AT1 Receptor Blocker Research Articles

Distinct Mechanisms of β-Arrestin-Biased Agonist and Blocker of AT1R in Preventing Aortic Aneurysm and Associated Mortality.

Aortic aneurysm (AA) is a "silent killer" human disease with no effective treatment. Although the therapeutic potential of various pharmacological agents have been evaluated, there are no reports of β-arrestin-biased AT1R (angiotensin-II type-1 receptor) agonist (TRV027) used to prevent the progression of AA. We tested the hypothesis that TRV027 infusion in AngII (angiotensin II)-induced mouse model of AA prevents AA. High-fat-diet-fed ApoE (apolipoprotein E gene)-null mice were infused with AngII to induce AA and co-infused with TRV027 and a clinically used AT1R blocker Olmesartan to prevent AA. Aortas explanted from different ligand infusion groups were compared with assess different grades of AA or lack of AA. AngII produced AA in ≈67% male mice with significant mortality associated with AA rupture. We observed ≈13% mortality due to aortic arch dissection without aneurysm in male mice. AngII-induced AA and mortality was prevented by co-infusion of TRV027 or Olmesartan, but through different mechanisms. In TRV027 co-infused mice aortic wall thickness, elastin content, new DNA, and protein synthesis were higher than untreated and Olmesartan co-infused mice. Co-infusion with both TRV027 and Olmesartan prevented endoplasmic reticulum stress, fibrosis, and vasomotor hyper responsiveness. TRV027-engaged AT1R prevented AA and associated mortality by distinct molecular mechanisms compared with the AT1R blocker, Olmesartan. Developing novel β-arrestin-biased AT1R ligands may yield promising drugs to combat AA.

Losartan attenuates sepsis-induced cardiomyopathy by regulating macrophage polarization via TLR4-mediated NF-κB and MAPK signaling

Sepsis-induced cardiomyopathy (SIC) is a serious complication of sepsis with high mortality but no effective treatment. The renin angiotensin (Ang) aldosterone system (RAAS) is activated in patients with sepsis but it is unclear how the Ang II/Ang II type 1 receptor (AT1R) axis contributes to SIC. This study examined the link between the Ang II/AT1R axis and SIC as well as the protective effect of AT1R blockers (ARBs). The Ang II level in peripheral plasma and AT1R expression on monocytes were significantly higher in patients with SIC compared with those in non-SIC patients and healthy controls and were correlated with the degree of myocardial injury. The ARB losartan reduced the infiltration of neutrophils, monocytes, and macrophages into the heart and spleen of SIC mice. Additionally, losartan regulated macrophage polarization from the M1 to the M2 subtype via nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways, thereby maintaining the mitochondrial dynamics balance in cardiomyocytes and reducing oxidative stress and cardiomyocyte apoptosis. In conclusion, the plasma Ang II level and AT1R expression on plasma monocytes are an important biomarker in SIC. Therapeutic targeting of AT1R, for example with losartan, can potentially protect against myocardial injury in SIC.

Angiotensin receptor blocker use is associated with upregulation of the memory-protective angiotensin type 4 receptor (AT4R) in the postmortem brains of individuals without cognitive impairment.

The reported primary dementia-protective benefits of angiotensin II type 1 receptor (AT1R) blockers (ARB) are believed, at least in part, to arise from systemic effects on blood pressure. However, there is a specific and independently regulated brain renin-angiotensin system (RAS). Brain RAS acts mainly through three receptor subtypes; AT1R, AT2R, and AT4R. The AT1R promotes inflammation and mitochondrial reactive oxygen species generation. AT2R increases nitric oxide. AT4R is essential for dopamine and acetylcholine release. It is unknown whether ARB use is associated with changes in the brain RAS. Here, we compared the impact of treatment with ARB on not cognitively impaired individuals and individuals with Alzheimer's dementia using postmortem frontal-cortex samples of age- and sex-matched participants (70-90years old, n = 30 in each group). We show that ARB use is associated with higher brain AT4R, lower oxidative stress, and amyloid-β burden in NCI participants. In AD, ARB use was associated with lower brain AT1R but had no impact on inflammation, oxidative stress, or amyloid-β burden. Our results may suggest a potential role for AT4R in the salutary effects for ARB on the brains of not cognitively impaired older adults.

Nature-inspired delivery of mitochondria-targeted angiotensin receptor blocker.

