Angiotensin AT1 Receptor Blockers Research Articles

Valsartan Mitigates the Progression of Methotrexate-Induced Acute Kidney Injury in Rats via the Attenuation of Renal Inflammation and Oxidative Stress.

Methotrexate (MTX) is a folic acid antagonist, commonly administered for the treatment of a variety of cancers. However, methotrexate toxicity including bone marrow suppression and hepatic and renal toxicity limits its use. Angiotensin AT1 receptor blockers including Valsartan (Val) possess the ability to ameliorate MTX-induced toxicity through various mechanisms. In this study, we explored the potential reno-protective effects of Val against MTX-induced acute kidney injury in rats. Twenty-four Wistar rats were randomly segregated into 3 groups. Group 1 served as the control group and received an oral dose of 1mL/kg of normal saline. Group 2 received a single dose of 20 mg/kg of MTX intraperitoneally (IP) for 5 days. Group 3 received a single IP dose of 20 mg/kg of MTX followed by an oral dose of 10 mg/kg of Valsartan for 5 days. At the end of the experiment, the levels of serum kidney biomarkers, inflammatory and oxidative stress markers were accessed. Furthermore, the effect of MTX on kidney tissue histology was examined. Our results showed that MTX treatment increased the level of serum kidney and inflammatory biomarkers and decreased the level of antioxidants SOD and GSH while increasing the lipid peroxidation contents. Furthermore, MTX treatment caused structural changes to kidney histology. However, the administration of Val significantly prevented these changes. Valsartan possesses nephroprotective potential and might serve as a potential therapeutic strategy against MTX-induced kidney injury.

Telmisartan and losartan: The marked differences between their chemical and pharmacological properties may explain the difference in therapeutic efficacy in hospitalized patients with COVID‐19

Telmisartan and losartan: The marked differences between their chemical and pharmacological properties may explain the difference in therapeutic efficacy in hospitalized patients with COVID‐19

Renin angiotensin system inhibition attenuates adipocyte-breast cancer cell interactions

Obesity is a significant breast cancer (BC) risk factor and is associated with 20–40% increased risk in obese post-menopausal women compared to their lean counterparts. Several obesity-related metabolic dysregulations have been linked to BC risk, including overactivation of the renin-angiotensin system (RAS). Currently, RAS inhibitors including angiotensin converting enzyme inhibitor (ACEi) and AT1 receptor blockers (ARBs), are used as safe and effective anti-hypertensive therapies in BC patients. However, it is uncertain how inhibition of RAS in adipose tissue impacts obesity-BC crosstalk. We hypothesized that adipose RAS inhibition will reduce BC cell motility and inflammation. We determined (1) the direct effects of Ang II, ACEi (captopril; Cap) or ARB (telmisartan; Tel) on receptor positive MCF-7 and receptor triple negative MDA-MB-231 cells; and (2) the effects of conditioned media (CM) from human mesenchymal stem cells differentiated into adipocytes, which were pretreated with RAS inhibitors, on BC cells. We demonstrated that direct treatments of BC cells with Ang II, Cap or Tel did not alter inflammatory cytokines in either BC cell line. However, CM from Ang II-pretreated adipocytes significantly increased secretion of pro-inflammatory markers at protein level. RAS inhibitors reduced their secretion in MDA-MB-231, but not in MCF-7 cells. Additionally, CM from adipocytes treated with RAS inhibitors significantly reduced markers of inflammation, fat synthesis, and angiogenesis in both BC cell lines. Furthermore, CM from ACEi pretreated adipocytes reduced cell motility in both BC cell lines. Findings from our study indicate an important role of adipose RAS inhibition in adipocyte and BC cell crosstalk.

Pregnancy outcome after first trimester use of angiotensin AT1 receptor blockers: an observational cohort study

