Renin-Angiotensin System Modulation With Synthetic Angiotensin (1-7) and Angiotensin II Type 1 Receptor-Biased Ligand in Adults With COVID-19: Two Randomized Clinical Trials.

Importance: Preclinical models suggest dysregulation of the renin-angiotensin system (RAS) caused by SARS-CoV-2 infection may increase the relative activity of angiotensin II compared with angiotensin (1-7) and may be an important contributor to COVID-19 pathophysiology. Objective: To evaluate the efficacy and safety of RAS modulation using 2 investigational RAS agents, TXA-127 (synthetic angiotensin [1-7]) and TRV-027 (an angiotensin II type 1 receptor-biased ligand), that are hypothesized to potentiate the action of angiotensin (1-7) and mitigate the action of the angiotensin II. Design, Setting, and Participants: Two randomized clinical trials including adults hospitalized with acute COVID-19 and new-onset hypoxemia were conducted at 35 sites in the US between July 22, 2021, and April 20, 2022; last follow-up visit: July 26, 2022. Interventions: A 0.5-mg/kg intravenous infusion of TXA-127 once daily for 5 days or placebo. A 12-mg/h continuous intravenous infusion of TRV-027 for 5 days or placebo. Main Outcomes and Measures: The primary outcome was oxygen-free days, an ordinal outcome that classifies a patient's status at day 28 based on mortality and duration of supplemental oxygen use; an adjusted odds ratio (OR) greater than 1.0 indicated superiority of the RAS agent vs placebo. A key secondary outcome was 28-day all-cause mortality. Safety outcomes included allergic reaction, new kidney replacement therapy, and hypotension. Results: Both trials met prespecified early stopping criteria for a low probability of efficacy. Of 343 patients in the TXA-127 trial (226 [65.9%] aged 31-64 years, 200 [58.3%] men, 225 [65.6%] White, and 274 [79.9%] not Hispanic), 170 received TXA-127 and 173 received placebo. Of 290 patients in the TRV-027 trial (199 [68.6%] aged 31-64 years, 168 [57.9%] men, 195 [67.2%] White, and 225 [77.6%] not Hispanic), 145 received TRV-027 and 145 received placebo. Compared with placebo, both TXA-127 (unadjusted mean difference, -2.3 [95% CrI, -4.8 to 0.2]; adjusted OR, 0.88 [95% CrI, 0.59 to 1.30]) and TRV-027 (unadjusted mean difference, -2.4 [95% CrI, -5.1 to 0.3]; adjusted OR, 0.74 [95% CrI, 0.48 to 1.13]) resulted in no difference in oxygen-free days. In the TXA-127 trial, 28-day all-cause mortality occurred in 22 of 163 patients (13.5%) in the TXA-127 group vs 22 of 166 patients (13.3%) in the placebo group (adjusted OR, 0.83 [95% CrI, 0.41 to 1.66]). In the TRV-027 trial, 28-day all-cause mortality occurred in 29 of 141 patients (20.6%) in the TRV-027 group vs 18 of 140 patients (12.9%) in the placebo group (adjusted OR, 1.52 [95% CrI, 0.75 to 3.08]). The frequency of the safety outcomes was similar with either TXA-127 or TRV-027 vs placebo. Conclusions and Relevance: In adults with severe COVID-19, RAS modulation (TXA-127 or TRV-027) did not improve oxygen-free days vs placebo. These results do not support the hypotheses that pharmacological interventions that selectively block the angiotensin II type 1 receptor or increase angiotensin (1-7) improve outcomes for patients with severe COVID-19. Trial Registration: ClinicalTrials.gov Identifier: NCT04924660.

Role of angiotensin receptor blockers in the context of Alzheimer's disease.