Mitochondria are critical regulators of cellular function and survival. We have previously demonstrated that functional angiotensin receptors embedded within the inner mitochondrial membrane modulate mitochondrial energy production and free radical generation. The expression of mitochondrial angiotensin II type-1 receptors increases during aging, with a complementary decrease in angiotensin II type-2 receptor density. To address this age-associated mitochondrial dysfunction, we have developed a mitochondria-targeted delivery system to effectively transport angiotensin type-1 receptor blocker—Losartan (mtLOS) into the inner mitochondrial membrane. We engineered mtLOS to become active within the mitochondria after cleavage by mitochondrial peptidases. Our data demonstrate effective and targeted delivery of mtLOS into the mitochondria, compared to a free Losartan, or Losartan conjugated to a scrambled mitochondrial target signal peptide, with significant shifts in mitochondrial membrane potential upon mtLOS treatment. Furthermore, engineered mitochondrial-targeting modalities could open new avenues to transport nonmitochondrial proteins into the mitochondria, such as other macromolecules and therapeutic agents.

SARS-CoV-2 triggers pericyte-mediated cerebral capillary constriction.

The SARS-CoV-2 receptor, ACE2, is found on pericytes, contractile cells enwrapping capillaries that regulate brain, heart and kidney blood flow. ACE2 converts vasoconstricting angiotensin II into vasodilating angiotensin-(1-7). In brain slices from hamster, which has an ACE2 sequence similar to human ACE2, angiotensin II evoked a small pericyte-mediated capillary constriction via AT1 receptors, but evoked a large constriction when the SARS-CoV-2 receptor binding domain (RBD, original Wuhan variant) was present. A mutated non-binding RBD did not potentiate constriction. A similar RBD-potentiated capillary constriction occurred in human cortical slices, and was evoked in hamster brain slices by pseudotyped virions expressing SARS-CoV-2 spike protein. This constriction reflects an RBD-induced decrease in the conversion of angiotensin II to angiotensin-(1-7) mediated by removal of ACE2 from the cell surface membrane, and was mimicked by blocking ACE2. The clinically-used drug losartan inhibited the RBD-potentiated constriction. Thus, AT1 receptor blockers could be protective in Covid-19 by preventing pericyte-mediated blood flow reductions in the brain, and perhaps the heart and kidney.

G Protein-Coupled Receptors-Receptors With New Tricks Up Their Sleeves.

G Protein-Coupled Receptors-Receptors With New Tricks Up Their Sleeves.

Pleiotropic activation of endothelial function by angiotensin II receptor blockers is crucial to their protective anti-vascular remodeling effects

There are no therapeutics that directly enhance chronic endothelial nitric oxide (NO) release, which is typically associated with vascular homeostasis. In contrast, angiotensin II (AngII) receptor type 1 (AT1R) blockers (ARBs) can attenuate AngII-mediated oxidative stress, which often leads to increased endothelial NO bioavailability. Herein, we investigate the potential presence of direct, AngII/AT1R-independent ARB class effects on endothelial NO release and how this may result in enhanced aortic wall homeostasis and endothelial NO-specific transcriptome changes. Treatment of mice with four different ARBs induced sustained, long-term inhibition of vascular contractility by up to 82% at 16 weeks and 63% at 2 weeks, an effect reversed by L-NAME and absent in endothelial NO synthase (eNOS) KO mice or angiotensin converting enzyme inhibitor captopril-treated animals. In absence of AngII or in tissues with blunted AT1R expression or incubated with an AT2R blocker, telmisartan reduced vascular tone, supporting AngII/AT1R-independent pleiotropism. Finally, telmisartan was able to inhibit aging- and Marfan syndrome (MFS)-associated aortic root widening in NO-sensitive, BP-independent fashions, and correct aberrant TGF-β signaling. RNAseq analyses of aortic tissues identified early eNOS-specific transcriptome reprogramming of the aortic wall in response to telmisartan. This study suggests that ARBs are capable of major class effects on vasodilatory NO release in fashions that may not involve blockade of the AngII/AT1R pathway. Broader prophylactic use of ARBs along with identification of non-AngII/AT1R pathways activated by telmisartan should be investigated.

Candesartan Effectively Preserves Cognition in Senescence Accelerated Mouse Prone 8 (SAMP8) mice.

