bluuebunny/crossref_metadata_2025 huggingface dataset:
No effect of angiotensin II AT2-receptor antagonist PD 123319 on cerebral blood flow autoregulation
Authors: Estrup Thalia M , Paulson Olaf B , Strandgaard Svend
Published: May 2007

Blockade of the renin-angiotensin system with angiotensin-converting enzyme inhibitors (ACE-I) or angiotensin AT1-receptor antagonists shift the limits of autoregulation of cerebral blood flow (CBF) towards lower blood pressure (BP). The role of AT2-receptors in the regulation of the cerebral circulation is uncertain. Hence, the present study investigated the effect on CBF autoregulation of blocking of angiotensin AT2-receptors with PD 123319 in spontaneously hypertensive rats (SHR). Anaesthetised and ventilated SHR were given PD 123319, 0.36 mg/kg/min, intravenously, and compared with a control group. CBF was measured by the intracarotid 133-xenon injection method and BP was raised by noradrenaline infusion and lowered by controlled haemorrhage in separate groups of rats. The limits of autoregulation were determined by computed least-sum-of-squares analysis. PD 123319 did not influence baseline CBF, but resulted in a minor BP decrease (10 control and 10 treated rats). The lower limit of CBF autoregulation (eight treated and eight control) as well as the upper limit of CBF autoregulation (eight treated and eight control) were not significantly different in PD 123319 and control animals (lower limit treated 102±4 mmHg and control 94±4; NS, and upper limit treated 171±10 mmHg and control 162±7; NS). These findings indicate that acute AT2-receptor blockade does not influence CBF autoregulation.
Angiotensin II receptor blockers and cardiovascular outcomes: The evidence now and in the future
Authors: Weber Michael
Published: May 2007

The blood-pressure-lowering efficacy of both angiotensin-converting enzyme inhibitors (ACE-I) and angiotensin II receptor blockers (ARBs) has been clearly demonstrated in recent years, although there is evidence that within the ARB class the individual therapies are not necessarily identical in terms of sustained and consistent antihypertensive efficacy over the entire dosing period. However, the results of the recent HOPE study have demonstrated that ACE-I have a wider role to play in treating cardiovascular disease, and support the idea that ACE inhibition specifically has a vascular protective effect. The most dramatic benefits were seen in patients with systolic blood pressures in the hypertensive range. The ability of the ACE-I to provide protective effects beyond blood pressure control may be due to their ability to attenuate the breakdown of kinins as well as a role in reducing angiotensin II. These data pose the question as to whether the pharmacological properties of the ARBs, in addition to their antihypertensive efficacy, may also play a significant role in influencing cardiovascular outcomes. A number of prospective long-term studies, including VALUE, SCOPE, LIFE, VALIANT, OPTIMAAL, VAL-HEFT and CHARM I-III, are investigating the effects of the ARBs of mortality and morbidity in patients with cardiovascular disease. These studies should answer important questions with respect to the role that ARBs may have in influencing cardiovascular outcomes, although it remains to be seen whether ARBs can match the protective effects of ramipril in high-risk patients. Given the excellent tolerability of the ARBs, it will be of value to examine the influence of ARBs on cardiovascular outcomes in all relevant patient groups.
Effects of candesartan on cardiac and arterial structure and function in hypertensive subjects
Authors: Spratt James CS , Webb David J , Shiels Annette , Williams Bryan
Published: May 2007

Objectives

To study the effect of candesartan cilexetil on left ventricular mass index (LVMI), left ventricular systolic and diastolic function, arterial structure and function and blood pressure (BP) in hypertensive patients.

Design and methods

Patients (n=35), aged >20 years, with hypertension and average baseline LVMI of 89 g/m2 were treated for 24 weeks with candesartan, 16 mg o.d., following a four-week placebo run-in period. If diastolic BP remained above 95 mmHg, hydrochlorothiazide, 12.5 mg o.d., was added. Left ventricular structure and function were assessed using transthoracic echocardiography. Arterial function and structure were assessed using pulse wave analysis to calculate augmentation index (AIx) and forearm plethysmography to calculate minimum vascular resistance. BP was measured in the office and by 24-hour ambulatory BP monitoring (ABPM).

Results

The mean reduction in LVMI was 4.4 g/m2 (p=0.022). Left ventricular systolic function was not significantly altered from baseline, but diastolic function significantly improved: the mean change in diastolic time was 54 ms (p=0.037), in peak velocity filling 6.3 cm/s (p=0.023); E:A ratio improved by 0.08 (p=0.049). The mean reduction in forearm vascular resistance was 15 units at rest (p=0.001) and 1.3 units after limb ischaemia (p=0.006). AIx decreased significantly, with a mean reduction of 9% (p<0.001). Central BP also significantly reduced (systolic blood pressure/ diastolic blood pressure 31/20 mmHg; p<0.001). BP was significantly reduced, both in the office (22/16 mmHg; p<0.001) and by 24-hour ABPM (18/12 mmHg; p<0.001).

Conclusions

Treatment with candesartan, 16 mg o.d., with or without hydrochlorothiazide, for 24 weeks, significantly reduced left ventricular mass and arterial hypertrophy in patients with hypertension. In parallel, there were significant improvements in left ventricular diastolic function and arterial function.
The SCOPE Trial
Authors: Sever Peter
Published: May 2007

The Study on Cognition and Prognosis in the Elderly (SCOPE) was designed to provide outcome data on cardiovascular endpoints and cognitive function in 4500 elderly hypertensive patients randomised to the angiotensin receptor blocker, candesartan, or to placebo and followed up for 4.5 years.