Ongoing discussion about the safety of renin-angiotensin inhibitors in the first trimester and limited data on pregnancy outcomes after exposure to angiotensin AT1 receptor blockers (ARBs). Observational cohort study compares outcomes of 215 prospectively ascertained pregnancies with first trimester exposure to ARBs with 642 non-hypertensive pregnancies. The rate of major birth defects in the ARB cohort (9/168, 5.4%) was higher than in the comparison group (17/570, 3%), but not significantly increased (ORadj 1.9, 95% CI 0.7-4.9). There was no distinct pattern of anomalies among infants with birth defects. The risk of spontaneous abortions was not increased (HRadj 0.9, 95% CI 0.5-1.6), although the cumulative incidence was in the upper normal range (0.22, 95% CI 0.15-0.32). Higher rates of prematurity (ORadj 3.0; 95% CI 1.7-5.1) and a reduced birth weight after adjustment for sex and gestational age were observed. There was no evidence for an increased risk for major birth defects, spontaneous abortions, or preterm birth in a sensitivity analysis comparing ARB exposed hypertensive women to hypertensive women without ARB exposure during the first trimester. Our study supports the hypothesis that ARBs are not major teratogens. Patients inadvertently exposed to ARBs during the early pregnancy may be reassured. Nevertheless, women planning pregnancy should avoid ARBs. In selected cases, ARBs might be continued under careful monitoring of menstrual cycle and discontinued as soon as pregnancy is recognized.

The benefit of angiotensin AT1 receptor blockers for early treatment of hypertensive patients.

ESC guidelines for management of arterial hypertension allow one to choose among five classes of antihypertensive drugs indiscriminately. They are based on the principle that in the management of hypertensive patients, it is fundamental to reduce blood pressure (BP), independently of the utilized drug. However, it has been demonstrated that the renin-angiotensin system (RAS) plays a relevant role in the hypertensive-derived development and progression of organ damage. Thus, antihypertensive drugs interfering with the RAS should be preferred in preventing and reducing target organ damage. The availability of two classes of drugs, ACE-inhibitors and angiotensin AT1 receptor blockers (ARBs), both interfering with the RAS, makes the choice between them difficult. Both pharmacological strategies offer an effective BP control, and a substantial improvement of prognosis in different associated pathologies. Regarding cardiovascular prevention, ACE-inhibitors have an extensive scientific literature regarding utility in high-risk patients. Nevertheless, there is evidence to support the concept that in the early phases of organ tissue damage, the RAS is activated, but the ACE pathway producing angiotensin II is not always employed. Accordingly, ACE-inhibitors appear to be less effective, whereas ARBs have a greater beneficial action in the initial stages of atherosclerotic disease. Moreover, patients undergoing ARBs therapy show a substantially lower risk of therapy discontinuation when compared to those treated with ACE-inhibitors, because of a better tolerability. In conclusion, ACE-inhibitors should be used in patients who have already developed organ damage, but tolerate this drug well, while ARBs should be the first choice in naïve hypertensive patients without organ damage or at the initial stages of disease.

Combined Angiotensin Receptor Modulation in the Management of Cardio-Metabolic Disorders.

Cardiovascular and metabolic disorders, such as hypertension, insulin resistance, dyslipidemia or obesity are linked with chronic low-grade inflammation and dysregulation of the renin–angiotensin system (RAS). Consequently, RAS inhibition by ACE inhibitors or angiotensin AT1 receptor (AT1R) blockers is the evidence-based standard for cardiovascular risk reduction in high-risk patients, including diabetics with albuminuria. In addition, RAS inhibition reduces the new onset of diabetes mellitus. Yet, the high and increasing prevalence of metabolic disorders, and the high residual risk even in properly treated patients, calls for additional means of pharmacological intervention. In the past decade, the stimulation of the angiotensin AT2 receptor (AT2R) has been shown to reduce inflammation, improve cardiac and vascular remodeling, enhance insulin sensitivity and increase adiponectin production. Therefore, a concept of dual AT1R/AT2R modulation emerges as a putative means for risk reduction in cardio-metabolic diseases. The approach employing simultaneous RAS blockade (AT1R) and RAS stimulation (AT2R) is distinct from previous attempts of double intervention in the RAS by dual blockade. Dual blockade abolishes the AT1R-linked RAS almost completely with subsequent risk of hypotension and hypotension-related events, i.e. syncope or renal dysfunction. Such complications might be especially prominent in patients with renal impairment or patients with isolated systolic hypertension and normal-to-low diastolic blood pressure values. In contrast to dual RAS blockade, the add-on of AT2R stimulation does not exert significant blood pressure effects, but it may complement and enhance the anti-inflammatory and antifibrotic/de-stiffening effects of the AT1R blockade and improve the metabolic profile. Further studies will have to investigate these putative effects in particular for settings in which blood pressure reduction is not primarily desired.