As the world's population ages, the prevalence of age-related neurological disorders such as Alzheimer's disease (AD) is increasing. There is currently no treatment for Alzheimer's disease, and the few approved medications have a low success rate in lowering symptoms. As a result, several attempts are underway worldwide to identify new targets for the therapy of Alzheimer's disease. In preclinical studies of Alzheimer's disease, it was recently found that inhibition of angiotensin-converting enzyme (ACE) and blocking of the angiotensin II receptors reduce symptoms of neurodegeneration, Aß plaque development, and tau hyperphosphorylation. Angiotensin II type I (AT1) blockers, such as telmisartan, candesartan, valsartan, and others, have a wide safety margin and are commonly used to treat hypertension. Renal and cardiovascular failures are reduced due to their vascular protective actions. Inhibition of AT1 receptors in the brain has a neuroprotective impact in humans, reducing the risk of stroke, increasing cognition, and slowing the progression of Alzheimer's disease. The review focuses on the mechanisms via which AT1 blockers may act beneficially in Alzheimer's disease. Although their effect is evident in preclinical studies, clinical trials, on the other hand, are in short supply to validate the strategy. More dose-response experiments with possible AT1 blockers and brain-targeted administration will be needed in the future.

Angiotensin II Type I Receptor Agonistic Autoantibody Induces Podocyte Injury via Activation of the TRPC6- Calcium/Calcineurin Pathway in Pre-Eclampsia.

BACKGROUND/AIMS: Angiotensin II type I receptor agonistic autoantibody (AT1-AA) is closely related to pre-eclampsia, which is characterized by proteinuria and hypertension. AT1-AA has been shown to enhance the effect of AngII in pre-eclampsia, such as production of endothelin-1, activation of ROS, and vasoconstriction, which are considered to be associated with hypertension; however, whether or not AT1-AA participates in podocyte damage leading to the generation of proteinuria has not been reported. In this study we investigated the role of pre-eclamptic serum AT1-AA on podocytes and the mechanism underlying the generation of proteinuria. METHODS: The levels of AT1-AA isolated from pre-eclamptic sera were determined by an enzyme-linked immunosorbent assay. Human podocytes were cultured in vitro and treated with various concentrations of AT1-AA. Whether or not an ERK1/2 inhibitor and TRPC6 siRNA inhibit the effect of AT1-AA on podocytes was determined. Western blot was used to detect the expression of podocyte-specific proteins (nephrin, synaptopodin, and podocin) and the phosphorylation of ERK1/2 and TRPC6. The arrangement of F-actin was observed by immunofluorescence. A Calcineurin Cellular Activity Assay Kit was used to detect calcineurin activity. Changes in the intracellular Ca2+ concentration was determined by confocal laser. RESULTS: AT1-AA induced a decrease in podocyte-specific protein expression and calcineurin activity and increased expression of p-ERK1/2 and TRPC6 protein and the intracellular Ca2+ concentration. Immunofluorescence revealed rearrangement of F-actin. PD98059, an inhibitor of ERK1/2, and TRPC6 siRNA attenuated the decreased expression of podocyte-specific proteins and decreased intracellular Ca2+ concentration. The expression of TRPC6 was reduced following the addition of ERK1/2 inhibitor. CONCLUSION: AT1-AA induced podocyte damage in a dose-dependent manner. The underlying mechanism might involve activation of the TRPC6 -calcium/calcineurin pathway. This study provides new details regarding podocyte injury and the mechanism underlying the generation of proteinuria in pre-eclampsia.

Plasminogen activator inhibitor-1 and angiotensin converting enzyme gene polymorphisms in Turkish asthmatic children

Background: Polymorphisms of plasminogen activator inhibitor-1 (PAI-1) and angiotensin-converting enzyme (ACE) genes have been implicated in susceptibility to asthma. In this study, we aimed to investigate whether there was any association between childhood asthma and polymorphisms of the PAI-1 and ACE genes. Methods: Two hundred and three Turkish children aged 5–15 years, including 102 asthmatic patients and 101 healthy control subjects were included in this study. The asthma group was divided into two groups as follows: Group I: Asthmatic children with positive family history for atopy (n=53), Group II: Asthmatic children without any family history for atopy (n=49). One hundred and twenty-eight atopic family members were also included in the study. The insertion/deletion (I/D) polymorphism of the ACE and PAI-1 4G/5G gene polymorphisms was carried out by polymerase chain reaction. Results: The prevalence of the PAI-1 4G allele was significantly greater in asthmatic children compared to control group (p<0.05, OR: 1.64 (1.11–2.43)) but there was no significant relation between ACE I/D genotypes and childhood asthma. No significant difference was detected between Groups I and II in terms of these ACE and PAI-1 genotypes and allele frequencies. No significant relationship was found between both gene polymorphisms and total serum IgE and skin prick test results. Conclusion: It has been established that PAI-1 4G allele may be a genetic risk factor for childhood asthma but ACE gene I/D polymorphisms do not play a role in the development of asthma in the sample of Turkish children(AU)

Telmisartan plus propranolol improves liver fibrosis and bile duct proliferation in the PSC-like Abcb4-/- mouse model.