The primary endpoint of combined cardiovascular mortality, non-fatal myocardial infarction and non-fatal stroke was not significantly reduced by active treatment (relative risk reduction 11%, p=0.19). There was also no significant difference in the decline of cognitive function between the two treatment arms.

Active treatment of the placebo group (mainly hydrochlorothiazide) reduced the blood pressure differences between the treatment arms to only 3.2/1.6 mmHg, thus markedly reducing the overall power of the study. In a number of non-prespecified subgroup analyses, advantages of candesartan over placebo were reported.
Review: Rationale for combination therapy in the treatment of hypertension
Authors: Sica Domenic A
Published: May 2007

The effective treatment of hypertension still poses many problems. In the last decade it has become apparent that in many patients multi-drug regimens are needed to effect blood pressure control. How best to combine medications and what might be a preferred order of initiating drugs is still open to debate and has proven the substance of many of the published guidelines on this theme. Like most matters in the clinical sector the approach to a disease — in this case hypertension — should remain highly individualised and cognisant of what can be significant cost considerations.
Review: The practical aspects of combination therapy with angiotensin receptor blockers and angiotensin-converting enzyme inhibitors
Authors: Sica Domenic A
Published: May 2007

Angiotensin-converting enzyme (ACE) inhibitors and/or angiotensin receptor blockers (ARBs) are widely prescribed for the management of hypertension. ACE inhibitors (ACE-I) and, more recently, ARBs have an established track record of success in the treatment of congestive heart failure (CHF), proteinuric renal disease and most recently the hypertensive patient with a high cardiac-risk profile. The individual success of each of these drug classes has fuelled speculation that given together the overall effect of both would exceed that of either given alone. This premise, although biologically plausible, has yet to be proven in a convincing enough fashion to support the routine use of these two drug classes in combination. Additional clarifying studies are needed to establish whether specific patient subsets exist that might benefit from such combination therapy.
Review: Vasopeptidase inhibitors in heart failure
Authors: Dawson Adelle , Struthers Allan D
Published: May 2007

Considerable attention has recently focused on the vasopeptidase inhibitors (VPI), a new class of drug that combines angiotensin-converting enzyme (ACE) inhibitor activity with inhibition of natriuretic peptide breakdown. In theory, a drug with these properties may be beneficial both in hypertension and in heart failure. Whilst the efficacy of VPIs in hypertension has been consistently demonstrated in pre-clinical and clinical studies, the role of VPIs, if any, in heart failure is less clear, since numerous small studies have produced conflicting results. Furthermore, preliminary results from the recently completed Omapatrilat Versus Enalapril Randomised Trial of Utility in Reducing Events (OVERTURE) study have failed to establish the VPI, omapatrilat, as a first line therapy in the treatment of chronic heart failure. We review the literature on VPIs in heart failure and discuss possible reasons for the reported lack of benefit over ACE inhibitors.
Mortality benefit of angiotensin-converting enzyme inhibitors after cardiac events in patients with end-stage renal disease
Authors: McCullough Peter A , Sandberg Keisha R , Yee Jerry , Hudson Michael P
Published: May 2007

Hypothesis/Introduction

The risks and benefits of angiotensin-converting enzyme (ACE) inhibitors in patients with end-stage renal disease (ESRD) after cardiac events are unknown. We sought to determine the independent effect of ACE inhibitors (ACE-I) on long-term mortality in ESRD patients after cardiac events.

Materials and methods

We analysed a prospective coronary care unit registry and identified 527 ESRD patients, 368 with complete data on medications prescribed, over eight years at a single, tertiary centre.

Results

The overall mean age was 64.4 13.8 years with 54.9% men, and 59.2% African-American. A total of 143/386 (37.0%) were prescribed ACE-I during the hospital stay for cardiac reasons, including congestive heart failure (CHF) 52.8% and acute coronary syndromes (ACS) 47.2%. There were no significant differences in the rates of hypotension or arrhythmias in those who were treated with ACE-I versus those who were not. Survival analysis over three years, adjusted for known confounders, demonstrated a 37% reduction in all-cause mortality in those who received ACE-I, (p=0.0145).

Conclusions

In the setting of coronary care unit admission for CHF and ACS, ESRD patients selected for ACE-I, did not have increased rates of adverse haemodynamic or arrhythmic complications. The use of ACE-I conferred an independent mortality reduction over long-term follow-up.
Review: The renin-angiotensin-aldosterone system and the eye in diabetes
Authors: Strain W David , Chaturvedi Nish
Published: May 2007

Diabetic retinopathy is the leading cause of blindness in the under 65s, and with the burden of disease case load expected to exceed 200 million worldwide within 10 years, much effort is being spent on prophylactic interventions. Early work focused on improving glycaemic control; however, with the publication of EURODIAB Controlled trial of Lisinopril in Insulin-dependent Diabetes (EUCLID) and United Kingdom Prospective Diabetes Study (UKPDS), the focus has recently moved to control of blood pressure and specifically the renin-angiotensin system (RAS). There is a large body of evidence for a local RAS within the eye that is activated in diabetes. This appears to be directly responsible, as well as indirectly through other mediators, for an increase in concentration of vascular endothelial growth factor (VEGF), a selective angiogenic and vasopermeability factor that is implicated in the pathogenesis of diabetic retinopathy. Inhibition of angiotensin-converting enzyme appears to reduce concentrations of VEGF, with a concurrent anti-proliferative effect independent of systemic VEGF levels or blood pressure. Angiotensin II (Ang II) Type 1 (AT1) receptor blockade has been shown to reduce neovascularisation independent of VEGF levels in animal models. This may be due to antagonism of activation of mitogen-activated protein kinase, which is a potent cellular proliferation stimulator, by Ang II, although this needs further evaluation.
The DIabetic Retinopathy Candesartan Trials (DIRECT) Programme, rationale and study design
Authors:   The DIRECT Programme Study Group, Chaturvedi Nish
Published: May 2007

