Angiotensin II type 2 receptor agonist attenuates LPS-induced acute lung injury through modulating THP-1-derived macrophage reprogramming.

Acute respiratory distress syndrome (ARDS) is a devastating respiratory disorder, characterized by overwhelming inflammation in the alveoli without effective pharmacological treatment. We aimed to investigate the effect and mechanism of angiotensin II type 2 receptor (AT2R) agonist, Compound 21 (C21), on the lipopolysaccharide (LPS)-induced acute lung injury (ALI) model. The protective effect of C21 was evaluated via enzyme-linked immunosorbent assay (ELISA), Western blot (WB), real-time PCR, and fluorescence microscopy in LPS-challenged THP1-derived macrophages. Besides, the in vivo efficacy of C21 was assessed using cell counting, ELISA, protein quantification, hematoxylin-eosin (H&E) staining, and WB in an LPS-induced ALI mouse model. The results showed that C21 significantly inhibited the secretion of pro-inflammatory cytokines (CCL-2, IL-6), overproduction of intracellular ROS, and activation of inflammatory pathways (NF-κB/NLRP3, p38/MAPK) in THP-1 cell-derived macrophages stimulated by LPS. In in vivo study, intraperitoneal injection of C21 could reduce airway leukocytes accumulation and chemokine/cytokine (keratinocyte chemoattractant (KC), IL-6) generation, as well as alleviate diffuse alveolar damage induced by LPS. Conclusively, the AT2R agonist C21 significantly inhibited LPS-stimulated excess inflammatory responses and oxidative stress in macrophages. Meanwhile, C21 could effectively alleviate acute inflammation and tissue damage in the lungs of ALI mice challenged by LPS. The results of this study bring new hope for the early treatment of ALI/ARDS.

Stimulation of angiotensin II type 2 receptor attenuates organ injury in rats with polymicrobial sepsis.

BACKGROUND: Both inflammation and oxidative stress contribute to the pathogenesis of sepsis and its associated organ damage. Angiotensin-(1-7), acting through the Mas receptor and angiotensin II-type 2 receptors (AT2R), could attenuate organ dysfunction and improve survival in rats with sepsis. However, the role of AT2R in inflammation and oxidative stress in rats with sepsis is unclear. Therefore, this study examined the modulatory effects and molecular mechanism of AT2R stimulation in rats with polymicrobial sepsis. METHODS: Male Wistar rats underwent cecal ligation and puncture (CLP) or sham surgery followed by the administration of saline or CGP42112 (a selective, high-affinity agonist of AT2R, 50 µg/kg intravenously) at 3 hours after sham surgery or CLP. The changes in hemodynamics, biochemical variables, and plasma levels of chemokines and nitric oxide were detected during the 24-hour observation. Organ injury was evaluated by histological examination. RESULTS: We found that CLP evoked delayed hypotension, hypoglycemia, and multiple organ injuries, characterized by elevated plasma biochemical parameters and histopathological changes. These effects were attenuated by treatment with CGP42112. CGP42112 significantly attenuated plasma chemokines and nitric oxide production and reduced liver inducible nitric oxide synthase and nuclear factor kappa-B expression. More importantly, CGP42112 significantly improved the survival of rats with sepsis (50% vs. 20% at 24 h after CLP, p < 0.05). CONCLUSION: The protective effects of CGP42112 may be related to anti-inflammatory responses, suggesting that the stimulation of AT2R is a promising therapeutic candidate for the treatment of sepsis.

Angiotensin Type 2 Receptor Pharmacological Agonist Relieves Neurocognitive Deficits via Reducing Neuroinflammation and Microglial Engulfment of Dendritic Spines.