Background:Alzheimer’s disease (AD) has become a worldwide crisis with no effective therapeutic options. The medications currently available for AD are only palliative; their effect is temporary, and they are associated with unfavorable side effects. Even the newest medication aducanumab, granted accelerated FDA approval in 2021, failed to show cognitive benefits in clinical trials and continued approval requires verification in subsequent clinical trials. There is an urgent need for safe and effective therapies to preserve cognition and effectively manage AD. Generally, a new drug product takes several years for FDA approval and exceeds 2.5 billion dollars in research and development, with most new drug products never even reaching the market. This has led to a recent shift for repurposing/repositioning existing FDA-approved medications, to new therapeutic indications.Objective:To investigate the effects of long-term treatment with candesartan, an FDA-approved angiotensin-II type-1 receptor blocker (ARB), on the development of cognitive impairment associated with premature aging.Methods:Candesartan was given at a dose of 1 mg/kg/d in an AD model of senescence-accelerated mouse prone-8 (SAMP8) and senescence-accelerated mouse resistant (SAMR1) mice. Oral treatment with candesartan or vehicle was started, in 2-month-old mice and administered continuously for 4-months.Results:Low-dose candesartan prevented the development of cognitive impairment, otherwise associated with accelerated aging, in SAMP8 mice, by reducing inflammation and nitro-oxidative stress. Candesartan did not affect the cognitive function of control SAMR1 mice.Conclusion:Early ARB treatment might be beneficial in preventing age-related cognitive deficits in AD-prone individuals.

INHIBITION OF RAS COMPONENTS ATTENUATES PROGRESSION OF MYOCARDIAL REMODELING IN BOTH NORMOTENSIVE AND HYPERTENSIVE RATS IN EXPERIMENTAL HEART FAILURE

Objective: New findings in the pathogenesis of heart failure (HF) with a focus on extracellular matrix (ECM) and communication in the heart are still relevant for more effective treatment. We focused on signaling pathways involved in cardiac structural remodeling in HF due to pressure and volume overload, as well as on investigating the efficacy of substances with possible antifibrotic potential. Design and method: We used as experimental model 28-week-old hypertensive (TGR) and normotensive (HSD) rats with created aortocaval fistula (ACF), supplemented with ACE inhibitor (ACEi) (Trandolapril, 15 weeks, 6 mg/L) and AT1 receptor blocker (ARB) (Losartan, 15 weeks, 200 mg/L). Results: Echocardiography confirmed an increase in cardiac output and a decrease in ejection fraction in both strains of rats. BW was higher in TGR vs HSD and it was not affected by VO. ACF-induced cardiac volume overload, elevated markers of heart failure and oxidative damage, ANP, BNP-45, and TBARS, were elevated in the blood serum of both strains. ACF induced profibrotic signaling by increasing TGF-, and mRNA collagen I, and collagen I protein expression in the left and right ventricles of HSD rats. In TGR rats ACF decreased TGF- and SMAD2 protein expression in the right ventricle similar to HSD rats, in which ACF also suppressed MMP-2 protein expression. Heart failure affected protein kinase signaling by reducing the protein expression of PKC, PKG, and in part, PKC in both chambers of the heart of both strains. ACF decreased the protein expression of Cx43 and its phosphorylated form, which is significantly proarrhythmic. Hypertension in TGR rats increased mRNA TGF- expression and collagen I, but decreased PKC and PKC protein expression and increased PKC. Conclusions: A notable finding was that the signaling pathways involved in cardiac remodeling were more normalized by the ARB, while proteins involved in intercellular communication, ACEi. The results of analyzes of both experiments indicate attenuated responses of the signaling pathways monitored by us in the heart of hypertensive strains reflecting adaptation to primarily induced pathophysiology. Scientific Grant Agency of the Ministry of Education, Science, Research and Sport of the Slovak Republic VEGA 2/0158/19, 2/0002/20