O60. Treatment of hypertension in pregnancy

Several international (2013 ESH/ESC guidelines, AHA/ISH guidelines, JNC-8) and national (NICE, French, Canadian, Hungarian, Chinese) guidelines have been published recently with recommendations for management of hypertension in pregnancy. Data-based opinions onantihypertensive treatment initiation and target blood pressure (BP), and drugs of choice are not similarly described in these guidelines. Main objectives of the presentation are to summarise data of the relevant literature. Review of the recently published guidelines. Treatment initiation: in addition to life-style changes, there is consensus that drug treatment of severe hypertension (⩾160/110 mmHg) in pregnancy is indicated and beneficial. The suggestion, in the 2007 European Society of Hypertension (ESH) and European Society of Cardiology (ESC) Guidelines, for considering treatment in all pregnant women with persistent elevation of BP ⩾150/95 mmHg is supported by recent US data, showing an increasing trend in the rate of pregnancy-related hospitalizations with stroke — especially during the postpartum period — and by an analysis of stroke victims with severe pre-eclampsia and eclampsia. However, the benefits of antihypertensive therapy are uncertain in pregnant women with mildly to moderately elevated blood pressure (⩽160/110 mmHg), either pre-existing or pregnancy-induced, except for a lower risk of developing severe hypertension. Despite lack of evidence, the Task Force of 2013 ESH/ESC Guidelines reconfirms that physicians should consider early initiation of antihypertensive treatment at values of BP ⩾140/90 mmHg in women with (i) gestational hypertension (with or without proteinuria), (ii) pre-existing hypertension with the superimposition of gestational hypertension or (iii) hypertension with asymptomatic organ damage (OD) or symptoms at any time during pregnancy. Target blood pressure: Guidelines mostly agree on that BP should be normalised (to <140/90 mmHg) in pregnant women with hypertension. Drug treatment: Drug treatment can be considered in pregnant women with persistent elevation of BP ⩾150/95 mmHg, and in those with BP ⩾140/90 mmHg in the presence of gestational hypertension, subclinical OD or symptoms due to increased BP. The recommendations to use methyldopa, labetalol and nifedipine as the only calcium antagonist really tested in pregnancy was confirmed in recent European and US guidelines. Beta-blockers (possibly causing foetal growth retardation if given in early pregnancy) anddiuretics (in pre-existing reduction of plasma volume) should be used with caution, only if other indications exist (e.g. ischemic heart disease, severe tachycardia, excess fluid retention). All agents interfering with the renin-angiotensin system (ACE inhibitors, angiotensin AT-1 receptor blockers, renin inhibitors) should absolutely be avoided. In emergency (pre-eclampsia), intravenous labetalol is the drug of choice with sodium nitroprusside (only for short term) or nitroglycerin in intravenous infusion being other options. According to recent guidelines, in the absence of randomised clinical trials recommendations how hypertension should be treated in pregnant women, can only be guided by experts’ opinion based on case reports and their meta-analyses.

Kinin Receptors in Vascular Biology and Pathology

Endogenous kinins are important vasoactive peptides whose effects are mediated by two G-Protein-coupled receptors (R), named B2R (constitutive) and B1R (inducible). They are involved in vascular homeostasis, ischemic pre- and post- conditioning, but also in cardiovascular diseases. They contribute to the therapeutic effects of angiotensin-1 converting enzyme inhibitors (ACEI) and angiotensin AT1 receptor blockers. Benefits derive primarily from vasodilatory, antiproliferative, antihypertrophic, antifibrotic, antithrombic and antioxidant properties, which are associated with the release of endothelial factors such as nitric oxide, prostacyclin and tissue plasminogen activator. Uncontrolled production of kinins or the inhibition of their metabolism may lead to unwanted pro-inflammatory side effects. Thus, B2R antagonism is salutary in angioedema, septic shock, stroke, and Chagas vasculopathy. B1R is virtually absent in healthy tissues, yet this receptor is induced by the cytokine pathway and the oxidative stress via the transcriptional nuclear factor NF-κB. The B1R may play a compensatory role for the lack of B2R, and its up-regulation during tissue damage may be a useful mechanism of host defense. Activation of both receptors may be beneficial, notably in neovascularisation, angiogenesis, heart ischemia and diabetic nephropathy. At the same time, B1R is a potent activator of inducible nitric oxide and NADPH oxidase, which are associated with vascular inflammation, increased permeability, insulin resistance, endothelial dysfunction and diabetic complications. The dual beneficial and deleterious effects of kinin receptors and, particularly B1R, raise an unsettled issue on the therapeutic value of B1R/B2R agonists versus antagonists in cardiovascular diseases. Hence, the Janus-face of kinin receptors needs to be seriously addressed in the upcoming clinical trials for each pathological setting.