Mechanically ventilated patients suffering critical illness are at high risk of developing neurocognitive impairments. Angiotensin type 2 receptor (AGTR2) has been demonstrated to be anti-inflammatory and neuroprotective. The present study thus aimed to investigate whether AGTR2 can alleviate cerebral dysfunction in mice subjected to cochallenge with lipopolysaccharide (LPS) and mechanical ventilation (MV), and to reveal the underlying mechanism. We utilized a mice model that received a single injection of LPS (1 mg/kg, intraperitoneally) followed 2 h later by MV (10 ml/kg, lasting for 2 h). Pretreatment with the AGTR2 pharmacological agonist C21 (0.03, 0.3, and 3 mg/kg, intraperitoneally, once daily, lasting for 10 days). Locomotor activity and behavioral deficits were evaluated 24 h post-MV by open-field and fear-condition tests. Brain hippocampus and prefrontal cortex tissues were collected for immunofluorescence staining and western blotting to evaluate the resulting impacts on microglia, including morphological traits, functional markers, synaptic engulfment, superoxide production, and signaling molecules. Compared with vehicle-control, pre-administrated C21 reduced the branch endpoints and length of microglia processes in a dose-dependent manner in mice subjected to LPS/MV. The neuroprotective effect of AGTR2 was behaviorally confirmed by the improvement of memory decline in LPS/MV-treated mice following C21 pretreatment. In addition to morphological alterations, C21 reduced microglial functional markers and reduced microglial-dendrite contact and microglial engulfment of synaptic protein markers. In terms of the underlying molecular mechanism, AGTR2 stimulation by C21 leads to activation of protein phosphatase 2A, which subsequently mitigates microglial PKCδ and NF-κB activation, and inhibites NOX2-derived ROS production. The AGTR2 agonist C21 alleviates behavioral deficits in those mice subjected to LPS/MV, via mechanisms that involve reactive microglia and abnormal synaptic plasticity in NOX2-derived ROS and the PKCδ-NFκB pathway.

A phase 2 trial investigating the effects of the angiotensin II type 2 receptor agonist C21 in systemic sclerosis-related Raynaud's.

OBJECTIVE: Our main aim was to investigate the effect of a single oral dose of C21, a selective angiotensin II type 2 receptor agonist, on cold-induced vasoconstriction in SSc-related RP. METHODS: This was a phase IIa, randomized, double-blind, cross-over, single-dose, placebo-controlled, single-centre study. Twelve female patients with SSc (median age 58.5 years, median duration of RP 19.0 years) attended on four occasions: screening, treatment visits 1 and 2 (separated by 3-7 days) and follow-up. At the first treatment visit, patients were randomized to receive either a single oral dose of C21 (200 mg) or placebo, then the opposite treatment on the second visit. Forty min after each treatment, each patient underwent a standard hand cold challenge. The primary end point was the area under the curve (AUC) for rewarming for each finger (eight fingers) over 15 min. Secondary end points included the maximum finger temperature after rewarming (MAX). Statistical analyses were performed by multiplicative ANCOVA models. RESULTS: For all eight fingers combined, mean AUC for rewarming was higher after treatment with C21 than after placebo (geometric mean 20 046°C*s vs 19 558°C*s), but not significantly (P = 0.380) and MAX (at 15 min) was also higher (geometric mean 23.5°C vs 22.5°C; P = 0.036). C21 was well tolerated. CONCLUSION: Despite the small trial size, a signal emerged suggesting that even in patients with established SSc, C21 may confer benefit for RP and deserves further investigation. TRIAL REGISTRATION: ClinicalTrials.gov, https://clinicaltrials.gov, NCT04388176.

Compound 21, a Direct AT2R Agonist, Induces IL-10 and Inhibits Inflammation in Mice Following Traumatic Brain Injury.