BACKGROUND: Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease leading to cirrhosis and cholangiocellular carcinoma. Inhibitors of the renin-angiotensin system or the sympathetic nervous system delay liver fibrogenesis in animal models. AIMS: We investigated the antifibrotic potential of telmisartan, an angiotensin II type 1 receptor antagonist, and the ß-adrenoceptor blocker propranolol in the PSC-like Abcb4 knockout mouse model. METHODS: Sixty-five Abcb4 (-/-) mice were treated with telmisartan for 3 or 5 months (T) and with telmisartan plus propranolol for 3, 5, or 8 months (TP), or for 2 or 5 months starting with a delay of 3 months (TP delayed). Liver hydroxyproline content, inflammation, fibrosis, and bile duct proliferation were assessed; fibrosis-related molecules were analyzed by real-time polymerase chain reaction and Western blotting. RESULTS: Compared to controls, telmisartan monotherapy had no significant influence on hydroxyproline; however, telmisartan plus propranolol reduced hydroxyproline (TP 3 months, p = 0.008), fibrosis score (TP 3 months and TP 8 months, p = 0.043 and p = 0.008, respectively; TP delayed 8 months, p < 0.0005), bile duct proliferation (TP 8 months and TP delayed 8 months, p = 0.006 and p < 0.0005, respectively), and procollagen α1(I), endothelin-1, TIMP-1 and MMP3 mRNA as well as α-SMA, CK-19, and TIMP-1 protein. CONCLUSIONS: Telmisartan plus propranolol reduces liver fibrosis and bile duct proliferation in the PSC-like Abcb4 (-/-) mouse model, even when started at late stages of fibrosis, and may thus represent a novel therapeutic option for cholestatic liver diseases such as PSC.

Effect of experimental hyperglycaemia on renal haemodynamics in prediabetic patients with and without AT1 receptor blockade.

BACKGROUND AND OBJECTIVES: To prevent diabetic nephropathy, knowledge about early renal impairment caused by a disturbed glucose homoeostasis is essential. The purpose of our study was to investigate haemodynamic changes of the kidney in subjects with impaired glucose tolerance (prediabetics, IGT) during experimental hyperglycaemia and the effect of angiotensin receptor blockade. DESIGN: In our prospective case control study, we measured renal haemodynamics in 13 non-albuminuric males with normal kidney function and IGT (diagnosed by an oral glucose tolerance test, OGTT) and in 13 matched controls with a normoglycemic response in the OGTT. Glomerular filtration rate (GFR) was assessed by determination of sinistrin clearance; renal plasma flow (RPF) by para-aminohippuric acid clearance. All measurements were performed at rest and during hyperglycaemic stress testing (clamp technique; target blood glucose approximately 170 mg dL(-1)). We examined renal effects of valsartan (4 weeks 160 mg day(-1)) at rest and during experimental hyperglycaemia. Metabolic (glycosylated haemoglobin, adiponectin) and inflammatory (high sensitive C-reactive protein) parameters were compared with and without valsartan in both groups. RESULTS: During experimental hyperglycaemia, GFR and RPF decreased significantly more in prediabetics compared with controls. Under valsartan, the hyperglycaemia induced decrease of GFR and RPF was blunted in part by valsartan. Hs-CRP and HbA1c were significantly higher in prediabetics when compared with controls and improved both under valsartan. Adiponectin was lower in prediabetics and increased significantly under valsartan. CONCLUSIONS: Hyperglycaemia induces impairments of renal haemodynamics as well as inflammatory and metabolic parameters in subjects with impaired glucose tolerance, which improve under valsartan.