The DIabetic Retinopathy Candesartan Trials (DIRECT) Programme consists of three randomised, double-masked, parallel, placebo-controlled studies to determine the impact of treatment with candesartan on diabetic retinopathy. In Type 1 diabetes, 1,700 patients without retinopathy will be randomised into a primary prevention study, and 1,200 with non-proliferative retinopathy into a secondary prevention study. In Type 2 diabetes, 1,600 patients with non-proliferative retinopathy will be randomised. Patients will be followed for at least three years. Eligible patients must be normotensive (systolic blood pressure [SBP] ≤ 130 mmHg and diastolic blood pressure [DBP] ≤ 85 mmHg) without antihypertensive medication in Type 1 diabetes, and either normotensive or treated hypertensive (SBP ≤ 160 mmHg and SBP ≤ 90 mmHg) and not taking angiotensin-converting enzyme inhibitors or AT1receptor blockers in Type 2 diabetes. All patients will be normoalbuminuric, based on two overnight urine collections. The primary endpoint is based upon retinal photographs, graded to the Early Treatment of Diabetic Retinopathy Study scale. A two-step increase on this scale defines incidence, and a three-step increase defines progression of retinopathy. The main secondary endpoint for each study is change in urinary albumin excretion rate. A positive outcome of the DIRECT Programme would be an important step forward in the clinical management of patients with diabetes.
Combination is better than monotherapy with ACE inhibitor or angiotensin receptor antagonist at recommended doses
Authors: Segura Julián , Praga Manuel , Campo Carlos , Rodicio José L , Ruilope Luis M
Published: May 2007

Objective

The combination of an angiotensin-converting enzyme (ACE) inhibitor and an angiotensin II (Ang II) receptor antagonist (ARB) could provide a higher degree of blockade of the renin-angiotensin system(RAS) than either agent alone. The primary aim of this study was to look at the effect of three therapeutic regimens (titrated ACE inhibitor (ACE-I) versus titrated ARB versus the combination of an ACE-I and an ARB) on the attainment of adequate blood pressure (BP) control and antiproteinuric effect. Both ACE-I and ARB were titrated as monotherapy up to the maximal recommended dose.

Methods

A pilot randomised, parallel group open-label study was conducted in 36 patients with primary renal disease, proteinuria above 1.5 g/day and BP >140/90 mmHg while on therapy with an ACE-I. Patients were randomly assigned to (1) benazepril, n=12; (2) valsartan, n=12; or (3) benazepril plus valsartan, n=12. Other antihypertensive therapies could also be added to attain goal BP (<140/90 mmHg). The primary endpoint was the change in proteinuria during six months of follow-up.

Results

In the presence of similar BP decreasesand stable creatinine clearance values, mean proteinuria decreases were 0.5±1.7, 1.2±2.0 and 2.5±1.8 g/day in groups 1, 2 and 3, respectively. When compared with baseline values, only the fall induced by the combination of ARB and ACE-I attained statistical significance (p<0.05).

Conclusion

The antiproteinuric capacity of monotherapy at recommended doses with either an ACE-I or an ARB is lower than that obtained with the combination of the two drugs.
Effect of angiotensin-converting enzyme inhibition on endothelial function and insulin sensitivity in hypertensive patients
Authors: Tezcan Hakan , Yavuz Dilek , Toprak Ahmet , Akpmar Ihsan , Koç Mehmet , Deyneli Oguzhan , Akalm Sema
Published: May 2007

Introduction

Evidence suggests an association between insulin resistance, hypertension and impaired endothelial function. Studies have shown that insulin resistance precedes the development of hypertension. By improving insulin sensitivity, it may be possible to improve hypertension and the subsequent damage to vessel walls. Some data indicates beneficial effects of angiotensin-converting enzyme (ACE) inhibitors on insulin sensitivity and endothelial function. We aimed to investigate these effects of ACE inhibition in the same group of patients with essential hypertension.

Materials and methods

Nine non-smoking, untreated hypertensive patients (38.3 9 years, 4/5 male/female) and 12 age-matched healthy subjects (35.2 6.7 years, 5/7 male/female) were included in the study. Hypertensive patients were given enalapril maleate (5—40 mg/day) for six months. The following parameters were studied at baseline and at the end of treatment period. Whole body insulin sensitivity was measured by a formula derived from an oral glucose tolerance test and named I as the insulin sensitivity index (ISI). Insulin was measured by chemiluminescence and glucose by a glucose oxidase method. Endothelial function was evaluated as flow-mediated dilatation (FMD) of the brachial artery by ultrasonography and expressed as a percentage change relative to baseline diameter. Endothelialindependent vasodilatation was measured after sublingual nitroglycerine.

Results

FMD was impaired in the hypertensive group compared with healthy subjects (7.3 3.1% vs. 15.3 4.8%, p<0.0005), and ISI values were 1.18 0.6 vs. 4.4 0.9 (p<0.0001) respectively. Both insulin sensitivity and FMD improved after the treatment period compared with baseline values, FMD increased from 7.3 3.1% to 16.0 2.9% (p<0.0005) and ISI from 1.18 0.6 to 4.2 1.0 (p<0.0001). FMD and ISI showed a significant positive correlation (r=0.67, p<0.001) in the hypertensive group.