Recent studies demonstrated that the angiotensin type 2 receptor (AT2R) agonist, compound 21 (C21), provides neuroprotection and enhances recovery in experimental stroke. However, C21 has never been tested in traumatic brain injury (TBI). Here, we aim to examine whether C21 confers protection after TBI. Unilateral cortical impact injury was induced in young adult C57BL/6 mice. C21 (0.03 mg/kg, i.p.) was administered at 1 h and 3 h post-TBI. After neurological severity score (NSS) assessments, all animals were sacrificed for immunoblotting analysis at 24 h post-TBI. C21 treatment significantly ameliorated NSS and reduced TBI's biomarkers [high mobility group box 1 (HMGB1), aquaporin-4 (AQ4)] and inflammatory markers [interlukin-1ß (IL-1ß) and tumor necrosis factor-α (TNF-α)] in the pericontusional areas compared to saline TBI. Further, C21 treatment induced interleukin-10 (IL-10) and phosphorylation of endothelial nitric oxide synthase (eNOS) after TBI. C21 also attenuated pro-apoptotic activation of poly (ADP-ribose) polymerase (PARP) and caspase-3. These findings support the therapeutic potential of C21 against TBI.

Interaction between age and vitamin D deficiency in severe COVID-19 infection / Interacción entre la edad y el déficit de vitamina D en la COVID-19 grave

INTRODUCTION: coronavirus disease 2019 (COVID-19) can induce an exaggerated inflammatory response. Vitamin D is a key modulator of the immune system. We hypothesized that vitamin D deficiency (VDD) could increase the risk of developing severe COVID-19 infection. METHODS: patients with confirmed COVID-19 seen at the emergency department of our hospital with recent measurements of 25(OH)D were recruited. We explored the association of vitamin D deficiency (VDD), defined as 25-hydroxyvitamin D < 20 ng/mL, with a composite of adverse clinical outcomes. RESULTS: we included 80 patients, of which 31 (39 %) presented the endpoint. VDD tended to predict an increased risk of developing severe COVID-19 after adjusting for age, gender, obesity, cardiac disease, and kidney disease [OR 3.2 (95 % CI: 0.9-11.4), p = 0.07]. Age had a negative interaction with the effect of VDD on the composite outcome (p = 0.03), indicating that the effect was more noticeable at younger ages. Furthermore, male gender was associated with VDD and with severe COVID-19 at younger ages. CONCLUSIONS: in this retrospective study, vitamin D deficiency showed a signal of association with severe COVID-19 infection. A significant interaction with age was noted, suggesting VDD may have a greater impact in younger patients. These findings should be confirmed in larger, prospective, adequately powered studies

INTRODUCCIÓN: la enfermedad por coronavirus 2019 (COVID-19) puede inducir una respuesta inflamatoria exagerada. La vitamina D es un modulador clave del sistema inmune. Planteamos que la deficiencia de vitamina D (VDD) podría aumentar el riesgo de desarrollar infección grave por COVID-19. MÉTODOS: se reclutaron pacientes consecutivos que acudieron al servicio de urgencias de nuestro centro con diagnóstico de COVID-19 confirmado (PCR-COVID-19 positiva) y mediciones recientes de 25(OH)D. Exploramos la asociación de la deficiencia de vitamina D (VDD), definida como una 25-hidroxivitamina D < 20 ng/ml, con un compuesto de resultados clínicos adversos. RESULTADOS: se incluyeron 80 pacientes, de los cuales 31 (39 %) presentaron el criterio de valoración primario. El VDD tendió a predecir un mayor riesgo de desarrollar COVID-19 grave después de ajustar edad, sexo, obesidad, enfermedad cardíaca y enfermedad renal [OR: 3,2 (IC 95 %: 0,9-11,4), p = 0,07]. La edad tuvo una interacción negativa con el efecto de la VDD en el resultado compuesto (p = 0,03), lo que indica que el efecto fue más notable a edades más tempranas. Además, el género masculino se asoció con la VDD y con la COVID-19 grave en las edades más jóvenes. CONCLUSIONES: en este estudio retrospectivo, la deficiencia de vitamina D mostró una tendencia de asociación con la infección grave por COVID-19. Se observó una interacción significativa con la edad, lo que sugiere que la VDD puede tener un mayor impacto en los pacientes más jóvenes. Estos hallazgos deben confirmarse en estudios más grandes, prospectivos y con potencia adecuada

The Molecular Concept of Atheromatous Plaques.

