Active Angiotensin-converting Enzyme Research Articles

The Need to Emphasize Nephrology Knowledge in Residents-in-Training.

Background:Chronic kidney disease is an increasingly prevalent health problem with the potential for poor outcome of end-stage renal disease. Hospitalized critically ill patients are prone to acute renal injury from numerous factors such as poor renal perfusion secondary to ischemia and hypotension, nephrotoxin exposure, and intravenous contrast exposure.Aims:We set to explore resident awareness and knowledge about chronic kidney disease management, timely nephrology referrals, preventing inadvertent acute kidney injury (AKI), and the understanding of basic electrolyte physiology.Materials and Methods:We conducted a cross-sectional study using an online questionnaire survey of internal medicine, Medicine/Pediatrics and Family Medicine residents in the United States to determine the knowledge of residents during their training about nephrology.Results:The survey questionnaire was sent out to 270 residents. Forty-seven (17%) respondents completed the survey. Out of them, 57% of the residents chose to refer a patient with an estimated glomerular filtration rate <30 mL/min/1.73 m2 to a nephrologist; 66% felt that it was safe to use aspirin in stage IV chronic kidney disease; 82% did not want to use metformin or Lovenox in stage IV chronic kidney disease; 87% answered that they would make the patient resume angiotensin converting enzyme inhibitor or angiotensin II receptor blockers (ARBs) about 48-72 h after contrast exposure. Only 7.5% decided to hold angiotensin converting enzyme inhibitors/ARBs before contrast exposure. Meanwhile, 70% correctly identified the efferent arteriole as the site of action of angiotensin converting enzyme inhibitors/ARBs and 76% identified nitrofurantoin as a contraindication in renal insufficiency.Conclusion:Residency offers a golden opportunity for resident physicians to create a strong foundation of concepts in medicine. There are several basic areas in the field of nephrology that need to be further emphasized during residency training to help improve patient care and potentially decrease the incidence of AKI.

Effects of Centrally Acting Angiotensin Converting Enzyme Inhibitors on Functional Decline in Patients with Alzheimer's Disease

Centrally acting angiotensin converting enzyme inhibitors (CACE-Is) are associated with reduced rates of cognitive decline in patients with dementia. CACE-Is may also improve exercise tolerance in functionally impaired older adults with normal cognition, suggesting that CACE-Is may positively influence activities of daily living (ADL) in dementia. To compare rates of decline in patients with mild to moderate Alzheimer's disease (AD) receiving CACE-Is to those not currently treated with CACE-Is (NoCACE-I), included in the Doxycycline and Rifampicin for Alzheimer's Disease study (n = 406). Patients were included if baseline and end-point (twelve months apart) scores were available for measures including the Standardized Alzheimer's Disease Assessment Scale - Cognitive Subscale; Quick Mild Cognitive Impairment screen; Clinical Dementia Rating Scale (CDR-SB), and Lawton-Brody ADL Scale. There was a significant, 25% difference (median one-point) in the 12-month rate of decline in ADL scores in patients taking CACE-Is (n = 91), compared to the NoCACE-I group (n = 274), p = 0.024. This remained significant after adjusting for age, gender, education, and blood pressure, p = 0.034. When individual CACE-Is were compared to the NoCACE-I group, a significant reduction in the rate of decline in ADLs (median one versus four points), were only observed for perindopril, p = 0.01. The CDR-SB was also reduced (median one-point) for the perindopril compared to the NoCACE-I group, p = 0.04. This observational study suggests that CACE-Is, and potentially perindopril in particular, are associated with a reduced rate of functional decline in patients with AD, without an association with mood or behavior. This suggests that CACE-Is may slow disease progression in AD.

Нужны ли споры на тему: лучше сартаны или ингибиторы АПФ? (часть 1)

Данная статья является первой частью обзора данных литературы о механизме действия и эффективности блокаторов рецепторов ангиотензина II (БРА) в снижении артериального давления и предупреждении поражения органов-мишеней. Проводится сопоставление с действием ингибиторов ангиотензинпревращающего фермента (иАПФ). Делаются выводы, что существенной разницы, которая имела бы клиническое значение, между БРА и иАПФ нет.