PERMISSIVE ROLE OF ANGIOTENSIN II IN MANTENANCE OF ENDOTHELIUM-DEPENDENT VASODILATION IN CEREBRAL MICROCIRCULATION

Objective: A number of data suggest, rather controversial, permissive role of angiotensin II (ANGII) in maintaining vasodilator responses in microcirculation, via its interaction with AT1 receptors (AT1R). This study aimed to determine the role of ANGII and AT1R in the mechanisms of flow-induced dilation (FID) in middle cerebral arteries (MCA) and incidence of oxidative stress at the functional, cellular and molecular level in the cerebral vasculature and in the serum of Sprague-Dawley (SD) rats fed high salt diet (HS). Design and method: Eleven-week old, male SD rats were randomly assigned to control group (CTRL, 0.4% NaCl in rat chow); Losartan group (rats on a standard diet given the AT1R blocker losartan (1 mg/mL) in drinking water); HS group (7 days 4% NaCl in rat chow) or HS+ANGII group (7 days HS with 3 days ANGII administration via osmotic minipumps (100 ng/kg/min on days 4–7)). FID of MCA was determined in absence/presence of the NOS inhibitor L-NAME, the non-selective cyclooxygenases inhibitor indomethacin, and the superoxide dismutase mimetic TEMPOL. Gene and protein expression of antioxidative enzymes and enzymes involved in FID mechanisms were determined by RT-qPCR and western blot. Vascular NO and superoxide/ROS levels were assessed by direct fluorescence. Serum systemic oxidative stress parameters was measured by spectrophotometry. All experimental procedures conformed to the EU Directive 2010/63/EU. Results: HS or AT1R blockade impaired FID and increased oxidative stress. Supplementation of ANGII restored the mechanisms of FID in MCA of rats fed HS diet to the ones present in CTRL rats without affecting arterial blood pressure by decreasing systemic oxidative stress and decreasing superoxide/ROS levels and increased NO bioavailability in the vascular wall of HS treated rats. The AT1R blockade resulted in significantly attenuated endothelium-dependent dilation, changed mechanisms of FID, increased vascular and systemic oxidative stress and decreased expression/ activity of antioxidative enzymes. Conclusions: ANGII is crucial in the preservation of vascular oxidative stress-antioxidant system balance and via AT1R, in maintenance of physiological vasodilation mechanisms of MCA. Suppression of ANGII is a key link between HS intake and development of endothelial dysfunction, and impaired regulation of cerebral blood flow.

Impact of renin-angiotensin-aldosterone system inhibitors on COVID-19.

Since the onset of the coronavirus disease 2019 (COVID-19) pandemic, the possible roles of renin–angiotensin system (RAS) inhibitors in COVID-19 have been debated as favorable, harmful, or neutral. Angiotensin-converting enzyme 2 (ACE2) not only is the entry route of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection but also triggers a major mechanism of COVID-19 aggravation by promoting tissue RAS dysregulation, which induces a hyperinflammatory state in several organs, leading to lung injury, hematological alterations, and immunological dysregulation. ACE inhibitors and angiotensin II type-1 receptor blockers (ARBs) inhibit the detrimental hyperactivation of the RAS by SARS-CoV-2 and increase the expression of ACE2, which is a counter-regulator of the RAS. Several studies have investigated the beneficial profile of RAS inhibitors in COVID-19; however, this finding remains unclear. Further prospective studies are warranted to confirm the role of RAS inhibitors in COVID-19. In this review, we summarize the potential effects of RAS inhibitors that have come to light thus far and review the impact of RAS inhibitors on COVID-19.

Abstract 543: Inhibition Of Renin-angiotensin System Failed To Suppress Beta-aminopropionitrile-induced Thoracic Aortopathies In Mice

Objective: Cross-linking of elastin and collagen fibers is a vital process in aortic development. Pharmacological inhibition of aortic cross-linking by β-aminopropionitrile (BAPN) leads to thoracic aortopathies, such as thoracic aortic aneurysm and dissection, in mice. Although the renin angiotensin system (RAS) contributes to several types of thoracic aortopathies, it remains unclear whether inhibition of the RAS protects against aortopathy formation caused by the impairment of elastin and collagen cross-linking in mice. Approach and Results: Either vehicle or losartan (15 mg/kg/d, AT1 receptor blocker) were administered through osmotic pumps for 4 weeks in male C57BL/6J mice (3-4-weeks-old, n=30/group). BAPN (0.5% wt/vol) was given through drinking water to induce aortopathies. Losartan increased plasma renin concentrations significantly compared to vehicle-infused mice, indicating effective blockade of at1 receptors. However, losartan did not suppress BAPN-induced aortic rupture and dilatation. Since losartan is a surmountable inhibitor, we also tested the effects of irbesartan, an insurmountable inhibitor of AT1 receptor blocker, on BAPN-induced aortopathy formation (50 mg/kg/day, diet, n=30/group). Despite the significant increase of plasma renin concentrations, irbesartan did not ameliorate aortic rupture and dilatation in BAPN-administered mice. Thus, BAPN-induced thoracic aortopathies were refractory to angiotensin receptor blockade. We next inhibited angiotensinogen, the unique substrate for angiotensin II, using an antisense oligonucleotide targeting angiotensinogen (AGT-ASO). AGT-ASO decreased plasma angiotensinogen concentrations, while aortic death and dilatations were not attenuated. Since hepatocytes are the major source of angiotensinogen, BAPN-induced thoracic aortopathy formation was also examined in mice with hepatocyte-specific angiotensinogen deletion. Although plasma angiotensinogen concentrations displayed 90% reduction compared to wild type littermates, aortic rupture and aneurysm formation were not suppressed. Conclusion: Inhibition of the RAS does not attenuate BAPN-induced thoracic aortopathy formation in mice.