BACKGROUND: Recently, there are scientific attempts to discover new drugs in the biotechnology industry in order to treat various diseases including atherosclerosis. OBJECTIVE: The main objective of the present review was to highlight the cellular, molecular biology and inflammatory process related to the atheromatous plaques. METHODS: A thorough literature search of Pubmed, Google and Scopus databases was done. RESULTS: Atherosclerosis is considered to be a leading cause of death throughout the world. Atherosclerosis involves oxidative damage to the cells with production of reactive oxygen species (ROS). Development of atheromatous plaques in the arterial wall is a common feature. Specific inflammatory markers pertaining to the arterial wall in atherosclerosis may be useful for both diagnosis and treatment. These include Nitric oxide (NO), cytokines, macrophage inhibiting factor (MIF), leucocytes and Pselectin. Modern therapeutic paradigms involving endothelial progenitor cells therapy, angiotensin II type-2 (AT₂R) and ATP-activated purinergic receptor therapy are notable to mention. CONCLUSION: Future drugs may be designed aiming three signalling mechanisms of AT₂R which are (a) activation of protein phosphatases resulting in protein dephosphorylation (b) activation of bradykinin/nitric oxide/cyclic guanosine 3&#039;,5&#039;-monophosphate pathway by vasodilation and (c) stimulation of phospholipase A(2) and release of arachidonic acid. Drugs may also be designed to act on ATP-activated purinergic receptor channel type P2X7 molecules which acts on cardiovascular system.

Adherence to guidelines in people with screen-detected type 2 diabetes, ADDITION, Denmark.

OBJECTIVE: In people with screen-detected type 2 diabetes in primary care, (1) to assess adherence to guidelines, recommending consultation with the GP every three months and treatment initiation with an ACE inhibitor or an angiotensin-II receptor antagonist when systolic BP was > 120 mmHg and/or diastolic BP was > 80 mmHg, and (2) to identify predictors for adherence. DESIGN: Prospective follow-up of a fixed cohort of patients. SETTING: Fifty-four Danish general practices. SUBJECTS AND MAIN OUTCOME MEASURES: A total of 361 people with screen-detected type 2 diabetes were followed up for 410 days to assess planned consultations with their GP and recording of BP. Some 226 people, with BP recorded above guideline threshold(s) and where treatment was not already initiated, were followed for up to 410 days to monitor prescription redemption. RESULTS: At 3, 6, 9 and 12 months 80%, 77%, 74%, and 73% of the cohort attended a consultation. A total of 89% of the cohort attended two of the four planned consultations. The probability of redeemed prescriptions for an ACE inhibitor or an angiotensin-II receptor antagonist according to the guideline during the first year following diagnosis was 51%. High initial BP was associated with prescription redemption. No other analysed individual or organisational characteristics were found to be associated with treatment initiation. CONCLUSION: The consultation attendance was reasonably high, and treatment initiation with an ACE inhibitor or an angiotensin-II receptor antagonist according to the guideline was found in half of the cases. High initial BP increased the probability of treatment initiation.

Papel actual de los antagonistas de los receptores de la angiotensina II y de sus combinaciones en el tratamiento de la hipertensión arterial / Current roleo fangiotens in II receptor antagonist sand their combination in the treatment of hypertension

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Efectos metabólicos del tratamiento con antagonistas de los receptores de la angiotensina II / Metabolic effect of treatment with angiotensin-II receptor antagonists