Conclusions

Patients with essential hypertension have impaired endothelial function and decreased whole body insulin sensitivity compared with healthy subjects. Treatment for six months with enalapril maleate seems to improve both FMD and ISI. This study confirms the beneficial effects of ACE inhibition on both endothelial function and insulin sensitivity tested in the same group of essential hypertensive patients. The mechanism of these favourable effects of ACE inhibition needs to be clarified.
Epidemiology and clinical aspects of congestive heart failure
Authors: Murray-Thomas Tarita , Cowie Martin R
Published: May 2007

Congestive heart failure (CHF) is an increasing problem for healthcare systems in all developed countries. The prevalence is increasing partly due to ageing of the population, but also due to improved survival from acute cardiac disease such as myocardial infarction. Advances in diagnostic techniques and better understanding of the pathophysiology offer many opportunities for substantial improvement in the management of CHF. This article reviews the current epidemiology of CHF and the related diagnostic issues.
Subfornical organ lesion attenuates chronic hypotensive effects of losartan in salt-replete rats
Authors: Collister John P , Hendel Michael D
Published: May 2007

Hypothesis/introduction Circumventricular organs are central nervous system brain sites thought to participate in neuroendocrine regulation of neural output. We have previously demonstrated a profound chronic hypotensive response to the angiotensin II (Ang II) AT1 antagonist, losartan (10 mg/kg/day), in normal rats. In addition, we have demonstrated that the area postrema, one of the circumventricular organs, partially mediates this response. The subfornical organ (SFO) is another circumventricular organ which has been shown to mediate actions of Ang II. The present study was designed to test the hypothesis that the SFO mediates the chronic hypotensive effects of losartan in normal rats.

Materials and methods Rats were randomly chosen for lesion of the SFO or sham operation and instrumented with intravenous catheters and radiotelemetric blood pressure transducers. After a control period, rats were infused with losartan (10 mg/kg/day) for nine days. Mean arterial pressure and heart rate responses were measured continuously throughout the protocol and examined as 12-hour day/night averages.

Results By day 7 of losartan treatment, night-time mean arterial pressure had dropped to 75±2 mmHg in sham rats (n=8) but only to 83±2 mmHg in SFO-lesioned rats (n=10). This trend continued throughout the treatment protocol.

Conclusions These results suggest that the SFO partially mediates the chronic hypotensive effects of chronic losartan treatment in normal rats.
Conclusions on the management of heart failure
Authors: Swedberg Karl
Published: May 2007

Activity of the renin-angiotensin-aldosterone system (RAAS) is increased in heart failure. Agents which act on the RAAS can be expected to benefit these patients. Recent trials which have furthered our understanding of drugs which are of benefit in heart failure – angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, β-blockers and aldosterone antagonists – are discussed. It is desirable to use multiple agents for best results in patients with heart failure. New European Society of Cardiology guidelines on the management of heart failure are expected later this year.
Vascular effects of quinapril completely depend on ACE insertion/deletion polymorphism
Authors: Voors Adriaan A , van Geel Peter P , Oosterga Margreeth , Buikema Hendrik , van Veldhuisen Dirk J , van Gilst Wiek H
Published: May 2007

Introduction

The angiotensin-converting enzyme (ACE) DD-genotype is associated with increased plasma and myocardial ACE-activity. The influence of the ACE insertion/deletion (I/D) polymorphism on the effects of ACE-inhibition on vascular responses has not been previously described.

Materials and methods

In the randomised, double-blind QUinapril On Vascular ACE and Determinants of Ischemia Study (QUO VADIS), 149 patients undergoing coronary bypass surgery were randomised to receive either the ACE inhibitor, quinapril, or placebo. In 82 patients, we obtained ACE-genotype, and measured vascular responses to angiotensin II (Ang II) in left internal mammary arteries.

Results

In the placebo group, the mean maximal vasoconstriction to Ang II was significantly lower in patients with the DD-genotype than in those with the ID/II genotype (36.2±5.11% [n=13] vs. 55.6±4.57% [n=25]; p=0.01). In the quinapril group, the mean maximal vasoconstriction to Ang II was similar [n=8] vs. 57.7±4.07% [n=35]; p=0.85). between DD- and ID/II-genotype (59.6±9.19%

Conclusions

DD-genotype patients showed decreased vascular responses to Ang II but treatment with quinapril completely restored the decreased vascular response in DD-genotype patients to the same level as II/ID-genotype patients, while no effect of quinapril was demonstrated in the II/ID-genotype patients.
How different urinary albumin excretion rates can predict progression to nephropathy and the effect of treatment in hypertensive diabetics
Authors: Huw Llewelyn DE , Garcia-Puig Juan
Published: May 2007

Hypothesis The efficacy of a treatment in a clinical trial depends in part on where the cut-off point is placed for the test result used to select patients for the trial, and this applies to irbesartan in the Irbesartan Microalbuminuria II (IRMA II) trial for preventing nephropathy.

Patients and methods Patients in the IRMA II trial were stratified into different pre-treatment albumin excretion rate (AER) ranges to compare the proportion of patients starting in these different ranges (i) that progressed to develop nephropathy within 24 months and (ii) whose AER was over 40 µg/minute at three months.