Characterization of cerebral arteries function and structure in a mouse model of Marfan syndrome: effects of exercise and Losartan treatment

Marfan syndrome (MFS) is a connective tissue disorder caused by mutations in the fibrillin‐1 (FBN1) gene. This mutation manifests in a variety of phenotypic changes in the musculoskeletal, cardiovascular, and pulmonary systems, with a notable vascular effect leading to aortic aneurysm, dissection, and rupture. This results in a significant increase in morbidity and mortality in these patients. Studies have shown that there is a connection between MFS and intracranial aneurysms (IA). The prevalence of IA in patients with aortic disease is quadrupled compared to that in the general population. There is a modestly increased prevalence of ischemic stroke in hospitalized patients with MFS when compared with healthy controls. The reduced cerebral blood flow triggered by cardiac and peripheral vascular dysfunction could further make the brain more vulnerable to vascular dementia and Alzheimer’s pathology. Studies have found that 50% school‐age children with MFS had one or more neuropsychologic deficits. Despite the reported neurological complications in MFS patients, our understanding of cerebrovascular function and structure in MFS is very limited. Losartan, an AT1R blocker has shown positive effects on slowing the progression of aortic root aneurysm in the well‐established mouse model of MFS (Fbn1 +/‐ p. Cys1041Gly). Alternatively, the cardiovascular benefits of moderate exercise training have been well documented in the literature. In addition, studies have shown that aerobic exercise can improve cognitive function, decrease neuropsychiatric and neurodegenerative symptoms. In this study we aim to investigate the impact of MFS pathogenesis and Losartan treatment and mild aerobic exercise on other vessels such as the posterior cerebral artery, coronary and pulmonary arteries.At 4 weeks of age, male and female mice were divided into experimental groups: control (Ctrl), MFS, MFS + Losartan, MFS + exercise. MFS mice received 0.6 g/L of Losartan in drinking water or subjected to an exercise regimen of 8m/min, 30min/day, 5days/week. At 6 months of age, in vivo ultrasound imaging was performed to measure aortic pulse wave velocity (PWV), and peak blood flow of the coronary, pulmonary and posterior cerebral arteries. Blood pressure (BP) measurements were also taken using the tail‐cuff method.Our results showed that PWV, an index of aortic stiffness is increased in MFS mice compared to Ctrl, while Losartan and exercise reduced the PWV in MFS mice bringing it back to the values of healthy Ctrl. The posterior cerebral artery peak blood flow was significantly reduced in MFS and MFS + Losartan groups compared to Ctrl. No significant difference was observed in the MFS + exercise group compared to Ctrl. The coronary and pulmonary peak blood flow showed no significant change between MFS and control groups and MFS and intervention groups. There was also no statistical significance in the systolic and diastolic BP between the groups.This study provides an early insight into the disease progression of MFS as well as investigates the preliminary potential effects of Losartan and exercise on peak blood flow in coronary, pulmonary and cerebral arteries in the well‐established MFS mouse model.

Genetic Evidence for A Critical Role of Intratubular Angiotensin II AT1aReceptors in The Proximal Tubules of The Kidney in Two‐Kidney, One‐Clip Goldblatt Hypertension in PT‐Agtr1a‐/‐Mice