Atrial tachyarrhythmia causes atrial imbalance of the Ace/Ace2 ratio in aged and hypertensive rats

Purpose: Arterial hypertension and age are the most predominant factors causing atrial fibrillation (AF). The exact proarrhythmogenic pathways involved are still unknown. The present study was designed to examine changes in the composition of atrial members of the renin-angiotensin system (RAS) in response to tachyarrhythmia in the presence of arterial hypertension at different ages. The local RAS plays a crucial role in remodelling processes in the heart, primarily through the action of angiotensin II (AngII), which is generated by angiotensin converting enzyme (ACE). ACE2 counterbalances the action of ACE by cleaving of AngII into peptides that act protective. Methods: Atrial tissue from spontaneously hypertensive male rats (SHR; n=6) and their normotensive controls, Wistar-Kyoto (n=6), were analysed at the age of 12 weeks and 6-8 months. Atrial slices were rapidly stimulated at 5 Hz up to 20h to resemble AF (n=4 per group and age). The changes in the expression of RAS components (ACE, ACE2, angiotensin receptors) as well as RAS-associated downstream effectors were estimated at the mRNA and protein levels. Moreover, the activation of MAPK and NF-κB signalling were analysed by immunoblotting. Results: Our data revealed that left atrium of SHR expressed constantly high levels of ACE protein (3.8±0.7; p=0.03) and mRNA (1.7±0.7; p=0.04) compared to normotensive controls (1.0) in each age group. ACE2-mRNA levels did not show any changes at 12 weeks between normotensive and hypertensive rats. With age the mRNA levels of ACE2 diminished in SHR (0.79±0.04; p=0.02). These molecular changes were accompanied by activation of MAPK, NF-κB signalling and the presence of the active caspase-3 in SHR. In response to the stimulation in the electrical field, the atrial tissue from hypertensive rats showed 1.6-fold (p=0.01) and of normotensive rats 3.0-fold increase (p=0.01) in the expression of ACE. In normotensive young rats, ACE2 counterbalanced this action at the mRNA (1.5±0.12; p=0.01) and protein level (2.7±0.80; p=0.11). This protective action of ACE2 decreased with age in normotensive rats, and it disappeared completely in SHR (mRNA: 0.94±0.13; protein: 0.98±0.11). Conclusions: Our data show that hypertension in SHR is accompanied by enhanced atrial expression of angiotensin-converting enzyme. This fact strongly implies a sustained exposure of atrial tissue to elevated levels of local AngII. The observed imbalance of the ACE/ACE2 ratio in aged hypertensive rats might facilitate the susceptibility to arrhythmia especially in this clinical scenario.

Time until incident dementia among Medicare beneficiaries using centrally acting or non‐centrally acting ACE inhibitors

Centrally active (CA) angiotensin-converting enzyme inhibitors (ACEIs) are able to cross the blood–brain barrier. Small observational studies and mouse models suggest that use of CA versus non-CA ACEIs is associated with a reduced incidence of Alzheimer's disease and related dementias (ADRD). The aim of this research was to assess the effect of CA versus non-CA ACEI use on incident ADRD. This is a retrospective cohort study with a non-equivalent control group. SETTING AND PATIENTS" This study used a national random sample of Medicare beneficiaries enrolled in Part D with an ACEI prescription. A prevalent ACEI user cohort included beneficiaries (n = 107 179) with an ACEI prescription prior to 30 April 2007; beneficiaries without an ACEI prescription before this date were defined as incident ACEI users (n = 9840). The main outcome was time until first diagnosis of ADRD in Medicare claims. The unadjusted, propensity-matched and instrumental variable analyses of both the prevalent and incident ACEI user cohorts consistently showed similar time until incident ADRD in those taking CA ACEIs compared with those who took non-CA ACEIs. The limitations of this study include the use of observational data, relatively short follow-up time and claims-based measure of cognitive decline. In this analysis of Medicare beneficiaries who were prevalent or incident users of ACEIs in 2007–2009, the use of CA ACEIs was unrelated to cognitive decline within 3 years of index prescription. Continued follow-up of these patients and more sensitive measures of cognitive decline are necessary to determine whether a cognitive benefit of CA ACEIs is realized in the long term.