Results The proportion of patients with pre-treatment AER values between 20 and 40 µg/minute progressing to develop nephropathy was 1.25% in the placebo group and 0.78% in the irbesartan group, while for pre-treatment AER values between 41 and 200 µg/minute, 24.4% and 11.2% develop nephropathy respectively in the placebo and irbesartan groups. In patients with a pre-treatment AER of 20 to 30 µg/minute, 32.5% and 13.6% respectively in the placebo and irbesartan groups had a value exceeding 40 µg/minute at three months.

Conclusions The data demonstrate that irbesartan is effective in reducing the onset of nephropathy within two years when the pre-treatment AER is above 40 µg/minute, but if the AER is below this level it progresses unusually to nephropathy within two years. Irbesartan also slows progression of AER to over 40 µg/minute for patients with pre-treatment AER values at or above 20 µg/minute and these patients should be treated.
How do thiazide and thiazide-like diuretics lower blood pressure?
Authors: Hughes Alun D
Published: May 2007

Thiazide diuretics are widely used for the treatment of hypertension, but the mechanism by which these drugs lower blood pressure in the long term remains unknown. This article reviews current knowledge about the hypotensive actions of thiazides and thiazide-like diuretics and discusses possible mechanisms of action.
Angiotensin II stimulates arachidonic acid release from bone marrow stromal cells
Authors: Richmond Renee S , Tallant E Ann , Gallagher Patricia E , Ferrario Carlos M , Strawn William B
Published: May 2007

Introduction Angiotensin II (Ang II) is recognised as a regulator of haematopoiesis, but its actions within the bone marrow are not fully understood. Support of haematopoiesis by bone marrow stromal cells (MSC) is dependent on factors that include arachidonic acid and macrophage colony stimulating factor (MCSF), both of which are increased by Ang II stimulation in other tissues. To further elucidate the mechanisms of Ang II-regulated haematopoiesis, we determined whether Ang II-stimulation alters arachidonic acid release and MCSF secretion from MSC.

Methods Cynomolgus monkey MSC isolated from bone marrow aspirates and the human HS-5 stromal cell line were studied for Ang II-mediated arachidonic acid (AA) release, while secretion of MCSF in response to Ang II was studied in HS-5 cells. Cells were labelled overnight with3H-AA and the release of3H-AA was measured in culture medium following 20 minutes stimulation with Ang II, alone or in combination with the AT1- or AT2-receptor antagonists, losartan and PD 123319, respectively. MCSF secretion into culture medium was measured using an enzyme immunoassay following 24 hours of treatment with Ang II alone or in combination with losartan or PD 123319. Phorbol-myristate-acetate, known to stimulate release of AA and MCSF, was used as a positive control in both experiments.

Results In response to Ang II, release of3H-AA from monkey and human MSC was increased (p<0.05) to 147±4% and 124±3% of control, respectively. The AT1- and AT2-receptor antagonists, losartan and PD 123319, individually reduced Ang II-stimulated3H-AA release. In contrast, Ang II had no effect on secretion of MCSF from HS-5 cells.

Conclusions These results provide mechanistic evidence for Ang II-mediated haematopoiesis through AA release that may, in part, explain Ang II-facilitated recovery of haematopoiesis in experimental myelosuppression and the anaemias associated with Ang II receptor blockade.
Preventing end stage renal disease in diabetic patients — genetic aspect (part I)
Authors: Jacobsen Peter Karl
Published: May 2007

Diabetic nephropathy is a major cause of diabetes-related morbidity and mortality; however the clinical course of the disease and the renal prognosis is highly variable among individuals. The current review will discuss the genetic influence on the development of end stage renal disease (ESRD) in diabetic patients and potential improvements to the current treatment strategy to slow the loss of kidney function in these patients. In this first part, the growing evidence that glucose-induced activation of the intra-renal and systemic renin-angiotensin systems plays an essential role in processes leading to destruction of renal function is summarised. Genetic variations, especially the angiotensin-converting enzyme (ACE)/ID polymorphisms in the gene coding for ACE, are involved in activation of the renin-angiotensin system and seem to influence the clinical course of diabetic nephropathy during treatment with ACE inhibitors. In addition, this polymorphism may interact with other polymorphisms within the reninangiotensin system, leading to high risk of ESRD. As new genetic approaches and methods develop, further understanding of diabetic nephropathy will evolve and genotyping will help prevent ESRD in diabetic patients.
Does Angiotensin (1-7) Contribute to the Antiproteinuric Effect of ACE-inhibitors?
Authors: van der Wouden Els A , Henning Robert H , Deelman Leo E , Roks Anton JM , Boomsma Frans , de Zeeuw Dick
Published: May 2007

Angiotensin-converting enzyme inhibitors (ACE-I) reduce proteinuria and protect the kidney in proteinuric renal disease. During ACE-I therapy, circulating levels of angiotensin (1-7) [Ang (1-7)] are increased. As cardiac and renal protective effects of Ang (1-7) have been reported, we questioned whether Ang (1-7) contributes to the antiproteinuric effects of ACE-I treatment.

Therefore, we evaluated whether Ang (1-7) infusion reduces proteinuria in a rat model of adriamycin-induced renal disease. In addition, the effect of a selective Ang (1-7) blocker, [D-Ala7]-Ang (1-7) (A779), was investigated in rats treated with the ACE-I, lisinopril (LIS). Six weeks after induction of proteinuria, therapy was started in four different groups: control, Ang (1-7), LIS, and LIS+A779. After two weeks, the rats were sacrificed. Six weeks after injection of adriamycin, the rats

had developed proteinuria of 323±40 mg/24 hours. The proteinuria remained stable in the control group and in the Ang (1-7) group, but was reduced in both LIS and LIS+A779-treated groups. Similarly, blood pressure (BP) was unchanged in the control and the Ang (1-7) groups, but reduced in both the LIS and the LIS+A779 groups. Plasma levels of Ang (1-7) were increased in the Ang (1-7) and in both LIS-treated groups.

