents. In particular, calcium channel blockers, angiotensin II receptor antagonists and alpha-blockers accentuate blood pressure reducing caused by local anesthesia. CLINICAL RELEVANCE: The blood pressure change with local anesthesia was associated with antihypertensive agents. This study was registered with the University Hospital Medical Information Network Clinical Trials Registry (number UMIN000030695).

The Clinical Characteristics and Antihypertensive Medications for Mortality of Elderly Hospitalized Hemodialysis patients: a Multicenter Retrospective Study in China.

This study aimed to evaluate the clinical characteristics and antihypertensive medications affecting elderly hemodialysis (HD) patient mortality. This retrospective cohort study enrolled patients (≥18 years old) discharged from 15 tertiary general hospitals in China between January 1, 2009, and December 31, 2011. The characteristics of elderly HD patients (≥60 years old) and antihypertensive medications for mortality were analyzed. A total of 7135 patients on maintenance HD, including 2738 elderly patients, were enrolled in this study. The mean levels of hemoglobin, albumin, serum calcium, phosphorus, and parathyroid hormone in elderly group were lower than the younger group (P <0.05). The top two reasons for the hospitalization of elderly patients were infection and cardiovascular disease (CVD). We compared the characteristics of 2492 survived elderly maintenance HD patients and 246 patients who died. Aging [odds ratio OR = 1.59, 95% confidence interval (CI): 1.13-2.24] and central venous catheter (CVC) (OR = 1.62, 95% CI: 1.53-1.72) were independently risk factors for mortality in elderly maintenance HD patients. Maintenance HD patients with high levels of hemoglobin (OR = 0.76, 95% CI: 0.73-0.79), albumin (OR = 0.87, 95% CI: 0.77-0.98), uric acid (OR = 0.90, 95% CI: 0.84-0.9) and those taking angiotensin-converting enzyme inhibitor or an angiotensin II receptor blocker (OR = 0.77, 95% CI: 0.58-0.90) had a lower risk of mortality. Other antihypertensive drugs including: ß-blockers, calcium channel blockers, and α-blockers were not significantly associated with mortality (P >0.05). CVD and infection were the most common causes of hospitalization and/or mortality in elderly HD patients. Age, anemia and malnutrition, use of CVCs, and low level of serum uric acid are the risk factors for mortality in elderly maintenance HD patients. Renin-angiotensin system blockade might provide a benefit in protecting elderly maintenance HD patients from mortality.