It was previously reported the activation of the renin‐angiotensin system (RAS) in the clipped kidney plays a critical role in the development of two‐kidney, one‐clip Goldblatt hypertension (2K1C). However, most of previous studies used the global angiotensin II (Ang II) type 1a (AT1a) receptor (Agtr1a‐/‐) knockout model or used systemic AT1receptor blockers (ARB) to determine renal mechanisms of 2K1C hypertension. The roles of intratubular AT1 (AT1a) receptors or its downstream target Na+/H+ exchanger 3 (NHE3) in the proximal tubules in the development of 2K1C hypertension has not been determined previously. In the present study, we tested the hypothesis that genetic deletion of AT1 (AT1a) receptors selectively in the proximal tubules attenuates the development of 2K1C hypertension via AT1 (AT1a) receptor‐mediated, Na+/H+ exchanger 3 (NHE3)‐dependent mechanisms. To test the hypothesis, 2K1C Goldblatt hypertension was induced by placing a silver clip, 0.12 mm internal diameter, on the left renal artery for 4 weeks in adult male wild‐type (WT), global Agtr1a‐/‐, proximal tubule (PT)‐specific PT‐Agtr1a‐/‐, or PT‐Nhe3‐/‐ (Na+/H+ exchanger 3) mice, respectively. As expected, systolic blood pressure increased in a time‐dependent manner in wild‐type mice, reaching a maximal response by Week 3 (Basal: 112 ± 2 vs. 2K1C: 149 ± 4 mmHg, n=12, P<0.01). 2K1C hypertension in WT mice was associated with increases in renin mRNA expression in the clipped kidney (Control: 2066 ± 255 vs. Clipped: 3144 ± 569 copies/ng RNA, P<0.01), and decreases in renin mRNA expression in the nonclipped right kidney (1738 ± 341 copies/ng RNA, P<0.05). Plasma Ang II levels were significantly increased in WT mice with 2K1C hypertension (Control: 50.2 ± 7.2 vs. 2K1C: 109.7 ± 17.2 pg/ml, P<0.05). Glomerular and tubulointerstitial fibrotic responses were also significantly increased in the clipped kidney (P<0.01). By comparisons, the development of 2K1C hypertension was entirely prevented in Agtr1a‐/‐ (Basal: 88 ± 4 vs. 2K1C: 92 ± 2 mmHg, n=9, n.s.), or significantly attenuated in PT‐Agtr1a‐/‐ mice (Basal: 101 ± 2 vs. 2K1C: 104 ± 4 mmHg, n=12, n.s.) or in PT‐Nhe3‐/‐ mice (Basal: 103 ± 3 vs. 109 ± 5 mmHg, n.s.). Renin mRNA expression was not different in clipped and nonclipped kidney of Agtr1a‐/‐ mice, but it was decreased in the nonclipped kidney of PT‐Agtr1a‐/‐ mice (P<0.05). Furthermore, glomerular and tubulointerstitial fibrotic responses were also markedly attenuated in the clipped kidney in PT‐Agtr1a‐/‐ mice (P<0.05). We conclude that the results of the present study provide strong evidence for a critical role of AT1a receptors and NHE3 in the proximal tubules of the kidney in the development of 2K1C Goldblatt hypertension in mice.

Losartan Mitigates Oxidative Stress in the Brains of Aged and Inflamed IL-10-/- Mice.

Chronic inflammation, oxidative stress, and dysregulation of the renin-angiotensin system are closely linked, and their crosstalk commonly contributes to age-related physical and cognitive decline. The primary dementia-protective benefits of Angiotensin II type 1 receptor (AT1R) blockers are believed to arise from systemic effects on blood pressure. However, there is an independently regulated brain-specific renin-angiotensin system. Here, we examined the impact of 4 weeks of oral Losartan treatment on the brains of aged (100 weeks old) IL-10-/- mice, an animal model of chronic inflammation and frailty. Our data show that aged IL-10-/- mice have higher AT1R and Nitrotyrosine (oxidative stress marker) levels in their frontal cortex tissue but not in cerebellar or hippocampal tissue compared to age- and sex-matched wild type mice. Losartan treatment for 4 weeks is associated with lower AT1R protein level, Nitrotyrosine, and Tau protein in the frontal cortex of aged IL-10-/- mice. Our results highlight the impact of Losartan, an AT1R blocker commonly prescribed for treating high blood pressure, on the brain-specific angiotensin system and AT1R-linked downstream effects such as brain oxidative stress damage and Tau burden in a frailty mouse model.

Telmisartan: An angiotensin receptor blocker regulates osteoclastogenesis via inhibition of the ERK triggering in osteoporotic male rats.