We conclude that systemic Ang (1-7) plays no major role in the antiproteinuric and BPlowering effects of ACE-I in this rat model of adriamycin-induced nephrosis.
Gene Polymorphisms of Angiotensin II Type 1 Receptor and Angiotensin-Converting Enzyme in Two Ethnic Groups Living in Zhejiang Province, China
Authors: Chunlan Yan  , Jinbiao Zhan  , Weihong Feng
Published: May 2007

Polymorphisms of ACE insertion/deletion (I/D) and angiotensin II type 1 receptor (AT1R) 1166A-C have been associated with many diseases, and distributions of their genotypes vary in different races and populations. The aim of this study was to investigate distributions of angiotensin-converting enzyme (ACE) and AT1R genotypes in Han and She populations in ZheJiang province. We determined ACE and AT1R genotypes in 189 Han and 163 She individuals. DNA was extracted from peripheral blood samples. Analyses of ACE and AT 1R genotypes were performed by polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP). The frequencies of ACE genotypes and alleles among the Han sample (41.3%II, 41.3%ID, 17.5%DD; 61.9%I allele, 38.1%D allele) were similar to those among She individuals (39.9%II, 39.3%ID, 20.9%DD; 59.5%I allele, 40.5%D allele), with p=0.660; p=0.421. However, significant differences in the distributions of ACE polymorphism between men and women among She population were observed, with p=0.042, p=0.014. AT1R genotype and allele frequencies in the Han population were (88.4%AA, 11.1%AC, 0.5%CC) and (93.9%A allele, 6.1%C) allele respectively. In the She population they were (78.0%AA, 21.3%AC, 0.6%CC) and (89.0%A allele, 11.0%C allele). The significant differences were found between Han and She populations with p=0.031, p=0.018, and within subgroups of women, with p=0.010, p=0.021. There were no significant differences within subgroups of men (p=0.476, p=0.261). The genotype distributions or allele frequencies of ACE and AT1R were significantly different between the samples of the She and Han populations.
Review: Aldosterone Inhibition Reduces the Risk of Sudden Cardiac Death in Patients with Heart Failure
Authors: Anand Kishlay , Mooss Aryan N , Mohiuddin Syed M
Published: May 2007

Sudden cardiac death (SCD) accounts for over 450,000 deaths annually in the USA. Sudden death is estimated to account for approximately 50% of all deaths from cardiovascular causes. Total cardiac mortality has decreased from 728,115 in 1989 to 719,456 in 1999 but the percentage of deaths that are sudden has actually increased from 38% to 47%. Prevention of SCD in patients with risk factors is a high priority for public health professionals. Aldosterone has been shown to be associated with myocardial inflammation, endothelial dysfunction and fibrosis. There is evidence from clinical trials suggesting the endothelial dysfunction and fibrosis. There is evidence from clinical trials suggesting role of aldosterone inhibition in prevention of SCD. We reviewed the potential mechanisms and discuss the clinical implications of Randomised ALdactone Evaluation Study (RALES) and Eplerenone Neurohormonal Efficacy and Survival Study (EPHESUS). The use of aldosterone receptor blockers had an overall effect of 21% risk reduction in SCD. Appropriate monitoring and counselling is essential while using either of the aldosterone inhibitors.
Aldosterone Blockade Over and Above ACE-Inhibitors in Patients with Coronary Artery Disease but without Heart Failure
Authors: Shah Nimit C , Pringle Stuart , Struthers Allan
Published: May 2007

Recent evidence points to a role for the renin-angiotensin-aldosterone system (RAAS) in the pathogenesis of atherosclerosis and its complications, including acute angina pectoris. Two large trials in heart failure have clearly demonstrated that blocking aldosterone improves mortality1,2 and that this benefit occurs over and above standard therapy with angiotensin-converting enzyme (ACE) inhibitors. The question that naturally arises from these landmark studies is whether aldosterone blockade would produce the same benefits in patients with coronary artery disease (CAD) but no heart failure.

There are three reasons to believe this might be the case. Firstly, angiotensin II (Ang II) and aldosterone produce similar biological effects and Ang II withdrawal has been shown to benefit patients with angina; aldosterone blockade may therefore follow in the footsteps of ACE inhibitors, as it did in heart failure, and produce benefits in vascular patients without heart failure. Secondly, one of the main mechanisms which is thought to be responsible for the benefit of aldosterone blockade in the Randomised ALdactone Evaluation Study (RALES) and Eplerenone Post-AMI Heart Failure Survival Study (EPHESUS), is that it improves endothelial/ vascular function3,4 and endothelial/vascular dysfunction is the fundamental abnormality in angina pectoris.

Finally, aldosterone blockade has been shown to reduce atherosclerosis in animal studies of atherosclerosis without heart failure, which are analogous to CAD patients.5
Renal Haemodynamics are not Related to Genotypes in Offspring of Parents with Essential Hypertension
Authors: Skov Karin , Madsen Jens Kristian , Hansen Hans Erik , Zagato Laura , Frandsen Erik , Bianchi Giuseppe , Mulvany Michael John
Published: May 2007

Introduction. The pathogenesis of essential hypertension (EH) has a major genetic component and is associated with renal abnormalities. Normotensive offspring of hypertensive parents are likely to develop EH and are a suitable population for identifying possible relations between genetic and renal abnormalities.