El objetivo del tratamiento de los pacientes hipertensos no sólo es reducir las cifras de presión arterial, sino también disminuir su riesgo cardiovascular total. Es importante, por lo tanto, que los fármacos utilizados, además de su acción hipotensora, posean un perfil metabólico beneficioso. Los antagonistas de los receptores de angiotensina II (AR-II) son de demostrada eficacia antihipertensiva y también tienen efectos beneficiosos en cuanto al metabolismo de los lípidos y los hidratos de carbono y en la prevención de nuevos casos de diabetes mellitus. Estas acciones se deben al bloqueo de los receptores AT1, pero en algunos ARA-II, aunque no parece que se trate de un efecto de clase, también a través de una acción parcialmente agonista de los receptores nucleares PPARγ. Si estos efectos metabólicos beneficiosos, demostrados hasta ahora experimentalmente y en algunos estudios, se corroboran en ensayos clínicos más amplios, los convertirían en los fármacos ideales para el tratamiento de los pacientes hipertensos con otros factores de riesgo cardiovascular y/o con síndrome metabólico (AU)

The aim of treatment in hypertensive patients is not only to reduce blood pressure but also to minimize the overall cardiovascular risk. It is important, therefore, that the drugs administered have a beneficial influence on metabolic parameters as well as an antihypertensive effect. It has been shown that angiotensin-II receptor antagonists (ARA IIs) are effective antihypertensives that also have a positive influence on lipid and carbohydrate metabolism. Moreover, they can help prevent the development of new-onset diabetes. These actions arise from the blockade of angiotensin-II type-1 (AT-1) receptors, while some ARA IIs, though this does not appear to be a class effect, are also able to act like partial agonists of the nuclear receptor peroxisome proliferatoractivated receptor-gamma (PPAR-Á). If these beneficial metabolic effects, which have been found in experimental studies and in a few clinical studies, are confirmed in larger clinical trials, ARA IIs will become the ideal drugs for treating hypertensive patients with other cardiovascular risk factors or with metabolic syndrome (AU)

Efecto de irbesartán en patología renal proteinúrica no diabética / Effect of irbesartan in proteinuric non-diabetic renal disease

Este estudio clínico aleatorizado, prospectivo, de dos brazos, evaluó el efecto antiproteinúricoy nefroprotector, así como la seguridad del tratamiento con un antagonistade los receptores de angiotensina II (irbesartán) en pacientes con glomerulonefritiscrónica (GNC), comparándolo con inhibidores del enzima convertidor deangiotensina (IECA). Un total de 50 pacientes con GNC diagnosticada mediantebiopsia renal y proteinuria en orina de 24 horas mayor a 1 g fueron incluidos. Todosellos recibieron tratamiento durante al menos 24 meses, 27 en el grupo 1 (irbesartán)y 23 en el grupo 2 (IECA). En los dos grupos encontramos una reducción significativa(p < 0,001) de la proteinuria (49,2% en el grupo 1 y 44,8% en el grupo 2)desde el tercer mes, que se confirma a los 12 y 24 meses de seguimiento (58,1% y62,7% en el grupo 1, y 56,8% y 55,4% en el grupo 2, respectivamente), aunque nose observaron diferencias significativas entre los dos grupos. No encontramos diferenciasrespecto al control tensional. En ninguno de los dos grupos encontramos undescenso significativo del filtrado glomerular, sin embargo, éste fue mayor en elgrupo tratado con EICA (2,98 ± 7,77 vs 1,64 ± 6,84 ml/min/año) aunque sin diferenciasignificativa respecto a irbesartán, mientras que tres pacientes inicialmentetratados con IECA mostraron intolerancia (tos). Como conclusión, en nuestro estudioirbesartán mostró un efecto antiproteinúrico y nefroprotector similar a los IECAen pacientes con glomerulonefritis crónica, siendo además segura su administración