Great attention was recently given to the importance of RAS in controlling inflammatory bone diseases, following the discovery of its local existence in skeletal tissues. Local RAS was found to be expressed on osteoblastic and osteoclastic cells and to exert its action via angiotensin II (AngII) receptors, including angiotensin II type 1 receptor (AT1 R) and angiotensin II type 2 receptors. Telmisartan (TLM), an AT1 R blocker (ARBs), was investigated in the present study for its therapeutic effect on bone health in osteoporotic rats. d-Galactose, a reducing sugar at a dose of 200 mg/kg/day/i.p., was used to induce osteoporosis in male rats. TLM, at a dose of 5mg/kg/day, was orally introduced in the osteoporotic rats for four consecutive weeks. Tibia and femur bone densitometry was estimated, bone formation and bone resorption biomarkers serum levels were measured, mineral content in blood was also valued, and finally the extracellular regulated kinase (ERK) expression in bone was determined. TLM considerably improved the deleterious effect of d-galactose on bone mineral density. It blunted serum bone-specific alkaline phosphatase and osteocalcin while elevating serum osteoprotegrin (OPG). On the other hand, TLM turned off the pronounced elevation in serum receptor activator of nuclear factor-κβ ligand (RANKL), tartrate-resistant acid phosphatase, and cathepsin K. Furthermore, it significantly hindered the bone expression of ERK which hampered osteoclastogenesis. AT1 R inhibition abolished the rise in serum calcium and phosphorus and normalized serum superoxide dismutase and catalase. These TLM protective effects in d-galactose-treated rats were confirmed by the histopathological examination. The results all together denote the potential therapeutic value of ARBs therapy in osteoporosis.

An Updated Review On Analytical Methods For Estimation Of Azelnidipine And Telmisartan

High blood pressure, also called hypertension, is a common condition that is characterized by having a higher amount of pressure in blood vessels than normal. Hypertension (HT) is a very common disorder, particularly past middle age. It is not a disease in itself, but is an important risk factor for cardiovascular mortality and morbidity. For improvement activity of hypertension, Azelnidipine and Telmisartan newer combination in market, which is effective in Hypertension. This combination was developed to improve medication for Stage II Hypertension. Azelnidipine is Ca2+ channel blocker and chemically 3-[1-(Benzyldrylazetidin-3-yl] 5-isopropyl- 2- amino 6 methyl-4-(3-nitrophenyl)-1,4- dihydropyridine-3, 5dicarboxylate.Telmisartan is AT1-receptor blocker and Chemically2-{4-[[4-methyl-6-(1-methylbenzimidazol-2yl)-2–propylbenzimidazol-1yl] methyl] biphenyl)-benzoic acid. It provides information about different analytical method development like UV spectrophotometry, HPTLC, HPLC, and LC-MS methods reported for Azelnidipine and Telmisartan for individual and other drug combination. All reported methods found to be simple, accurate, economic, precise and reproducible in nature. This Review focuses on recent development in analytical method development for Azelnidipine and Telmisartan, and there were two methods reported for this combination as per our knowledge.

Angiotensin II Promotes Skeletal Muscle Angiogenesis Induced by Volume-Dependent Aerobic Exercise Training: Effects on miRNAs-27a/b and Oxidant-Antioxidant Balance.

Aerobic exercise training (ET) produces beneficial adaptations in skeletal muscles, including angiogenesis. The renin–angiotensin system (RAS) is highly involved in angiogenesis stimuli. However, the molecular mechanisms underlying capillary growth in skeletal muscle induced by aerobic ET are not completely understood. This study aimed to investigate the effects of volume-dependent aerobic ET on skeletal muscle angiogenesis involving the expression of miRNAs-27a and 27b on RAS and oxidant–antioxidant balance. Eight-week-old female Wistar rats were divided into three groups: sedentary control (SC), trained protocol 1 (P1), and trained protocol 2 (P2). P1 consisted of 60 min/day of swimming, 5×/week, for 10 weeks. P2 consisted of the same protocol as P1 until the 8th week, but in the 9th week, rats trained 2×/day, and in the 10th week, trained 3×/day. Angiogenesis and molecular analyses were performed in soleus muscle samples. Furthermore, to establish ET-induced angiogenesis through RAS, animals were treated with an AT1 receptor blocker (losartan). Aerobic ET promoted higher VO2 peak and exercise tolerance values. In contrast, miRNA-27a and -27b levels were reduced in both trained groups, compared with the SC group. This was in parallel with an increase in the ACE1/Ang II/VEGF axis, which led to a higher capillary-to-fiber ratio. Moreover, aerobic ET induced an antioxidant profile increasing skeletal muscle SOD2 and catalase gene expression, which was accompanied by high nitrite levels and reduced nitrotyrosine concentrations in the circulation. Additionally, losartan treatment partially re-established the miRNAs expression and the capillary-to-fiber ratio in the trained groups. In summary, aerobic ET promoted angiogenesis through the miRNA-27a/b–ACE1/Ang II/VEGF axis and improved the redox balance. Losartan treatment demonstrates the participation of RAS in ET-induced vascular growth. miRNAs and RAS components are promising potential targets to modulate angiogenesis for combating vascular diseases, as well as potential biomarkers to monitor training interventions and physical performance.