[Individual renal hemodynamic response to chronic angiotensin II receptor blockade and the influence on the renin-angiotensin system gene polymorphisms].

INTRODUCTION: Our study was aimed at determining whether the polymorphism of genes for different components of the renin-angiotensin-aldosterone system could influence the renal hemodynamic response to losartan treatment. MATERIAL AND METHOD: The study included 35 patients with type I diabetes mellitus and persistent albuminuria, genotyped for the 1166 A/C polymorphism gene for the angiotensin II type 1 receptor and I/D polymorphism of the angiotensin-converting enzyme gene. The participants were divided into groups according to the combinations of A or C allele: AA, AC, CC; and according to the combinations of I or D allele: II, ID and DD genotype. The patients received losartan therapy for 12 weeks. The renal hemodynamic measurements were determined at baseline and after the examination period. RESULTS: Losartan therapy significantly reduced the filtration fraction from the baseline by 0.018 +/- 0.024 (p = 0.012) only in the AC genotype. The glomerular filtration rate remained unchanged in all genotype groups. A significant increase in the effective renal plasma flow was obtained only in AC genotype (544 +/- 88 vs 575 +/- 90 ml/min; p = 0.02), while significant reductions in the renal vascular resistance were found in AA group (115 +/- 25 vs 95 +/- 21 mmHg x l(-1) x min(-1), p = 0.001) and in AC group (118 +/- 30 vs 101 +/- 28 mmHg x l(-1) x min(-1); p = 0.001). A significant reduction of the glomerular filtration rate by 8 +/- 10 ml/min was obtained only in the DD genotype (p = 0.016), and only the DD genotype achieved a significant reduction of the filtration fraction by 0.019 +/- 0,022 (p = 0.008). The most pronounced increase of the effective renal plasma flow was found only in the ID genotype (536 +/- 75 vs 591 +/- 63 ml/min; p = 0.01). The reduction of the renal vascular resistance was independent of ACE gene polymorphism. CONCLUSION: Our study shows that individual renal vascular response to losartan treatment in diabetic patients with persistent albuminuria, could be influenced by genetic polymorphisms.

The evolving story of the RAAS in hypertension, diabetes and CV disease: moving from macrovascular to microvascular targets.

The phylogenetically old renin-angiotensin-system (RAS) was originally described as a circulating hormonal system and a main cardiovascular regulator. However, there also exist 'local RASs' which are situated in cardiovascular as well as non-cardiovascular tissues where they are involved in physiological and patho-physiological processes such as inflammation, fibrosis, proliferation or apoptosis. Local RASs are activated in diabetes, preferentially in organs affected by hyperglycaemic injury such as the kidney or the retina. Increased renal or retinal Ang II levels may contribute to diabetic tissue injury in two ways: (i) by stimulating the angiotensin AT1-receptor and downstream pathological chains of events and (ii) by bidirectional interaction with the 'classical' hyperglycaemia-induced pathobiochemical pathways (oxidative stress, generation of advanced glycation end products, increased polyol pathway flux, activation of protein kinase C, increased hexosamine pathway flux). The involvement of the RAS in the pathomechanisms underlying diabetic end organ damage suggests pharmacological RAS inhibition as a therapeutic approach in these disorders. This assumption has been supported by numerous animal studies. Clinically, RAS inhibition is currently the first line, guideline-approved treatment in diabetic nephropathy. The recently published DIRECT, RASS and AdRem studies provided evidence that RAS inhibition may also be beneficial in diabetic retinopathy; however, evidence for RAS-inhibition in retinopathy is still much weaker than for nephropathy. The present article reviews the emerging knowledge about cardiovascular and non-cardiovascular effects of the RAS with an emphasis on the mechanisms of RAS involvement and pharmacological RAS inhibition in diabetic end organ damage.