IgE-Mediated Anaphylaxis to Foods, Venom, and Drugs: Influence of Serum Angiotensin Converting Enzyme Levels and Genotype

Circulating angiotensin-II protects the circulation against sudden falls in blood pressure and is generated by the enzymatic action of angiotensin converting enzyme (ACE) on angiotensin-I. The ACE genes have 2 allelic forms, “I” and “D.” The “D” genotype has both highest angiotensin-II generation and serum ACE levels compared to “I”. 120 patients with IgE-anaphylaxis, 119 healthy controls, and 49 atopics had serum ACE levels, ACE genotype, and renin levels determined. Plasma renin levels were identical for all groups. Serum ACE levels and genotypes were similar for healthy controls (HC) and atopics, but lower in anaphylaxis (P = 0.012), with ACE genotypes also showing increased “I” genes (P = 0.009). This effect was more pronounced in subjects manifesting airway angioedema and cardiovascular collapse (AACVS) than mild cutaneous and respiratory (CRA) symptoms. AACVS was significantly associated with the presence of “I” genes. For “ID” genotype OR is 5.6, 95% CI 1.8 to 17.4, and for “II” genotype OR is 44, 95% CI 5 to 1891 within the anaphylaxis group = 0.001. The results show a difference in the genotype frequency between control and anaphylaxis, suggesting a role for the renin angiotensin system in anaphylaxis manifesting with airway angioedema and cardiovascular collapse.

Separation methods for captopril in pharmaceuticals and biological fluids

Captopril (CAP) is an orally active angiotensin-converting enzyme (ACE) inhibitor and has been widely used for management of hypertension and congestive heart failure. CAP lacks an aromatic chromophore required for facile direct UV detection and also has two chiral centers. These factors can render the determination of CAP in complex matrices challenging. This review covers more than 20 years of analytical research on this drug, focusing mainly on pharmaceutical and biological applications. The primary separation techniques discussed are gas chromatography, liquid chromatography, and capillary electrophoresis. The structures of the CAP derivatizing agents as well as a table summarizing various HPLC methods are provided. A discussion of key recent chromatographic and electrophoretic methods for other ACE inhibitors is also present.

Angiotensin-Converting Enzyme 2: The First Decade

The renin-angiotensin system (RAS) is a critical regulator of hypertension, primarily through the actions of the vasoactive peptide Ang II, which is generated by the action of angiotensin-converting enzyme (ACE) mediating an increase in blood pressure. The discovery of ACE2, which primarily metabolises Ang II into the vasodilatory Ang-(1-7), has added a new dimension to the traditional RAS. As a result there has been huge interest in ACE2 over the past decade as a potential therapeutic for lowering blood pressure, especially elevation resulting from excess Ang II. Studies focusing on ACE2 have helped to reveal other actions of Ang-(1-7), outside vasodilation, such as antifibrotic and antiproliferative effects. Moreover, investigations focusing on ACE2 have revealed a variety of roles not just catalytic but also as a viral receptor and amino acid transporter. This paper focuses on what is known about ACE2 and its biological roles, paying particular attention to the regulation of ACE2 expression. In light of the entrance of human recombinant ACE2 into clinical trials, we discuss the potential use of ACE2 as a therapeutic and highlight some pertinent questions that still remain unanswered about ACE2.

Effect of a centrally active angiotensin converting enzyme inhibitor, perindopril, on cognitive performance in chronic cerebral hypo-perfusion rats

We have previously demonstrated that perindopril, an angiotensin-converting enzyme (ACE) inhibitor, ameliorated the cognitive deficits in Alzheimer's disease model animals, independently of its anti-hypertensive effect. In this study, we again investigated the effects of perindopril on cognitive function in a vascular dementia model animal, comparing it with other ACE inhibitors. We also determined ACE activity in the brain and extracellular acetylcholine (ACh) concentration in the perirhinal cortex in order to elucidate the mechanism(s) responsible for the effects of these ACE inhibitors on cognitive function. Perindopril was suggested to be more centrally active than imidapril and enalapril, in consideration of the relative distribution of their active metabolites in the brain. This property was at least partially attributed to the lipophilicity of the compound. While the 3day treatment with perindopril, imidapril or enalapril lowered blood pressure to the same level in spontaneous hypertensive rats, only perindopril reversed the decline in the recognition index in chronic cerebral hypo-perfusion rats, regarded as an animal model of vascular dementia, during an object recognition task. Using the same dosing regimen, perindopril inhibited the brain ACE activities of rats more than imidapril or enalapril. Moreover, a single treatment with perindopril enhanced the extracellular level of ACh in the perirhinal cortex of normal rats. Therefore, we confirmed that only centrally active ACE inhibitors, such as perindopril, can inhibit the ACE in the brain, augmenting cholinergic neurotransmission and thereby ameliorating cognitive impairment in the animal model of vascular dementia.