Methods. We investigated if renin-angiotensin-aldosterone system associated genotypes (angiotensinogen [M235T] and ACE [I/D]) are related to blood pressure (BP), renal haemodynamics and sodium excretion in sex and age-matched (18—35 years) healthy Caucasian offspring of either two parents with EH (n=101, EH-offspring) or two normotensive parents (n=50, controls). The alpha-adducin polymorphism (G460W) was also investigated.

Results. Compared to controls, BP, heart rate, renal vascular resistance (RVR) and urinary sodium excretion were, respectively, 5%, 7%, 15% and 20% higher in EH-offspring. In controls, the TT-genotype of the M235T angiotensinogen polymorphism was associated with higher BP and higher plasma angiotensinogen. By contrast, in EHoffspring the TT-genotype was associated with lower BP and unchanged plasma angiotensinogen. Plasma angiotensinogen correlated positively with BP in EH-offspring, with a similar tendency (p=0.08) in controls. The distributions of the three candidate polymorphisms were similar in EH-offspring and controls. There were no associations between any of the polymorphisms and any of the renal parameters measured.

Conclusion. The markedly greater RVR, proportionally larger than the greater BP, supports a role for RVR in the pathogenesis of EH. The lack of association between the candidate polymorphisms and the investigated parameters, even in this homogenous and for hypertension strongly predisposed group, suggests that the polymorphisms investigated do not play important roles in the pathogenesis of hypertension.
Effects of ACE Inhibition and Angiotensin II Receptor Blockade on Glomerular Basement Membrane Protein Excretion and Charge Selectivity in Type 2 Diabetic Patients
Authors: Deyneli Oguzhan , Yavuz Dilek , Velioglu Ayliz , Cacma Hasan , Aksoy Nihal , Haklar Goncagül , Taga Yavuz , Akalm Sema
Published: May 2007

Angiotensin-converting enzyme (ACE) inhibitors may reduce urinary albumin excretion (UAE) by decreasing glomerular pressure and increasing glomerular charge selectivity through preservation of glycosaminoglycans. The effect of Angiotensin II antagonism on glomerular charge selectivity remains to be determined. The aim of this study was to compare the effects of an AT1 blocker losartan and an ACE inhibitor (ACE-I) enalapril on UAE, extracellular matrix proteins, glycosaminoglycan excretion (UGAG) and red blood cell anionic charge (RBCCh) which are the indirect markers of glomerular basement membrane anionic content in hypertensive Type 2 diabetic patients. Twenty-four patients were randomised into two groups and received either enalapril (5—20 mg/d) or losartan (50—100 mg/d). All parameters were measured at baseline and after six months of treatment. At the end of six months, systolic and diastolic blood pressures (BP), UAE rates, UGAG excretion and RBCCh were significantly and equally reduced in both treatment groups compared with baseline. RBCCh was negatively correlated with UAE (r=-0. O 57, p<0.0001) and UGAG excretion (r=-0.57, Rp<0.0001); UAE was correlated with UGAG excretion (r=0.58, p<0.0001). In conclusion, enalapril and losartan treatment were equally effective in reducing BP, UAE as well as UGAG excretion and preserving RBCCh in hypertensive Type 2 diabetic patients. ACE inhibition and AT1-receptor blockade may have favourable effects on preserving glomerular anionic content in hypertensive diabetic patients.
Are current therapies for hypertension achieving their goal?
Authors: Poulter Neil
Published: May 2007

The majority of adults with hypertension do not get their blood pressures controlled to currently recommended targets, despite relatively consistent blood pressure targets in guidelines from around the world. This requires major preventative and treatment strategies to be implemented both in the general population and in the hypertensive population. The reasons behind the failure to achieve blood pressure targets are many and varied and include physician inertia, ineffective drugs, poor patient compliance, side-effects and poor communication of guidelines. Physician inertia is perhaps the most important contributor to under-treatment. The recent A/CD algorithm in guidelines co-produced by the British Hypertension Society and the National Institute for Health and Clinical Excellence in the UK and Ireland provide a memorable, pragmatic and logical approach to guide drug sequencing with a view to achieving blood pressure targets for most patients.
Chronic blockade of angiotensin II AT1-receptors increased cell-to-cell communication, reduced fibrosis and improved impulse propagation in the failing heart
Authors: De Mello Walmor C
Published: May 2007

Introduction. The influence of chronic administration of losartan on gap junction conductance (gj), conduction velocity and interstitial fibrosis was investigated in the failing heart of 4-month-old cardiomyopathic hamsters (TO-2).After two months of administration of losartan (25 mg/kg/day/po) the number of cell pairs showing very low values of gj (2—8 nS) was significantly reduced whereas the group of cell pairs with larger values of gj (18-45 nS) was significantly increased.The conduction velocity measured with intracellular microelectrodes in the wall of the left ventricle was enhanced from 38+2.3 cm/s (n=25) (control) to 49+2 cm/s (n=24) (p<0.05) after losartan administration. Moreover, the number of ventricular fibres showing non-propagated action potentials was significantly decreased (p<0.05) by losartan.The % area of interstitial fibrosis measured in the wall of the left ventricle was reduced from 22+1.4% (n=18) to 14 1.3% (n=18) (p<0.05) after losartan administration.