Aliskiren Reduces Myocardial Ischemia–Reperfusion Injury by a Bradykinin B 2 Receptor– and Angiotensin AT 2 Receptor–Mediated Mechanism

Angiotensin-converting enzyme inhibitors and angiotensin AT1 receptor blockers reduce myocardial ischemia-reperfusion injury via bradykinin B2 receptor- and angiotensin AT2 receptor-mediated mechanisms. The renin inhibitor aliskiren increases cardiac tissue kallikrein and bradykinin levels. In the present study, we investigated the effect of aliskiren on myocardial ischemia-reperfusion injury and the roles of B2 and AT2 receptors in this effect. Female Sprague-Dawley rats were treated with aliskiren (10 mg/kg per day) and valsartan (30 mg/kg per day), alone or in combination, together with the B2 receptor antagonist icatibant (0.5 mg/kg per day) or the AT2 receptor antagonist PD123319 (30 mg/kg per day), for 4 weeks before myocardial ischemia-reperfusion injury. Aliskiren increased cardiac bradykinin levels and attenuated valsartan-induced increases in plasma angiotensin II levels. In vehicle-treated rats, myocardial infarct size (% area at risk, mean±SEM, n=7-13) was 43±3%. This was reduced to a similar extent by aliskiren, valsartan, and their combination to 24±3%, 25±3%, and 22±2%, respectively. Icatibant reversed the cardioprotective effects of aliskiren and the combination of aliskiren plus valsartan, but not valsartan alone, indicating that valsartan-induced cardioprotection was not mediated by the B2 receptor. PD123319 reversed the cardioprotective effects of aliskiren, valsartan, and the combination of aliskiren plus valsartan. Aliskiren protects the heart from myocardial ischemia-reperfusion injury via a B2 receptor- and AT2 receptor-mediated mechanism, whereas cardioprotection by valsartan is mediated via the AT2 receptor. In addition, aliskiren attenuates valsartan-induced increases in angiotensin II levels, thus preventing AT2 receptor-mediated cardioprotection by valsartan.

An update on telmisartan/hydrochlorothiazide combinations for the management of hypertensive patients with additional cardiovascular risk factors

International hypertension guidelines endorse the use of combination therapy to achieve blood pressure control in the majority of patients. Angiotensin AT1 receptor blockers, in combination with diuretics, are among the preferred combinations, with telmisartan plus hydrochlorothiazide (HCTZ) being an effective and well-tolerated combination. This article provides an up-to-date review of the existing data on telmisartan/HCTZ combination for the management of hypertension in patients with additional cardiovascular risk factors, including reports emerging from a number of recent clinical trials and secondary analyses of older trials. The accumulated evidence from clinical trials demonstrates that telmisartan/HCTZ combinations are effective and well tolerated in patients with mild-to-severe hypertension, including subgroups of patients with cardiovascular risk factors such as advanced age, obesity, chronic kidney disease, diabetes mellitus and treatment-resistant hypertension.

Different cross-talk sites between the renin–angiotensin and the kallikrein–kinin systems

Targeting the renin-angiotensin system (RAS) constitutes a major advance in the treatment of cardiovascular diseases. Evidence indicates that angiotensin-converting enzyme inhibitors and angiotensin AT1 receptor blockers act on both the RAS and the kallikrein-kinin system (KKS). In addition to the interaction between the RAS and KKS at the level of angiotensin-converting enzyme catalyzing both angiotensin II generation and bradykinin degradation, the RAS and KKS also interact at other levels: 1) prolylcarboxypeptidase, an angiotensin II inactivating enzyme and a prekallikrein activator; 2) kallikrein, a kinin-generating and prorenin-activating enzyme; 3) angiotensin-(1-7) exerts kininlike effects and potentiates the effects of bradykinin; and 4) the angiotensin AT1 receptor forms heterodimers with the bradykinin B2 receptor. Moreover, angiotensin II enhances B1 and B2 receptor expression via transcriptional mechanisms. These cross-talks explain why both the RAS and KKS are up-regulated in some circumstances, whereas in other circumstances both systems change in the opposite manner, expressed as an activated RAS and a depressed KKS. As the cross-talks between the RAS and the KKS play an important role in response to different stimuli, taking these cross-talks between the two systems into account may help in the development of drugs targeting the two systems.