This randomized, prospective, two-arm clinical study evaluated the antiproteinuricand nephroprotective effects and the safety of treatment with an angiotensin II receptorantagonist (irbesartan) in patients with cronic glomerulonephritis (CGN) ascompared to angiotensin-converting enzyme inhibitors (ACEIs). A total of 50 patientswith CGN diagnosed by renal biopsy and protein levels in 24-hour urine higherthan 1 g were enrolled. All patients received treatment for at least 24 months, 27 in group 1 (irbesartan) and 23 in group 2 (ACEs). A significant decrease in proteinuria(p < 0.001) was seen in both groups (49.2% in group, 1, and 44.8% in group 2)since the third month, and confirmed at 12 and 24 months of follow-up (58.1% and62.7% in group 1, and 56.8% and 55.4% in group 2, respectively), with no significantdifferences being seen between the two groups. No differences were found inblood pressure control. No significant decrease was found in any of the groups inthe glomerular filtration rate, but this showed higher values in the group treated withACEIs (2.98 ± 7.77 vs 1.64 ± 6.84 ml/min/year), though the difference with irbersartanwas not statistically significant. No side effects occurred among patients treatedwith irbesartan, whereas three patients initially treated with ACEIs showed intolerance(cough). In conclusion, irbesartan showed in our study an antiproteinuric andnephroprotective effect similar to ACEIs in patients with chronic glomerulonephritis,and its administration was also shown to be safe

Farmacogenética del sistema de la angiotensina en la nefropatía no diabética / Pharmacogenetics of angiotensin system in non diabetic nephropathy

Antecedentes: La variación genética podría contribuir a la respuesta farmacológica en los pacientes con nefropatía. Así, entre los pacientes con albuminuria diabética aquellos con el genotipo DD para el gen de la enzima convertidora de la angiotensina (ECA, polimorfismo inserción/delección, I/D) tendrían una menor respuesta renoprotectora ante los inhibidores de la ECA, comparados con los pacientes con genotipo II. Métodos: Estudiamos 71 pacientes con nefropatía crónica no diabética, de los cuales 37 habían sido tratados con losartán y 34 con amlodipino. Determinamos la tensión arterial y la proteinuria antes y después de ser tratados, y los valores medios se compararon estadísticamente. Todos los pacientes fueron genotipados para los polimorfismos I/D de la ECA, 1166 A/C del receptor de tipo 1 de la angiotensina I (AGTR1), y M235T del angiotensinógeno (AGT), y los valores medios de la reducción de la tensión sanguínea y la proteinuria fueron comparados entre los genotipos. Resultados: No hallamos diferencias en la reducción de la presión sanguínea diastólica o sistólica entre los diferentes genotipos de los polimorfismos de la ECA y el AGT, tanto para los pacientes tratados con losartán como con amlodipino. En los pacientes tratados con losartán hubo una reducción significativa de la presión diastólica entre aquellos con genotipo AGTR1-AA comparados con los heterocigotos AC (p = 0,0024). No hallamos diferencias en el nivel de reducción de la proteinuria entre los diferentes genotipos, tanto entre los tratados con losartán como con amlodipino. Conclusiones: De acuerdo con nuestros resultados, los valores medios de reducción de la presión sanguínea en los pacientes con nefropatía no diabética y tratados con losartán o amlodipino serían similares entre los diferentes genotipos de la ECA y el AGT. Aunque nuestro estudio se basó en un número reducido de pacientes, el genotipo AGTR1-AA podría estar asociado con una mayor reducción de la presión diastólica entre los pacientes tratados con losartán

