bluuebunny/crossref_metadata_2025 huggingface dataset:
Pre-treatment with candesartan protects from cerebral ischaemia
Authors: Ito Takeshi , Nishimura Yasuaki , Saavedra Juan
Published: May 2007

Angiotensin II (Ang II) regulates cerebral blood flow by stimulating cerebral vasoconstriction via AT1receptors. In adult spontaneously hypertensive rats (SHR), the cerebrovascular autoregulatory curve is shifted to the right, in the direction of higher blood pressures, an indication of excessive cerebrovascular vasoconstriction. A restricted capacity to dilate cerebral blood vessels may be responsible for the enhanced vulnerability to cerebrovascular ischaemia during hypertension. We found that chronic treatment with the AT1-receptor antagonist, candesartan, (0.5 mg/kg/day for 14 days, via osmotic minipumps implanted in the subcutaneous tissue) blocked Ang II binding to AT1 -receptors in cerebral blood vessels and in brain areas involved in the regulation of cerebrovascular flow, and increased the ratio of lumen-wall area in the middle cerebral artery. Candesartan treatment normalised the lower part of the autoregulatory curve in SHR, and markedly decreased cerebral ischaemia as a consequence of middle cerebral artery occlusion with reperfusion. Protection from ischaemia is related to arterial remodelling, enhanced compensatory vasodilatation in the peripheral area of ischaemia, decreased reduction in cerebral blood flow following the occlusion of a major cerebral blood vessel, and protection from injury in the periphery of the lesion. Our results indicate that pre-treatment with AT1-antagonists such as candesartan could be of benefit in the prevention and treatment of brain ischaemia.
Effect of telmisartan on arterial distensibility and central blood pressure in patients with mild to moderate hypertension and Type 2 diabetes mellitus
Authors: Asmar Roland
Published: May 2007

Arterial wall stiffness is an important independent risk factor for cardiovascular disease in hypertensive patients, which is further exacerbated by co-existent diabetes mellitus. Increased arterial stiffness is directly associated with an increase in pulse wave velocity (PWV) and indirectly with increased central and peripheral blood pressure. Following a two-week placebo run-in period, 27 patients with mild to moderate essential hypertension and Type 2 diabetes mellitus, were randomised to once daily treatment with either telmisartan 40 mg or placebo for three weeks, and after a two-week washout period, crossed-over to the alternative treatment for a further three weeks. Carotid/femoral and carotid/radial PWV were measured non-invasively using the automatic Complior® device, and central parameters (central blood pressure, pulse contour analysis, and augmentation index) were measured using the SphygmoCor® system, at the start and end of each treatment period. Compared with placebo, treatment with telmisartan significantly reduced carotid/femoral PWV (mean adjusted treatment difference -0.95 m/s, 95% confidence intervals: -1.67, -0.23 m/s, p=0.013), as well as peripheral and central diastolic, systolic and pulse pressure. In conclusion, the results of this study show that telmisartan is effective in reducing arterial stiffness in hypertensive patients with Type 2 diabetes mellitus, and may potentially have beneficial effects on cardiovascular outcomes, beyond blood-pressure lowering effects, in this patient group.
Hyperglycaemia-induced intrarenal RAS activation: the contribution of metabolic pathways
Authors: Lansang M Cecilia , Osei Suzette Y , Coletti Caroline , Krupinski Janelle , Hollenberg Norman K
Published: May 2007