Angiotensin AT1–Receptor Blockers Enhance Cardiac Responses to Parasympathetic Nerve Stimulation via Presynaptic AT1 Receptors in Pithed Rats

In the present study, we investigated the effects of angiotensin AT1-receptor blockers, KT3-671 and losartan, on the cardiac vagal neurotransmission in pithed rats. The bradycardia induced by vagal nerve stimulation (VNS, at 5 Hz) was potentiated significantly and dose-dependently by KT3-671 and also losartan. This enhancement effect of KT3-671 (10 mg/kg) was slightly potent than that of losartan (10 mg/kg). On the other hand, an angiotensin AT2-receptor blocker, PD123319 (10 mg/kg), did not affect VNS-induced bradycardia. KT3-671 and losartan did not affect the exogenous acetylcholine-evoked bradycardia. Intravenous infusion of AngII (100 ng/kg per min) attenuated the VNS-induced bradycardia. This inhibitory effect of AngII on bradycardia was restored by both KT3-671 and losartan. These results suggest that endogenous AngII can have a tonic inhibitory effect on cardiac vagal transmission by stimulating the presynaptic AT1 receptors not AT2 receptors. Suppression of this mechanism by the AT1-receptor blockers causes the facilitation of acetylcholine release from vagal nerve endings. This acceleratory effect of AT1-receptor blockers on cardiac vagal neurotransmission may contribute to the lack of reflex tachycardia following hypotension.

Aliskiren vs. other antihypertensive drugs in the treatment of hypertension: a meta-analysis

To investigate the antihypertensive effects and tolerability of aliskiren in comparison with other antihypertensive drugs and placebo in patients with hypertension, a meta-analysis was performed of studies published between 1950 and 2012. A systematic literature search of MEDLINE and the Cochrane Library was conducted for randomized controlled trials. Weighted mean differences and relative risk with 95% confidence intervals were calculated for continuous and dichotomous data, respectively. In all, 14 studies with 6741 participants were included in the present meta-analysis. Nine studies included trial arms with placebo, four included angiotensin (Ang) AT1 receptor blockers (ARBs), three included Ang-converting enzyme inhibitors (ACEIs), two included calcium channel blockers (CCBs), one included a β-blocker, and one included hydrochlorothiazide (HCTZ). We found that aliskiren, which lowered blood pressure (BP) effectively in patients with mild-to-moderate hypertension, was similar to HCTZ but inferior to CCBs in BP reduction, response rates and control rates. Furthermore, aliskiren was superior to ACEIs in lowering diastolic BP (DBP), while it had similar effects to ACEIs on systolic BP (SBP) reduction, response rates and control rates. Additionally, the present meta-analysis showed the superiority of atenolol over aliskiren in DBP reduction and BP response but showed that atenolol was inferior in SBP reduction and BP control. No difference was found in the rates of therapeutic response between aliskiren and ARBs, while more patients achieved BP control with aliskiren. Further studies will be needed to determine the antihypertensive effects and tolerability of aliskiren in comparison with other antihypertensive drugs.

Mechanisms of Fetal and Neonatal Renal Impairment by Pharmacologic Inhibition of Angiotensin

The renin-angiotensin system is highly conserved through evolutionary history, and has multiple functions in addition to maintaining cardiovascular homeostasis: these include the regulation of renal cell survival and cell death, and development of the kidney. The importance of angiotensin (ANG) in normal kidney development was first recognized in infants with renal maldevelopment born to mothers treated with angiotensin converting enzyme (ACE) inhibitors or with ANG AT1 receptor blockers. The molecular role of ANG in renal development has been elucidated using gene targeting in mice, revealing major effects in branching morphogenesis, vasculogenesis, development of the papilla and renal concentrating mechanism. Although exposure of the fetus to ANG inhibitors is potentially harmful throughout pregnancy, effects are greater in late compared to early gestation. Significant differences between humans and rodents in placental transfer of ANG and timing of renal development contributed to initial delays in recognizing the teratogenic effects of ANG inhibitors. Although administration of ACE or AT1 receptor inhibitors can slow progression of renal disease in older children, ANG inhibition in the neonatal period can aggravate renal injury due to congenital urinary tract obstruction. Neonates are also far more sensitive than older children to the hypotensive actions these agents and doses must be markedly reduced to avoid precipitating oliguria. Understanding the complex interactions of the maturing renin-angiotensin system in the perinatal period is essential in the use of ANG or renin inhibitors in women during childbearing years or in neonates with cardiovascular or renal disease.