Drugs Modulating Renin-Angiotensin System in COVID-19 Treatment.

A massive worldwide vaccination campaign constitutes the main tool against the COVID-19 pandemic. However, drug treatments are also necessary. Antivirals are the most frequently considered treatments. However, strategies targeting mechanisms involved in disease aggravation may also be effective. A major role of the tissue renin-angiotensin system (RAS) in the pathophysiology and severity of COVID-19 has been suggested. The main link between RAS and COVID-19 is angiotensin-converting enzyme 2 (ACE2), a central RAS component and the primary binding site for SARS-CoV-2 that facilitates the virus entry into host cells. An initial suggestion that the susceptibility to infection and disease severity may be enhanced by angiotensin type-1 receptor blockers (ARBs) and ACE inhibitors (ACEIs) because they increase ACE2 levels, led to the consideration of discontinuing treatments in thousands of patients. More recent experimental and clinical data indicate that ACEIs and, particularly, ARBs can be beneficial for COVID-19 outcome, both by reducing inflammatory responses and by triggering mechanisms (such as ADAM17 inhibition) counteracting viral entry. Strategies directly activating RAS anti-inflammatory components such as soluble ACE2, Angiotensin 1-7 analogues, and Mas or AT2 receptor agonists may also be beneficial. However, while ACEIs and ARBs are cheap and widely used, the second type of strategies are currently under study.

Effects and Safety of Allisartan Isoproxil Combined With Amlodipine or Indapamide in Patients With Hypertension Who Failed Allisartan Monotherapy

Abstract Background To primarily evaluate the effects and safety of a selective angiotensin II type 1 (AT1) receptor blocker (ARB) allisartan isoproxil combined with amlodipine or indapamide in the treatment of patients with essential hypertension who failed allisartan monotherapy. Methods Patients aged 18–75 years with mild-to-moderate essential hypertension [office systolic blood pressure (SBP) 140 to <180 and/or office diastolic blood pressure (DBP) 90 to <110 mm Hg] in 44 study centers between 2016 and 2018 were recruited. Allisartan isoproxil tablet 240 mg was administered per day for 4 weeks, and continued for 8 weeks if office blood pressure (BP) achieved the target of SBP/DBP <140/90 mm Hg. The nonachievers were 1:1 randomly divided into allisartan isoproxil 240 mg + indapamide sustained-release tablet 1.5 mg, or allisartan isoproxil 240 mg + amlodipine besylate 5 mg groups for further 8 weeks of combined therapy. The BP target achieving rate, reduction of sitting BP from baseline, safety and compliance were evaluated as the primary efficacy endpoint. Results A total of 2,212 patients were enrolled, among them 2,126 patients were included in the efficacy analysis, with an average age of 55.1 ± 10.2 years. A total of 1,463 cases (68.8%) were effective after 4 weeks allisartan treatment, and the mean SBP and DBP were significantly decreased by 14.7 ± 12.2 and 8.0 ± 8.4 mm Hg compared with the baseline levels (all P < 0.001). In nonachievers, allisartan combined with indapamide for 8 weeks significantly lowered the sitting BP (SBP/DBP) by 14.0 ± 12.2/8.3 ± 9.2 mm Hg, respectively, compared with 4 weeks monotherapy with allisartan with a BP targeting rate of 57.7% (169/293). In the allisartan + amlodipine group, the SBP/DBP were significantly decreased by (14.4 ± 12.1/8.2 ± 8.2) mm Hg, respectively, with a BP targeting rate of 62.8% (181/288). There was no statistical significance in BP reduction, targeting rate, or adverse reactions between the 2 combined therapies. Conclusions Allisartan isoproxil combined with indapamide or amlodipine can further improve the BP targeting rate when allisartan monotherapy failed in essential hypertension. The 2 combined therapies have similar efficacy and safety.