Background: Genetic variability could contribute to the response to pharmacological treatment in patients with nephropathy. In albuminuric diabetic patients the renoprotective effect of angiotensin I-converting enzyme (ACE) inhibition should be lower among homozygotes for the deletion allele (DD) compared to II-homozygotes. Methods: A total of 71 non-diabetic chronic nephropathy patients were treated with losartan (n = 37) or amlodipine (n = 34). Blood pressure and proteinuria were determined before and after the treatment, and changes in the mean values were statistically compared. Patients were genotyped for the ACE-I/D, angiotensin I receptor type 1 (AGTR1)-1166 A/C, and angiotensinogen (AGT)-M235T polymorphims, and the reduction of blood pressure and proteinuria between the different genotypes were compared. Results: The reduction in systolic or diastolic blood pressure was not found to be different between the ACE-I/D or AGT-M/T genotypes in patients treated with losartan or amlodipine. In patients treated with losartan, we found a signiticantly higher reduction of diastolic blood pressure in AGTR1-AA patients compared to AC patients (p = 0,0024). We did not find differences in proteinuria-reduction between the different genotypes in patients treated with losartan or amlodipine. Conclusions: Our data show that the effects of losartan and amlodipine on the absolute mean reduction of blood pressure and proteinuria in non-diabetic nephropathy patients are similar between the different ACE or AGT genotypes. Although based on a small number of patients, the AGTR1-AA genotype was associated with a significantly higher reduction in diastolic blood pressure among losartan-treated patients. Additional studies are necessary to refute or confirm this association

Sistema renina angiotensina en la nefropatía diabética / Renin-angiotensin system in diabetic nephropathy

La importancia atribuida al SRA en el desarrollo y progresión de la nefropatíadiabética se confirma con las evidencias recientes que demuestran que se puedeprevenir el desarrollo de nefropatía en los pacientes diabéticos mediante la intervenciónterapéutica con bloqueantes del SRA. Por ello, es necesaria la promociónde programas preventivos para la detección de microalbuminuria, desde las fasestempranas de la diabetes, que deben de incluir un adecuado control tensional,glucémico y lipídico. Si se detecta microalbuminuria, la administración de un bloqueantedel SRA, aún en presencia de cifras tensionales clásicamente consideradascomo normales puede prevenir la progresión a nefropatía diabética

The importance of the renin angiotensin system (RAS) in the development andprogression of the diabetic nephropathy is confirmed with the recent demonstrationthat the development of nephropathy in the diabetic patients can be avoidedby blockers of the RAS. For that reason, the promotion of preventive programsfor the detection of microalbuminuria, from the early phases of thediabetes is needed. Control of blood pressure, of glucose and lipids are needed.If microalbuminuria is present, the administration of a blocker of RAS, even inthe presence of normal blood pressure can prevent the progression to diabeticnephropathy. The main objective to prevent the development and progressionof nephropathy in the diabetic patients, as well as the cardiovascular risk, is astrict control of the PA

Clinical and experimental aspects of olmesartan medoxomil, a new angiotensin II receptor antagonist.

Olmesartan medoxomil is a new orally active angiotensin II (Ang II) type 1 receptor antagonist. It is a prodrug and is rapidly de-esterified during absorption to form olmesartan, the active metabolite. Olmesartan is a potent, competitive and selective Ang II type 1 receptor antagonist. Olmesartan is not metabolized by the cytochrome P-450 and has a dual route of elimination, by kidneys and liver. In patients with essential hypertension olmesartan medoxomil administered once daily at doses of 10-80 mg dose-dependently reduced diastolic blood pressure (DBP). Troughto-peak ratios for both DBP and systolic blood pressure (SBP) were above 50%. At the recommended once-daily starting doses, olmesartan medoxomil (20 mg) was more effective than losartan (50 mg), valsartan (80 mg) or irbesartan (150 mg) in reducing cuff DBP in patients with essential hypertension. The results of cuff SBP and mean 24-h DBP and SBP were similar to those of cuff DBP measurement. In mild-to-moderate hypertensive patients the recommended starting dose of olmesartan medoxomil was as effective as that of amlodipine besylate (5 mg/day) in reducing both cuff and 24-h blood pressure. In lowering DBP olmesartan medoxomil, at 10-20 mg/day, was as effective as atenolol at 50-100 mg/day. In mild-to-moderate hypertensive patients, olmesartan medoxomil, at 5-20 mg once daily, was more effective than captopril at 12.5-50 mg twice daily. At 20-40 mg once daily olmesartan medoxomil was as effective as felodipine, at 5-10 mg once daily. Olmesartan medoxomil has minimal adverse effects with no clinically important drug interactions. Animal studies have shown that olmesartan medoxomil provides a wide range of organ protection. Olmesartan medoxomil ameliorated atherosclerosis in hyperlipidemic animals and ameliorated cardiac remodeling and improved survival in rats with myocardial infarction. Olmesartan medoxomil has renoprotective effects in a remnant kidney model and type 2 diabetes models. Future investigation should reveal whether these beneficial effects of olmesartan medoxomil are applicable to human diseases.