Angiotensin AT1 receptor blockers suppress oxidized low-density lipoprotein-derived formation of foam cells

Although angiotensin II potently affects blood pressure and fluid balance, it is also involved in deterioration in atherosclerotic cardiovascular disease. Recently, angiotensin AT1 receptor blockers have been demonstrated to be effective in patients with atherosclerotic disease, but the exact mechanisms of these blockers are still controversial. Atherosclerotic plaques are characterized by cholesterol ester accumulation and acyl-CoA:cholesterol acyltransferase-1 (ACAT-1) expression, which are both parameters of degeneration of macrophage-derived foam cells. We examined the effects of angiotensin AT1 receptor blockers on the formation of foam cells from macrophages.When macrophages from a human cell line were stimulated with oxidized low-density lipoprotein (oxLDL), the angiotensin AT1 receptor blockers candesartan and losartan attenuated the intracellular accumulation of cholesterol ester and the increases in mRNA and protein levels of ACAT-1. Moreover, the increase in oxLDL-induced ACAT-1 was reduced by AG1478, an inhibitor of the epidermal growth factor (EGF) receptor. Additionally, oxLDL up-regulated the protein level of heparin-binding EGF-like growth factor (HB-EGF), a ligand of the EGF receptor. Inhibitors of angiotensin-converting enzyme affected neither cholesterol ester accumulation nor the expression of ACAT-1. Although oxLDL itself increased the secretion of angiotensin II, the amount of secreted angiotensin II was insufficient to induce expression of ACAT-1 protein.Thus, we first demonstrated that angiotensin AT1 receptor blockers suppress ACAT-1 expression and cholesterol ester accumulation through an oxLDL-activated EGF receptor, but it is unclear how oxLDL activates angiotensin AT1 receptor in an angiotensin II-independent manner. The therapeutic mechanism of angiotensin AT1 receptor blockers for atherosclerosis may be at least partially explained by our present results.

Low-Dose and Very Low-Dose Spironolactone in Combination Therapy for Essential Hypertension: Evaluation by Self-Measurement of Blood Pressure at Home

Low-dose (25 mg) or very low-dose (12.5 mg) spironolactone were added among 86 uncontrolled hypertensive patients who were undergoing monotherapy with calcium channel blockers (CCBs), angiotensin-converting enzyme inhibitors (ACEIs), or angiotensin AT1-receptor blockers (ARBs). Morning home systolic/diastolic blood pressure (BP) reduction was similar among the CCB (n = 30, −8.2/−2.6 mmHg), ACEI (n = 22, −13.0/−4.7 mmHg), and ARB (n = 34, −11.5/−5.1 mmHg) groups. An increase in serum potassium correlated positively with the decline in morning systolic BP. Even very low-dose (12.5 mg) spironolactone is clinically effective, although serum potassium should be carefully monitored.

Are angiotensin AT1 receptor blockers better at preventing dementia than angiotensin converting enzyme inhibitors? An update

curriculum developed by the author that combines memory exercises and games invented by American and Japanese scholars. Methods: This study evaluates a pilot program of a 10-week memory training program conducted among an elderly population in the community. A total of 30 older adults in two separate groups participated in the program. The study examined many aspects of the elderly before and after they participated in the program, including memory function, social support, quality of life, life satisfaction, and motivation for learning. In addition, observational notes were used to examine changes among the elderly in attitudes and behaviors during the period of the memory training program. Results: The results indicated that the elderly (aged 65 to 78) who had participated in the study had a significant improvement in their learning attitudes, life satisfaction, continual practice using the memory training techniques, and increased attention to memory in their daily lives. In addition, a slight improvement in quality of life and better social support relationships were reported. Conclusions: Although the intervention may be simple in design and has not been tested in conjunction with medical examinations, those who participated in the program indicated stronger wills to be more active in maintaining their memory functions and in continually practicing the memory exercises. The memory training program also can be widely disseminated in the community as a preventive approach to help the elderly population maintain their memory and general well-being.