Hyperglycaemia-induced activation of the renin-angiotensin system (RAS) has been observed in normal and diabetic humans. Our main objective was to determine whether the mechanism involved a physical or metabolic effect of glucose. First, Sprague-Dawley rats of the CD strain were given sequential intravenous (i.v.) doses of 0.01, 0.1, 1.0, and 3.0 mg/kg candesartan 30 minutes apart, in the presence of a continuous i.v. infusion of dextrose 20% in water (D20W). The 0.1 mg/kg dose produced a maximal renal blood flow (RBF) response and was used thereafter. Another set of animals then received an infusion of either normal saline (NS), dextrose 5% in water (D5W) or dextrose 20% in water (D20W) for 2 hours, followed by candesartan 0.1 mg/kg i.v. Finally, the response to candesartan 0.1 mg/kg i.v. during D20W infusion was compared with that during infusion of 2-deoxyglucose (2DG), a glucose analogue that competitively inhibits the glycolytic enzyme, hexokinase. RBF (electromagnetic flowmeter), blood pressure (BP), blood glucose, and urine glucose were monitored. There was no significant RBF response to candesartan on either NS (6.01±0.48 to 6.20±0.49 ml/minute/g kidney; p=0.216) or D5W (7.63±1.20 to 7.58±1.39 ml/minute/g kidney; p=0.965), whereas there was a significant response to D20W (6.64±0.59 to 7.46±0.67 ml/minute/g kidney; p=0.002). The RBF response was significantly enhanced by D20W compared with 2DG (change in RBF: 0.82±0.22 vs. -0.04±0.26; p=0.05), despite similar BP, blood glucose, and urine glucose. Glucose acts, at least in part, through intracellular utilisation to induce RAS activation, as manifested by an enhanced renal vascular response to an angiotensin II antagonist.
Forearm vasodilator response to angiotensin II in elderly women receiving candesartan: role of AT2- receptors
Authors: Phoon Stephen , Howes Laurence Guy
Published: May 2007

The effects of angiotensin II (Ang II) and the Ang II type 2 (AT2) receptor antagonist, PD 123319, on forearm vascular resistance (FVR) were studied in elderly women during Ang II type 1 (AT1) receptor antagonist therapy. Eight women, aged 67±6 years, received the AT1-receptor antagonist, candesartan, 8—16 mg once-daily for three weeks. FVR responses to intra-brachial arterial infusions of Ang II (8—32 ng/minute) during the co-infusion of PD 123319 (8 µg/minute) or placebo were measured at the end of the second and third weeks in a randomised, double-blind, crossover study.

Ang II produced dose-dependent reductions in FVR during both the placebo and PD 123319 infusions. However, FVR was significantly higher during PD 123319 infusions than during placebo infusions. Candesartan therapy unmasks a vasodilator response to Ang II in forearm resistance vessels of elderly women. AT2-receptor blockade increases FVR, but does not prevent vasodilator responses to Ang II, suggesting that other vasodilator mechanisms may also be involved.
Strain differences in angiotensin-converting enzyme and angiotensin II type I receptor expression. Possible implications for experimental chronic renal transplant failure
Authors: Smit-van Oosten Annemieke , Henning Robert H , van Goor Harry
Published: May 2007

Background The Fisher to Lewis (F-L) model of renal transplantation (Rtx) is widely used. Rtx from F to L without immunosuppressive treatment results in 50% survival, whereas L to F results in survival rates similar to syngrafts. When treated with an angiotensin-converting enzyme (ACE) inhibitor or antihypertensive triple therapy, renal damage is markedly reduced in F-L allografts. Despite similar reductions in blood pressure, the ACE inhibitor (ACE-I) is more effective than antihypertensive triple therapy, suggesting that the inhibition of intrarenal ACE plays an additional role in the attenuation of renal damage.

Methods In the present study, we investigated strain-related differences in intrarenal ACE activity between F and L rats and whether treatment with ACE-I in F-L allografted rats results in reduction of intrarenal ACE. Intrarenal ACE was measured by activity assays, immunohistochemistry and PCR.

Results In control kidneys from healthy F rats (n=8), we found a four-fold higher ACE activity than in native L rats (n=8, p<0.01). This was confirmed by a three-fold difference in ACE mRNA expression (n=5 for both, p<0.01). Using immunohistochemistry, we found strong tubular ACE expression in the F rat, whereas the L rat had no tubular ACE at all. In F-L allografts (n=9) we noted significant glomerulosclerosis and proteinuria after 34 weeks. Treatment with ACE-I in F-L (n=8) prevented the development of these changes. Although ACE mRNA and ACE protein expression were similar in treated and untreated allografts, intrarenal ACE activity was reduced by 50% in allografts with ACE-I.