Angiotensin converting enzyme-gene polymorphisms in normal subjects, atopic individuals and those with anaphylaxis to venom, food and drugs

Background Circulating angiotensin-2 levels (A2) protect the circulation against sudden falls in blood pressure. A2 is generated by the enzymatic action of angiotensin converting enzyme (ACE) on angiotensin-1. The ACE genes have 2 allellic forms, with the presence ‘I’ or absence ‘D’ of a 287 base pair intron of the gene. The deletion ‘DD’ genotype is associated with high A2 generation & higher serum ACE levels, while the insertion ‘I I’ with lower serum ACE levels & ACE activity.

Contribution of the tissue angiotensin converting enzyme to the antihypertensive effect of altiopril calcium (MC-838) in spontaneously hypertensive rats

The effect of a new orally active angiotensin converting enzyme (ACE) inhibitor, calcium (-)-N-[(S)-3-[(N-cyclohexylcarbonyl-D-alanyl)thio]-2-methylpropionyl+ ++]-L- prolinate (MC-838, altiopril calcium), on systemic blood pressure (SBP) and tissue ACE activity has been examined in conscious spontaneously hypertensive rats (SHRs). MC-838 (3 mg kg-1) given orally to SHRs elicited a long-lasting hypotension lasting over 24 h. With the development of the hypotension, MC-838 significantly reduced ACE activity in the lung, kidney and aorta, but not in the brain and heart. Suppression of plasma ACE and rise of plasma renin activity occurred only transiently at an earlier stage.

Loss of ACE2 Accelerates Pressure Overload-Induced Myocardial Oxidative Stress and Ventricular Dysfunction

Introduction: Pressure overload activates the cardiac renin-angiotensin system (RAS) in association with myocardial oxidative stress and left ventricular dysfunction. The key peptidase action of angiotensin converting enzyme 2 (ACE2) is degradation of angiotensin (Ang) II to Ang (1–7), functioning effectively as a negative regulator of the RAS. Hypothesis: We hypothesized that ACE2 exerts its protective roles against myocardial oxidative stress and ventricular dysfunction by modulation of NADPH oxidase activity. Methods: Male wildtype (WT) mice, ACE2 knockout (KO) and ACE2/p47phox double KO mice of 10 weeks of age underwent aortic banding model of pressure-overload for 3 weeks. We characterized the functional, structural and molecular changes in the heart in response to pressure overload by echocardiography, TaqMan real-time PCR, Western blot analysis and assessed NADPH oxidase activity. Results: Compared with WT mice, loss of ACE2 resulted in a marked increase in pressure overload-induced myocardial oxidative stress in banded ACE2 KO mice, associated with decreased cardiac function, increased expression of hypertrophy markers (ANF and BNP) and elevated NADPH oxidase activities including p47phox, and Nox2 and Nox4 mRNA expression. These changes were linked with activation of PKCα protein and phosphorylation of the extracellular signal-regulated protein kinase (ERK1/2), Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) signaling in ACE2 KO mice. Loss of p47 subunit prevented the increase in NADPH oxidase activity and attenuated the adverse remodeling in the ACE2 KO mice. Conclusions: Loss of ACE2 accelerates pressure-overload induced myocardial oxidative stress, ventricular dysfunction by activation of the NADPH oxidase subunits with the p47 subunit playing a key role. ACE2 suppresses the myocardial NADPH oxidase system possible by reducing Ang II levels. Introduction: Pressure overload activates the cardiac renin-angiotensin system (RAS) in association with myocardial oxidative stress and left ventricular dysfunction. The key peptidase action of angiotensin converting enzyme 2 (ACE2) is degradation of angiotensin (Ang) II to Ang (1–7), functioning effectively as a negative regulator of the RAS. Hypothesis: We hypothesized that ACE2 exerts its protective roles against myocardial oxidative stress and ventricular dysfunction by modulation of NADPH oxidase activity. Methods: Male wildtype (WT) mice, ACE2 knockout (KO) and ACE2/p47phox double KO mice of 10 weeks of age underwent aortic banding model of pressure-overload for 3 weeks. We characterized the functional, structural and molecular changes in the heart in response to pressure overload by echocardiography, TaqMan real-time PCR, Western blot analysis and assessed NADPH oxidase activity. Results: Compared with WT mice, loss of ACE2 resulted in a marked increase in pressure overload-induced myocardial oxidative stress in banded ACE2 KO mice, associated with decreased cardiac function, increased expression of hypertrophy markers (ANF and BNP) and elevated NADPH oxidase activities including p47phox, and Nox2 and Nox4 mRNA expression. These changes were linked with activation of PKCα protein and phosphorylation of the extracellular signal-regulated protein kinase (ERK1/2), Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) signaling in ACE2 KO mice. Loss of p47 subunit prevented the increase in NADPH oxidase activity and attenuated the adverse remodeling in the ACE2 KO mice. Conclusions: Loss of ACE2 accelerates pressure-overload induced myocardial oxidative stress, ventricular dysfunction by activation of the NADPH oxidase subunits with the p47 subunit playing a key role. ACE2 suppresses the myocardial NADPH oxidase system possible by reducing Ang II levels.