Bloqueo neurohormonal al alta en pacientes con insuficiencia cardiaca / Neurohormonal blockade in patients with heart failure at discharge from hospital

Con el objetivo de valorar el grado de cumplimiento del tratamiento farmacológico en pacientes con ICC se diseñó el estudio de adherencia terapéutica en insuficiencia cardiaca (ATICA). Durante el periodo de inclusión se han obtenido datos demográficos, sociales, educacionales, antecedentes personales, exploración física y analítica de los pacientes. Estos datos mencionados son los que se reflejan en el presente estudio piloto. El total de pacientes incluidos es de 586, la mayoría de los cuales son mujeres, la edad media es avanzada y presentan una fracción de eyección conservada en más de la mitad. Respecto al esquema terapéutico únicamente se recogió información de grupos con acción neurohormonal y de reconocimiento en el tratamiento de la ICC. El grupo farmacológico más utilizado son los IECA, sin embargo fármacos como la espirolactona o los BB, siguen mostrando un grado de infrautilización preocupante, aunque presentan una prescripción mayor que en otras series

With the objective to value the degree of fulfillment of the pharmacological processing in patients with heart failure was designed the study of therapeutic adherence in heart failure (ATICA). During the period of inclusion educational, social, demographic data have been obtained, personal antecedents, analytic and physical exploration of the patients. These data mentioned are the ones that are reflected in the present pilot study. The total of patients included is 554, the majority of which are women, the middle ages is advanced and they present a fraction of eyección conserved in more than the half. In the therapeutic plan only was collected information of groups with neurohormonal action and of great recognition in the processing of the heart failure. The most utilized pharmacological group are the IECA, nevertheless medicines as the espirolactona or the betablocker continue showing a worrying degree of infrautilización, although they present a greater prescription that in other series

Angiotensin II-mediated calcium signals and mitogenesis in human prostate stromal cell line hPCPs.

Western blots and immunocytochemistry were used to detect angiotensin 1 (AT(1)) and angiotensin 2 (AT(2)) receptors in human primary cultures of the prostate stromal compartment (hPCPs). Immunohistochemistry was performed on human prostate tissue-embedded paraffin. In addition, pharmacological tools were applied in combination with photometry experiments to characterize the physiological activity of AT(1) and AT(2) receptors in hPCPs cell culture. A proliferation assay was used to describe the mitogenic activity of angiotensin II (Ang II) on hPCPs cells. Only the AT(1) receptor was detected in Western blot analysis. Immunocytochemistry of hPCPs cells showed that the AT(1) receptor is present in both the smooth muscle type and the fibroblastic type. In the stromal compartment of human prostate tissue, immunoreaction with antibodies against the AT(1) receptor was detectable.Fura-2-loaded hPCPs cells showed an instantaneous and linear rise in free intracellular calcium ion concentration ([Ca(2+)](i)) after local perfusion with Ang II in concentrations of 10 nM. Removing of external calcium or emptying intracellular calcium stores before Ang II application diminished or abolished this [Ca(2+)](i) response. The response to Ang II was also diminished when hPCPs cells were perfused with the AT(1) receptor inhibitor losartan prior to Ang II application. No inhibition of the [Ca(2+)](i) increase was detectable after perfusion with PD 123319, a specific inhibitor of the AT(2) receptor.hPCPs cells were stimulated with Ang II in various concentrations over a period of 2 days. The subsequently performed proliferation assay revealed a mitogenic effect of Ang II on hPCPs in concentrations starting at 10 nM. This effect could be inhibited by losartan.

Stroke prevention with the angiotensin II type 1-receptor blocker candesartan in elderly patients with isolated systolic hypertension: the Study on Cognition and Prognosis in the Elderly (SCOPE).