Angiotensin II type 2 receptor gene transfer elicits cardioprotective effects in an angiotensin II infusion rat model of hypertension.

The role of the angiotensin II type 2 receptor (AT2R) in cardiovascular physiology remains elusive. We have developed an in vivo lentiviral vector-mediated gene transfer system to study the physiological functions of the AT2R. Our objectives in this study were to determine whether the AT2R influences cardiac hypertrophy and myocardial and perivascular fibrosis in a nongenetic rat model of hypertension. Lentiviral vector containing the AT2R or saline was injected intracardially in 5-day-old Sprague-Dawley rats. This resulted in a persistent overexpression of the AT2R in cardiac tissues. At 15 wk of age, animals were infused with either 200 ng x kg(-1) x min(-1) of angiotensin II or saline by implantation of a 4-wk osmotic minipump. This resulted in an increase in blood pressure (BP) that reached maximal by 2 wk of treatment and was associated with a 123% increase in left ventricular wall thickness (LVWT) and a 129% increase in heart weight to body weight ratios (HW/BW). In addition, the increase in cardiac hypertrophy was associated with a 300% and 158% increase in myocardial and perivascular fibrosis, respectively. Cardiac transduction of the AT2R resulted in an 85% attenuation of LVWT, 91% attenuation of HW/BW, and a 43% decrease in myocardial fibrosis induced by angiotensin infusion. These improvements in cardiac pathology were observed in the absence of attenuation of high BP. Thus our observations indicate that long-term expression of the AT2R in the heart attenuates cardiac hypertrophy and fibrosis in a nongenetic rat model of hypertension.

Is the angiotensin II Type 2 receptor cerebroprotective?

Most of the deleterious effects of angiotensin II (Ang II) on blood pressure (BP), cardiovascular remodeling, and atherosclerosis are mediated by Ang II type 1 (AT1)-receptor activation. This explains why Ang-II-decreasing or blocking drugs have been successful in decreasing global cardiovascular morbimortality in patients with cardiac complications. However, in primary or secondary stroke prevention trials in patients with low cardiac risk, b-blockers and angiotensin-converting enzyme inhibitors (ACEIs), which decrease Ang II formation, seem to be less protective than thiazides and dihydropyridines, which increase Ang II. When compared with a beta-blocker, an Ang II-increasing AT1-receptor blocker better protects against stroke but not against cardiac events, whereas an ACEI gives the same protection against both cardiac and cerebral events. This dissociation between blood-pressure-independent cardiac and cerebral protection between b-blockers or ACEIs versus AT1-blockers in patients with low cardiac risk can be best explained if, besides the beneficial vascular effect of AT1-receptor blunting, there is evidence of a beneficial effect of non-AT1-receptor activation. In this review, we present experimental evidence for AT2- and AT4-receptor-mediated brain-anti-ischemic mechanisms and propose a direct comparison of AT1-blockers with ACEIs to prove the clinical effectiveness of non-AT1-mediated mechanisms in stroke prevention, particularly in patients with a higher risk for stroke than for cardiac complications.

Elevación de la presión de pulso. ¿Marcador de riesgo u objetivo terapéutico? / Elevated pulse pressure: risk marker or therapeutic target?

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