Conclusion In conclusion, intrarenal levels of ACE may play a role in the development of renal damage in experimental chronic renal transplant failure.
Renal graft failure after addition of an angiotensin II receptor antagonist to an angiotensin-converting enzyme inhibitor: unmasking of an unknown iliac artery stenosis
Authors: Kamper Anne-Lise , Nielsen Arne Høj , Bækgaard Niels , Just Svend
Published: May 2007

Combined treatment with an angiotensin-converting enzyme (ACE) inhibitor and an angiotensin II (Ang II) receptor blocker (ARB) has been suggested in order to achieve a more complete blockade of the renin-angiotensin-aldosterone system in cardiovascular and renal disease. The present report describes a case of acute renal graft dysfunction following the addition of an ARB to existing ACE inhibition. This unmasked an unknown iliac artery stenosis. The case indicates a possible important role of Ang II generated by non-ACE pathways in this situation.
Review: Vasopeptidase inhibitors
Authors: Sagnella Giuseppe A
Published: May 2007

Vasopeptidase inhibitors are a new class of drugs that have dual inhibitory effects on two key enzymes involved in the metabolism of vasoactive peptides. Essentially, they inhibit angiotensin-converting enzyme (ACE), thereby blocking the generation of angiotensin II (Ang II); at the same time they prevent the breakdown of natriuretic peptides by the enzyme neutral endopeptidase. The combination of reduction of Ang II on a background of increased natriuretic peptide activity has several potential advantages for the treatment of cardiovascular and renal disease and in particular, hypertension and congestive heart failure (CHF). Several vasopeptidase inhibitors, such as sampatrilat, fasidotril, gemopatrilat and omapatrilat (VanlevTM, the most clinically developed vasopeptidase inhibitor to date) are under intensive clinical investigation. Recent clinical trials have demonstrated effective antihypertensive activity in hypertension, independent of age, renin and salt status or ethnic origin, and have also highlighted the potential for vasopeptidase inhibition as a new therapeutic modality for the treatment of CHF. Moreover, ongoing research suggests that this new class of drugs may be an important approach, not only for the treatment of hypertension and of conditions associated with overt volume overload but also for ischaemic heart disease.
Cognitive decline and dementia in the elderly hypertensive
Authors: Hanon Olivier , Leys Didier
Published: May 2007

The prevention of cognitive disorders and dementia represents a major challenge in the coming years. The identification and management of the risk factors for these incapacitating conditions must therefore be a priority in order to define the best tools for early prevention. Studies over the past few years indicate that hypertension is involved not only in cerebro-vascular morbidity and mortality, but also in the pathogenesis of cognitive disorders and dementia. The existence of cognitive deficits and dementia syndromes in certain hypertensive elderly subjects has led a number of authors to study the relationships between cognitive functions and blood pressure (BP). Although the results of cross-sectional studies diverge, longitudinal studies show that subjects’ cognitive level is often inversely proportional to their BP values measured 15 or 20 years previously. The higher their BP used to be, the poorer their cognitive function. Data from certain recent therapeutic trials suggest that antihypertensive treatment might prevent the occurrence of dementia (of all aetiologies) in hypertensive patients aged 60 years and over. In this context, the effect of antihypertensive treatment on cognitive functions should represent one of the main criteria of evaluation of future morbidity and mortality studies, some of which are already in progress, with results available in the near future.
Therapy in the elderly hypertensive
Authors: Meredith Peter A , Trenkwalder Peter
Published: May 2007

The number of people over the age of 65 years continues to increase. In most societies blood pressure (BP) increases with age and elevated levels of BP are common in the elderly. The elderly are also a high-risk group for cardiovascular (CV) disease, which is the leading cause of death in most developed countries. Several intervention trials have confirmed lower CV disease risk in hypertensive patients aged into their early eighties when treated with a variety of antihypertensive drugs. Whilst there is some limited evidence to suggest that β-blockers may not be as effective as thiazide diuretics in reducing coronary heart disease (CHD) or total mortality in the elderly, the combination of the two agents and thiazides alone appear to be as effective as newer agents, such as angiotensin-converting enzyme inhibitors (ACE-I) and calcium antagonists. There was no evidence from these trials that BP reduction in the elderly was associated with any deleterious effects.

Whilst the benefits of treating the elderly hypertensive are well established, some issues remain to be clarified, particularly in relation to treating the very elderly and the potential benefits beyond BP control that may be afforded by newer antihypertensive agents.
Stimulation of collagen gel contraction by angiotensin II and III in cardiac fibroblasts
Authors: Lijnen Paul , Petrov Victor , Rumilla Kandelaria , Fagard Robert
Published: May 2007

Objective The aim of the present study was to investigate whether angiotensin II (Ang II), angiotensin III (Ang III) or Ang II (2-8), angiotensin IV (Ang IV) or Ang II (3-8) and Ang II (1-7), Ang II (4-8), Ang II (5-8) and Ang II (1-4) can stimulate collagen gel contraction in cardiac fibroblasts in serum-free conditions.