Effect of a centrally active angiotensin-converting enzyme inhibitor, perindopril, on cognitive performance in a mouse model of Alzheimer's disease

Angiotensin-converting enzyme (ACE) inhibitors have clinically been widely used as anti-hypertensive agents. In the present study, we compared the effects of a centrally active ACE inhibitor, perindopril, with those of non-centrally active ACE inhibitors, imidapril and enalapril, on cognitive performance in amyloid β(Aβ) 25–35-injected mice, a rodent model of Alzheimer's disease. We also determined the brain ACE activity in order to elucidate the relationship between the cognitive function and ACE inhibition in the brain. Aβ 25–35-injected mice showed a cognitive impairment in spontaneous alteration and object recognition tests, the indices of immediate working memory and relatively long-term recognition memory, respectively. As indicated by these tests, the oral administration of perindopril (0.1, 0.3 or 1 mg/kg/day) significantly reversed the cognitive impairment in these mice, whereas neither imidapril (0.3, 1 or 3 mg/kg/day) nor enalapril (1, 3 or 10 mg/kg/day) had any effect on cognitive performance. Perindopril (1 mg/kg/day), imidapril (3 mg/kg/day), or enalapril (10 mg/kg/day) all inhibited the plasma ACE activities by more than 90%. Using the same dosing regimen, only perindopril inhibited the brain ACE activities by more than 50%, whereas imidapril and enalapril showed much less potent effects. These results suggest that perindopril ameliorated the cognitive impairment in the Alzheimer's disease model mice through the inhibition of brain ACE activity, but not peripheral ACE activity. Based on our observations, we concluded that a centrally active ACE inhibitor, perindopril, may therefore have a beneficial effect on Alzheimer's disease as well as hypertension.

ACE I and ACE II: immunohistochemical study in primary pterygium

Pterygium is a common conjunctival disorder exhibiting degenerative and hyperplastic changes as well as proliferative, inflammatory features and a rich vasculature. Epidemiological studies indicate chronic exposure to the sun and most probably ultraviolet B light as an important factor in the development of pterygium. Recent report assumes Renin-angiotensin system (RAS) as a new potential mediator for growth factor and an immunomodulator that influences cell proliferation, apoptosis, tissue fibrosis and participates in inflammatory responses. RAS is classically conceived as a coordinated hormonal cascade in the control of cardiovascular, renal, and adrenal functions, mainly through the actions of Angiotensin II (Ang II), moreover novel studies assume RAS may be involved in the inflammatory process. Ang II is not only a potent vasoconstrictor and a stimulant of the aldosterone release, but also a growth factor and an immunomodulator that influences cell proliferation, apoptosis, and tissue fibrosis, and participates in inflammatory responses in a non-hemodynamic manner. Furthermore, the Ang II enhances vascular endothelial growth factor and contributes to the recruitment of inflammatory cells by inducing chemokines and adhesion molecules. Ang II is generated by enzymatic action of Angiotensin Converting Enzyme (ACE I). Besides the action of Ang II, exists an “alternative” way mediated by Angiotensin-(1-7). Angiotensin-(1-7) [Ang-(1-7)] is an alternative metabolite of the RAS system with actions in opposition to those of Ang II. It is generated by enzymatic action of Angiotensin Converting Enzyme II (ACE II). These evidences may suggest the RAS system such as a double antagonist model: a vasoconstrictor/proliferative role in which the major player is Ang II; and a vasodilator/anti-proliferative role in which the major effector is Ang-(17). Due to the relationship among UVB damage, molecular mechanisms of conjunctival cells alterations and pterygium features, ACE I and ACE II were immunohistochemically examined to investigate the possible overexpression, and their relationship, in primary pterygium. The results will be discussed.