Pathophysiological mechanisms potentially implied in the better prevention of dementia with angiotensin AT1 receptor blockers than with angiotensin converting enzyme inhibitors

Pathophysiological mechanisms potentially implied in the better prevention of dementia with angiotensin AT1 receptor blockers than with angiotensin converting enzyme inhibitors

Angiotensin AT1-receptor blockers and cerebrovascular protection: do they actually have a cutting edge over angiotensin-converting enzyme inhibitors?

First, an update of the vascular systemic and tissue renin–angiotensin–aldosterone system is provided to explain how it is regulated at the systemic and tissue levels, and how many angiotensin peptides and receptors can be modulated by the various antihypertensive drugs. Second, experimental data is presented to support the hypothesis that antihypertensive drugs that increase angiotensin II formation, such as diuretics, AT1-receptor blockers and dihydropyridines, may have greater brain anti-ischemic effects than antihypertensive drugs that decrease angiotensin II formation, such as β-blockers and angiotensin-converting enzyme inhibitors, because they increase activation of angiotensin AT2 and AT4 receptors. Indeed, these trigger brain anti-ischemic mechanisms by favouring cerebral blood flow (angiogenesis and recruitment of pre-existing collateral circulation, specifically in the ischemic brain where AT2 receptors are overexpressed) or by directly increasing neuronal resistance to anoxia. Third, we review most of the large primary and secondary stroke prevention trials as well as the ACCESS acute stroke trial in which antihypertensive drugs were evaluated. With the exception of the secondary stroke prevention trial PRoFESS, most trials support the hypothesis that angiotensin II-increasing drugs confer specific blood pressure-independent brain ischemia protection when compared with angiotensin II-decreasing drugs or placebo. A careful analysis of the PRoFESS trial, however, reveals study design limitations, the main one being that diastolic BP (<80 mmHg) in the first month post-stroke may have been too low in at least one third of the population with baseline systolic blood pressure less than 130 mmHg, because a high dose of telmisartan was given after a very short post-stroke delay (median 15 days) without discontinuation of the baseline antihypertensive treatment.

Prevention of dementia by antihypertensive drugs: how AT1-receptor-blockers and dihydropyridines better prevent dementia in hypertensive patients than thiazides and ACE-inhibitors

Our review of cohort studies and clinical trials evaluating antihypertensive drugs in the prevention of cognition decline and all dementia in patients with hypertension indicates that two antihypertensive drug classes have greater protective effects, independent of blood pressure decrease: dihydropyridine calcium-channel blockers as shown in the Syst-Eur trial and angiotensin-AT1 receptor blockers as found in the MOSES and ONTARGET trials. By contrast, diuretics and angiotensin-converting enzyme-inhibitors (ACEIs) prevent dementia only in patients with a stroke history, provided they are combined, and prevent stroke recurrence. A Japanese cohort study and a small trial in patients already suffering from Alzheimer’s disease (AD) suggest, however, that the BBB-penetrating ACEI may slow down cognitive decline. Only cohort studies support the hypothesis that diuretics, (especially potassium-sparing diuretics), may decrease the risk of AD. β-blockers worsen cognition decline, or are neutral, according to whether or not they cross the BBB. Centrally-acting sympatholytic agent have a negative impact on cognition as BBB-penetrating β-blockers, probably by blunting the adrenergic pathways. The AD protective effect of DHP appears related to the blockade of neuronal calcium channels. The ambiguous effect of ACEI on cognitive decline and dementia prevention may be explained by the fact that brain ACE is not specific for angiotensin-I. Brain ACE also catabolizes cognition-enhancing brain peptides, amyloid peptides and converts toxic Aβ42 into less toxic Aβ40. Therefore, ACEIs may have short-term cognition-enhancing properties and may increase in the long term Aβ42 brain burden and cognitive decline. The clinical relevance of this scenario, mainly observed in animals, cannot be excluded in man, since the ACE gene has been associated with AD via the human whole genome analysis. To support the hypothesized deleterious effect of ACEI on human AD, confirmation that the ACE gene polymorphism DD is associated with protection against AD is necessary, since this polymorphism increases ACE activity. Independently of their preventive impact on β-amyloid degenerative neuropathological process by overexpressing insulin degrading enzyme which catabolyses amyloid, the angiotensin AT1-receptor-blockers may have greater cognition protective effects than ACEI (observed in the ONTARGET trial), as they share with ACEI cognition-enhancing effects directly linked with a common AT1-blunting effect. In addition, they increase angiotensin II and IV formation and therefore stimulate non-opposed AT2 and AT4 receptors, whose activation in cognitive processes is well established.