Conclusion. Chronic blockade of angiotensin II type 1 receptors increased gj in the failing heart. Moreover,the conduction velocity was enhanced remodelling in part by the increase of gj and in part by the decrease of interstitial fibrosis and structural remodelling.
The angiotensin type 1 receptor antagonist valsartan attenuates pathological ventricular hypertrophy induced by hyperhomocysteinemia in rats
Authors: Kassab Salah , Garadah Taysir , Abu-Hijleh Marwan , Golbahar Jamal , Senok Solomon , Wazir Javed , Gumaa Khalid
Published: May 2007

Introduction. Clinical and experimental studies have reported the role of homocysteine in ventricular hypertrophy. Activation of the reninangiotensin system mediated by angiotensin II type 1 (AT1) receptor has also been suggested to contribute to the pathogenesis of ventricular hypertrophy. There are also reports suggesting the affect of angiotensin II (Ang II) on cardiac hypertrophy is mediated by hyperhomocysteinemia. However, there is limited information on the mechanisms of the possible relationship between homocysteine and Ang II in ventricular hypertrophy. In this study we tested the hypothesis that hyperhomocysteinemia induced ventricular hypertrophy and remodelling may be mediated through activation of Ang II AT1-receptors in rats.

Methods. This study was conducted on control non-treated rats (n=13), methionine-treated rats (1.5 mg/kg/day, n=18) and methionine plus oral AT1 antagonist (valsartan, 30 mg/kg/day, n=13) treated rats for 56 days. Systolic blood pressure (SBP) was determined in rats at baseline, 28 and 56 days. Echocardiography was also performed in all rats after eight weeks, and blood samples were obtained for determination of plasma tHcy. Rats were then sacrificed for histopathological and biochemical assessment of cardiac structure.

Results. The SBP in the methionine-treated rats was significantly higher compared with controls and significantly lower compared with the methionine-valsartan group at 28 and 56 days (p<0.001). In addition, left ventricular wall thickness (LVWT) in the methionine-valsartan group (4.36±0.11 mm) was significantly lower compared with the methionine group (5.0±0.23 mm, p=0.03). Furthermore, cardiac collagen to total protein ratio was significantly lower in the methionine-valsartan group (2.19±0.11%) compared with the methionine group (2.64±0.08%, p=0.026). Fractional shortening (FS) was not significantly different between groups.

Conclusion. Results from this study suggest that hyperhomocysteinemia-induced hypertension and ventricular hypertrophy in rats are mediated, at least partly; by Ang II activation of AT1-receptors.
The effects of telmisartan and amlodipine on metabolic parameters and blood pressure in type 2 diabetic, hypertensive patients
Authors: Negro Roberto , Hassan Haslinda
Published: May 2007

Introduction. Hypertension in type 2 diabetes represents a strong risk factor for cardiovascular events. Either calcium channel blockers or angiotensin receptor blockers (ARBs) may reduce insulin resistance. One of the ARBs, telmisartan (Telm) acting as a PPARγ agonist, significantly reduces HbA1C levels.The aim of this study was the comparison of the effects on glycaemic control of amlodipine (Aml) and Telm in hypertensive type 2 diabetic patients.

Materials and methods. Forty diabetic hypertensive subjects were assigned to two groups. Group A: rosiglitazone (RSG) 4 mg + Telm 80 mg; Group B: RSG 4 mg + Aml 10 mg. All the patients were already treated with metformin, but not with antihypertensive drugs.

Results. After four months treatment, both groups showed a significant reduction of mean blood pressure (Group A: - 13.5%; Group B: - 13.3%) and a positive influence on glycaemic control and insulin resistance. Lower values of glucose, HbA1C, HOMA index and higher adiponectin levels were observed in Group A compared to Group B.

Conclusions. In type 2 diabetic hypertensive patients, the association of Telm 80 mg and RSG 4 mg seems to display a metabolic advantage compared to Aml 10 mg.The simultaneous beneficial effects on blood pressure and insulin sensitivity may confer make Telm particularly suitable in the treatment of the metabolic syndrome.
Review: Novel roles of intracrine angiotensin II and signalling mechanisms in kidney cells
Authors: Zhuo Jia L , Li Xiao C
Published: May 2007

Angiotensin II (Ang II) has powerful sodium-retaining, growth-promoting and proinflammatory properties in addition to its physiological role in maintaining body salt and fluid balance and blood pressure homeostasis. Increased circulating and local tissue Ang II is one of the most important factors contributing to the development of sodium and fluid retention, hypertension and target organ damage.The importance of Ang II in the pathogenesis of hypertension and target organ injury is best demonstrated by the effectiveness of angiotensin-converting enzyme (ACE) inhibitors and AT1-receptor antagonists in treating hypertension and progressive renal disease including diabetic nephropathy.The detrimental effects of Ang II are mediated primarily by the AT -receptor, while the AT2-receptor may oppose the AT1-receptor. The classical view of the AT1-receptor-mediated effects of Ang II is that the agonist binds its receptors at the cell surface, and following receptor phosphorylation, activates downstream signal transduction pathways and intracellular responses. However, evidence is emerging that binding of Ang II to its cell surface AT1-receptors also activates endocytotic (or internalisation) processes that promote trafficking of both the effector and the receptor into intracellular compartments. Whether internalised Ang II has important intracrine and signalling actions is not well understood.The purpose of this article is to review recent advances in Ang II research with focus on the mechanisms underlying high levels of intracellular Ang II in proximal tubule cells and the contribution of receptor-mediated endocytosis of extracellular Ang II. Further attention is devoted to the question whether intracellular and/or internalised Ang II plays a physiological role by activating cytoplasmic or nuclear receptors in proximal tubule cells.This information may aid future development of drugs to prevent and treat Ang II-induced target organ injury in cardiovascular and renal diseases by blocking intracellular and/or nuclear actions of Ang II.