OBJECTIVES: The aim of this study was to test the hypothesis that the angiotensin II type 1 receptor blocker (ARB) candesartan can reduce the risk of stroke in elderly patients with isolated systolic hypertension (ISH). BACKGROUND: Isolated systolic hypertension is the predominant form of hypertension in the elderly, and stroke is the most common cardiovascular (CV) complication. METHODS: In the Study on Cognition and Prognosis in the Elderly (SCOPE), 4,964 patients age 70 to 89 years were randomly assigned to double-blind candesartan or placebo with open-label antihypertensive therapy (mostly thiazide diuretics) added as needed to control blood pressure. Of the 4,964 patients, 1,518 had ISH (systolic blood pressure >160 mm Hg and diastolic blood pressure <90 mm Hg). The present study is a predefined subgroup analysis of outcome results in the ISH patients. RESULTS: Of the ISH patients, 754 were randomized to the candesartan group and 764 to the control group. Over the study period, blood pressure was reduced by 22/6 mm Hg in the candesartan group and by 20/5 mm Hg in the control group (difference between treatments 2/1 mm Hg; p = 0.101 and 0.064). A total of 20 fatal/non-fatal strokes occurred in the candesartan group (7.2/1,000 patient-years) and 35 in the control group (12.5/1,000 patient-years); relative risk (RR) was 0.58 (95% confidence interval 0.33 to 1.00), that is, a RR reduction of 42% (p = 0.050 unadjusted, p = 0.049 adjusted for baseline risk). There were no marked or statistically significant differences between the treatment groups in other CV end points or all-cause mortality. CONCLUSIONS: In elderly patients with ISH, antihypertensive treatment based on the ARB candesartan resulted in a significant 42% RR reduction in stroke in comparison with other antihypertensive treatment, despite little difference in blood pressure reduction.

Eprosartan effect on fibrinolytic/hemostatic variables in arterial hypertension: a comparative study to losartan.

Essential hypertension is often accompanied by abnormalities of the coagulation/fibrinolytic system predisposing to a procoagulant state. The aim of the present study was to examine the comparative efficacy of the angiotensin II type 1 receptor antagonists eprosartan and losartan on plasma levels of hemostatic/fibrinolytic and endothelial function markers in a cohort of previously untreated hypertensive patients. A total of 86 patients whose hypertension was controlled by monotherapy with eprosartan 600 mg (45 patients) or losartan 100 mg (41 patients) were studied. The plasma levels of plasminogen activator inhibitor-1 (PAI-1) antigen, tissue plasminogen activator inhibitor (tPA) antigen, thrombomodulin (TM), tissue factor pathway inhibitor (TFPI) antigen, and fibrinogen were determined before and after 6 months of therapy. Age, sex distribution, body mass index, lipid profile, systolic and diastolic blood pressure levels, and baseline values of the measured markers were similar in both groups. After 6 months of therapy, systolic blood pressure was significantly lower in patients treated with eprosartan, while no differences were observed with respect to diastolic blood pressure. Treatment with both drugs was associated with a significant decrease in PAI-1 antigen, TM, fibrinogen plasma levels and an increase in tPA antigen. The favorable modification of all the above parameters was significantly greater in the eprosartan than in the losartan group, while TFPI plasma levels were decreased to a similar extent with both drugs. In conclusion, the results of our study indicate that 6-month monotherapy with a new angiotensin II type 1 receptor blocker, eprosartan, is associated with a more favorable modification of hemostatic/fibrinolytic status than with losartan.

Cerebrovascular protection and antihypertensive therapy.

PURPOSE OF REVIEW: Our aim is to review the association between blood pressure and stroke and analyse data from randomized controlled trials involving diverse therapies, especially those regarding the renin-angiotensin system. In addition, an overview of stroke pathogenesis is given and its relationship with treatment action mechanisms reviewed. RECENT FINDINGS: Stroke is a leading cause of death worldwide. In addition, many survivors of stroke suffer different degrees of disability. Because of the ageing of the global population, especially in regions of rapid economic growth, stroke will remain the second leading cause of death and in terms of disability it will be among the five most important causes in both developing and developed countries. High blood pressure is the most important risk factor for stroke, either ischemic or haemorrhagic, and established hypertension is the most prevalent modifiable risk factor. Data from controlled trials of blood-pressure-lowering treatment have demonstrated that treatment considerably lowers the risk of stroke within a few years of starting treatment. However, there exists controversy about the most efficient treatment regimen for primary and secondary prevention of stroke among the different blood-pressure-lowering treatments. SUMMARY: Debate rages as to whether the benefits of treating high blood pressure are simply determined by the quality of blood-pressure control, or whether the choice of drug therapy adds or detracts from the expected benefits of blood-pressure reduction. The desirable future interventional comparative studies should consent to determine specific effects of drug classes on cardiovascular risk in the absence of the confounding effect of a relevant blood-pressure reduction that may counteract the potential blood-pressure-independent benefits of specific drug classes.