Possible beneficial effects of amlodipine, lisinopril, and their Combination on lipid profile in hypertensive patients

It is well known that monotherapy does not provide therapeutic response in all hypertensive. Somepatients show an excellent response, while in others there is a poor response. Combinationantihypertensive therapy is administered when blood pressure is inadequately controlled bymonotherapy to achieve a balanced and additive antihypertensive effect with minimum adverse effects.Both angiotensin converting enzyme (ACE) inhibitors and dihydropyridine type of calcium antagonistsare well established and widely used in monotherapy. An understanding of differences in themechanism of action of these agents allows a logical approach for the use of these agents as acombination therapy. This study was designed to evaluate the possible beneficial effects of long actingcalcium channel blocker, amlodipine and the long acting Angiotensin converting enzyme (ACE)inhibitor, lisinopril given either alone or in combination in patients with essential hypertension on lipidprofile (LDL-C and HDL-C) and on other parameters using a randomized double blind, crossoverstudy. The study includes 150 patients with systolic blood pressure (SBP)&gt;140 mmHg and diastolicblood pressure (DBP) &gt;90 mmHg received amlodipine 5 mg, lisinopril 5 mg and their combinationprior randomization schedule. Systolic, diastolic blood pressure and pulse rate were recorded at weeklyintervals while, serum levels of urea, creatinine, LDL-C and HDL-C where recorded at monthlyintervals, the duration of this study was 3 months. Results were obtained using paired students t-test,differences were considered significant with (p&lt;0.05).A significant decline in SBP and DBP in all treatment groups (p&lt;0.05) was recorded, the reductiontend to be more pronounced in the combination group. Moreover, there was a significant effect ofcombination on the heart rate, serum level of urea and creatinine, beside that, the level of HDL wassignificantly elevated with amlodipine and combination. We concluded that combination had additionalblood pressure lowering effect when compared either with amlodipine or lisinopril alone, in addition tothe greater effect on lipid profile which demonstrated that this combination is potentialantiatherosclerotic agent.

Thirtieth Anniversary of Hypertension

This year marks the 30th anniversary of Hypertension , the leading journal dedicated to research on blood pressure regulation and the pathophysiology, clinical treatment, and prevention of hypertension. Although the past 3 decades have brought remarkable changes in the technologies and science of high blood pressure research, the basic goals for Hypertension have remained remarkably constant–to publish the highest quality basic, clinical, and population science research and to promote better care of hypertensive patients. The 1970s was an exciting time for hypertension researchers, distinguished by the translation of many decades of research into effective, new approaches for treating high blood pressure. For example, the first peptide angiotensin II receptor blockers and angiotensin-converting enzyme inhibitors became widely available to researchers in the early 1970s, and the first orally active angiotensin-converting enzyme inhibitor was described in 1977. After decades of increasing death rates from cardiovascular disease, the 1970s heralded declining rates of cardiovascular mortality attributed, in large part, to the development and use of more effective drugs to treat patients with hypertension. Publications in the field of hypertension increased exponentially. Yet, establishing a journal devoted solely to hypertension had a difficult beginning. Lou Tobian, Chair of the American Heart Association (AHA) Council for High Blood Pressure from 1975 to 1977, reminisced in his editorial, “I was looking for a special project … the entire field of high blood pressure was expanding at a fast clip. The whole situation cried out for a new journal dedicated to the general area of hypertension. It would be the first in the world …. The idea was broached informally and met some stiff resistance.” The chair of the AHA Publications Committee was, according to Tobian, “… strongly opposed to the creation of this new journal.”1 Fortunately, the chair was absent when Tobian made his pitch …