Effects of angiotensin II and insulin on ERK1/2 activation in fibroblasts from hypertensive patients.

BACKGROUND: Insulin resistance, a frequent finding in hypertensive patients, leads to accelerated cardiovascular damage. It has been suggested that a crosstalk between angiotensin II and insulin signaling pathways may provoke insulin resistance, and may contribute to the development of cardiovascular damage. To identify a common pathophysiologic pathway between metabolic disorders and cardiovascular remodeling, we investigated the effect of angiotensin II and insulin on extracellular signal regulated kinases 1 and 2 (ERK1/2), isoforms of mitogen-activated protein kinases (MAPK) involved in cellular proliferation and extracellular matrix deposition. METHODS: Skin fibroblasts from normotensive subjects, insulin sensitive hypertensive subjects, and insulin resistant hypertensive subjects were cultured and used after four passages. The ERK1/2 expression and phosphorylation were measured by Western blot using specific antibodies, respectively anti-ERK1/2 and anti-pERK1/2. Expression of AT1 receptor for angiotensin II was determined by reverse transcriptase-polymerase chain reaction in real time. RESULTS: The ERK1/2 were similarly expressed in skin fibroblasts from all groups; ERK1/2 phosporylation evoked by angiotensin II was significantly higher in fibroblasts from hypertensive patients in comparison to normotensive subjects, but the increase was observed only in insulin resistant hypertensive subjects. The effect of insulin on ERK1/2 phosphorylation was not significantly different in the three groups. Treatment with the combination of insulin and angiotensin II increased ERK1/2 phosphorylation to a greater extent in comparison to the single agonists in normotensive subjects and in insulin sensitive but not in insulin resistant hypertensive subjects. CONCLUSIONS: Angiotensin II stimulated ERK1/2 activation is increased in insulin resistant hypertensive subjects, and it may play a role in the pathogenesis of insulin resistance and accelerated cardiovascular damage.

Challenges in improving prognosis and therapy: the Ongoing Telmisartan Alone and in Combination with Ramipril Global End point Trial programme.

Hypertension is one of the most important modifiable risk factors for cardiovascular pathology, such as atherosclerosis and cardiac left ventricular hypertrophy, including acute events such as stroke and myocardial infarction (MI). In particular, the risk of ischaemic and haemorrhagic stroke is directly and continuously related to high blood pressure levels. The renin-angiotensin system (RAS) plays an important role in volume homeostasis and blood pressure regulation. It also helps to prevent cell and organ damage from ischaemia during acute volume loss. However, angiotensin-II (A-II)--the main effector peptide of the RAS--also exerts a number of pathological effects, which are mediated by the AT 1 receptor. The Ongoing Telmisartan Alone and in Combination with Ramipril Global End point Trial (ONTARGET) programme consists of two parallel trials where ONTARGET as a large, long-term study compares the efficacy of the angiotensin-receptor antagonist, telmisartan, the renin-angiotensin-converting enzyme (ACE) inhibitor, ramipril and combination therapy with telmisartan plus ramipril for reducing cardiovascular and cerebral risk. Telmisartan, due to its long duration of action, compares favourably with other angiotensin-receptor antagonists. In the Heart Outcomes Prevention Evaluation (HOPE) study, ramipril was shown to reduce the risk for MI and other cardiovascular events in patients at high risk for pathological cardiac events, but without heart failure or a low ejection fraction. The cardiovascular outcomes of high-risk patients using the same criteria as those of the HOPE study will be assessed in both trials. TRANSCEND differs from ONTARGET in that this trial will enrol patients who do not tolerate ACE inhibitors. This parallel study will therefore be able to compare telmisartan and placebo treatment. Both ONTARGET and TRANSCEND trials feature the same primary composite end point: death caused by cardiovascular disease, acute MI, stroke and hospitalisation because of congestive heart failure. The secondary end points will focus on reductions in the development of Type 2 diabetes mellitus, nephropathy, cognitive decrease and dementia as well as atrial fibrillation.

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.