Angiotensin-Converting Enzyme Inhibitors and Cognitive Decline in Older Adults With Hypertension

Hypertension (HTN) is a risk factor for dementia, and animal studies suggest that centrally active angiotensin-converting enzyme (ACE) inhibitors (those that cross the blood-brain barrier) may protect against dementia beyond HTN control. Participants in the Cardiovascular Health Study Cognition Substudy with treated HTN and no diagnosis of congestive heart failure (n = 1054; mean age, 75 years) were followed up for a median of 6 years to determine whether cumulative exposure to ACE inhibitors (as a class and by central activity), compared with other anti-HTN agents, was associated with a lower risk of incident dementia, cognitive decline (by Modified Mini-Mental State Examination [3MSE]), or incident disability in instrumental activities of daily living (IADLs). Among 414 participants who were exposed to ACE inhibitors and 640 who were not, there were 158 cases of incident dementia. Compared with other anti-HTN drugs, there was no association between exposure to all ACE inhibitors and risk of dementia (hazard ratio [HR], 1.01; 95% confidence interval [CI], 0.88-1.15), difference in 3MSE scores (-0.32 points per year; P = .15), or odds of disability in IADLs (odds ratio [OR], 1.06; 95% CI, 0.99-1.14). Adjusted results were similar. However, centrally active ACE inhibitors were associated with 65% less decline in 3MSE scores per year of exposure (P = .01), and noncentrally active ACE inhibitors were associated with a greater risk of incident dementia (adjusted HR, 1.20; 95% CI, 1.00-1.43 per year of exposure) and greater odds of disability in IADLs (adjusted OR, 1.16; 95% CI, 1.03-1.30 per year of exposure) compared with other anti-HTN drugs. While ACE inhibitors as a class do not appear to be independently associated with dementia risk or cognitive decline in older hypertensive adults, there may be within-class differences in regard to these outcomes. These results should be confirmed with a randomized clinical trial of a centrally active ACE inhibitor in the prevention of cognitive decline and dementia.

Vascular biology of angiotensin and the impact of physical activity

The renin-angiotensin system (RAS) is important for regulating blood pressure and extracellular fluid. The concept of the RAS has recently evolved from a classical systemic endocrine system to an appreciation of local RASs functioning in a paracrine manner, including in the vascular wall. Angiotensin II (AII), the main effector of the RAS, is a potent vasoconstrictor formed by the action of angiotensin-converting enzyme (ACE). ACE is multifunctional and also destroys the endogenous vasodilator bradykinin. A recently discovered novel ACE2 enzyme is responsible for forming a vasodilatory compound, angiotensin 1-7, from AII. Thus, the actions of ACE and ACE2 are antagonistic. Tissue actions of AII are mediated by specific receptors, AT1 and AT2, with AT1 mediating the classical actions. AT1-stimulated vasoconstricton occurs via phospholipase-D-mediated second messenger generation directly, and indirectly via the coupling of AT1 to the prooxidant enzyme NADPH oxidase. Since the vascular NADPH oxidase is a major source of vascular reactive oxygen species generation and is responsible for the breakdown of the vasodilator nitric oxide (NO), there is another potential link between RAS and regulation of vasodilatory pathways. AT2 signaling is antagonistic to AT1 signaling, and results in bradykinin and NO formation. Chronic AII signaling induces vascular dysfunction, whereas pharmacological management of the RAS can not only control blood pressure, but also correct endothelial dysfunction in hypertensives. Exercise training can also improve endothelial function in hypertensives, raising the question of whether there is a potential role for RAS in mediating the vascular effects of exercise training. Recent studies have demonstrated reductions in the expression of NADPH oxidase components in the vascular wall in response to exercise training, thus tempering one of the main cellular effectors of AII, and this is associated with reduced vascular ROS production and enhanced NO bioavailability. Importantly, it has now been demonstrated in human arteries that exercise training also tempers vascular AT1 receptor expression and AII-induced vasoconstriction, while enhancing endothelium-dependent dilation. The signals responsible for these chronic adaptations are not clearly understood, and may include changes in RAS components prompted by acute exercise. ACE genotype may have an effect on physical activity levels and on the cardiovascular responses to exercise training, and the II genotype (compared with ID and DD) is associated with the largest endothelium-dependent dilations in athletes compared with those in sedentary individuals. Thus, the tissue location of the RAS, the complement of ACE/ACE2, the receptor expression of AT1/AT2, and the ACE genotype are all variables that could impact the vascular responses to exercise training, but the responses of most of these variables to regular exercise training and the mechanisms responsible have not been systematically studied.

Angiotensin II-mediated oxidative stress and inflammation mediate the age-dependent cardiomyopathy in ACE2 null mice

The peptidase action of angiotensin converting enzyme 2 (ACE2) allows it to function as a negative regulator of the renin-angiotensin system. Current pharmacotherapies for human heart failure, such as ACE inhibitors and angiotensin and aldosterone receptor blockers, increase the activity of ACE2 in the heart. In this study, we investigate the mechanism for the age-dependent cardiomyopathy in ACE2 null mice. Ace2(-/y) mutant mice develop a progressive age-dependent dilated cardiomyopathy with increased oxidative stress, neutrophilic infiltration, inflammatory cytokine and collagenase levels, mitogen-activated protein kinase (MAPK) activation and pathological hypertrophy. The angiotensin II receptor-1 (AT1) blocker, irbesartan, prevented the dilated cardiomyopathy in aged Ace2(-/y) mutant mice, confirming a critical role of angiotensin II (Ang II)-mediated stimulation of AT1 receptors. Ang II activation of AT1 receptors triggers G-protein-coupled receptor (GPCR)-activated phosphoinositide 3-kinase gamma (PI3Kgamma) and its downstream pathways. We showed that p110gamma, the catalytic subunit of PI3Kgamma, is a key mediator of NADPH oxidase activation in response to Ang II. The double mutant mice (Ace2(-/y)/p110gamma(-/-)) exhibited marked reductions in oxidative stress, neutrophilic infiltration, and pathological hypertrophy resulting in myocardial protection, suggesting that PI3Kgamma plays a critical role in Ang II-mediated cardiomyopathy. Our findings demonstrate that the age-dependent cardiomyopathy in ACE2 null mice is related to increased Ang II-mediated oxidative stress and neutrophilic infiltration via AT1 receptors. Our combination of genetic and pharmacological approaches defines a critical role of ACE2 in the suppression of Ang II-mediated heart failure.

Development of liquid chromatographic method for fosinoprilat determination in human plasma using microemulsion as eluent

Fosinopril sodium presents a prodrug for the active angiotensin converting enzyme (ACE) inhibitor, fosinoprilat. The dual elimination of fosinoprilat by the liver and the kidney distinguishes fosinopril from other angiotensin converting enzyme inhibitors. Such ways of elimination are important for antihypertensive therapy of patients on haemodialysis. The paper presents development and evaluation of a new and sensitive liquid chromatographic (LC) method for the analysis of fosinoprilat in plasma obtained from patients on haemodialysis. A microemulsion system mixture as mobile phase has been used for the separation and analysis of fosinoprilat in plasma samples. The plasma samples were injected directly onto the HPLC system (Waters Breeze) after appropriate sample dilution with mobile phase. Separations were performed on the Bakerbond ENV 4.6 mm × 150 mm, 5 μm particle size column with UV detection at 220 nm. The flow rate was 1.00 mL min −1. The mobile phase consisted of 1.0% (w/v) of diisopropyl ether, 2.0% (w/v) of sodium dodecyl sulphate (SDS), 6.0% (w/v) of n-propanol and 91% (w/v) of aqueous 25 mM di-sodium hydrogen phosphate, pH adjusted to 2.8 with 85% orthophosphoric acid. The developed method was then subjected to method validation according to the criteria stated in the FDA bioanalytical method validation guidance. The results for specificity, linearity, low limit of quantification (LLOQ), precision, accuracy and stability were within the accepted criteria. The unique approach applied in this paper makes possible the determination of fosinoprilat even in the presence of metabolites of other drugs, so the method can be used for obtaining the reliable results in a fast and simple way.