Methods Cardiac fibroblasts (from male adult Wistar rats) from passage 2 were cultured to confluency and added to a hydrated collagen gel in a Dulbecco's Modified Eagle's Medium, with or without foetal bovine serum, for one, two or three days. The area of the collagen gels embedded with cardiac fibroblasts was determined by a densitometric analysis. Collagen gel contraction was characterised by a decrease in the gel area.

Results Ang II dose-dependently stimulated the contraction of collagen mediated by cardiac fibroblasts after one, two or three days of incubation in a serum-free medium. Telmisartan completely blocked the Ang II-induced collagen contraction by cardiac fibroblasts.

PD 123319 and des-Asp 1-Ile8-Ang II had no effect on the Ang II-induced collagen contraction by cardiac fibroblasts. Ang III also stimulated the contraction of collagen mediated by cardiac fibroblasts after one, two or three days of incubation in a serum-free medium. des-Asp1-lle8-Ang II and telmisartan completely blocked the Ang III-induced collagen gel contraction by cardiac fibroblasts. des-Asp1-Ile8-Ang II, however, had no effect on the Ang II-induced collagen gel contraction by cardiac fibroblasts. Ang IV and Ang II (4-8), (5-8), (1-7) and (1-4), however, had no effect on collagen gel contraction by cardiac fibroblasts. Addition of telmisartan, PD 123319 or des-Asp1-Ile8-Ang II alone did not affect collagen gel contraction by cardiac fibroblasts.

Conclusion Our data demonstrate that the effects of Ang II on the collagen gel contraction by adult rat cardiac fibroblasts in serum-free conditions are Ang II type 1(AT1)-receptor-mediated, because they are abolished by the specific AT1receptor antagonist, telmisartan, and not by the AT2receptor antagonist PD 123319 or by the Ang III antagonist des-Asp1-Ile 8-angiotensin. The Ang IIIstimulated contraction of collagen by cardiac fibroblasts is completely blocked by the Ang III receptor antagonist, des-Asp 1-Ile8-angiotensin II, and by telmisartan.
Antiproteinuric effect of candesartan cilexetil in patients with chronic glomerulonephritis
Authors: Kurokawa Kiyoshi , Abe Keishi , Saruta Takao , Arakawa Masaaki , Kikkawa Ryuichi , Ueda Naohiko , Onoyama Kaoru , Tomita Kimio , Ogawa Nobuya
Published: May 2007

A prospective, randomised, double-blind, parallel-group, dose-response trial was conducted to investigate the antiproteinuric effect of candesartan cilexetil, the angiotensin II type 1 receptor blocker, in patients with chronic glomerulonephritis. Patients (n=280) were treated for 12 weeks with candesartan cilexetil 2, 4, or 8 mg given orally once-daily (o.d.). The improvement in urinary protein excretion observed at the end of the treatment period was 15.9% in the 2 mg group, 25.6% in the 4 mg group, and 34.6% in the 8 mg group, respectively, showing a clear dose-response (2 mg <4 mg <8 mg; p=0.003). The mean reduction in urinary protein excretion was 11.3% in the 2 mg group, 26.3% in the 4 mg group, and 26.0% in the 8 mg group, showing a dose-response pattern, in that the effect of 4 mg and 8 mg was greater than that of 2 mg (2 mg <4 mg ~8 mg; p=0.010). As the observed reduction in urinary protein excretion failed to correlate with changes in mean blood pressure, it could not be attributed to the antihypertensive effect of the study drug alone. This suggests that candesartan cilexetil, 4—8 mg o.d., has antiproteinuric effects in patients with chronic glomerulonephritis.
Between-patient differences in the renal response to renin-angiotensin system intervention: clue to optimising renoprotective therapy?
Authors: Laverman Gozewijn D , de Zeeuw Dick , Navis Gerjan
Published: May 2007

Renin-angiotensin-aldosterone system (RAAS) blockade with angiotensin-converting enzyme inhibitors (ACE-I) or angiotensin II (Ang II), AT1receptor blockers (ARB) is the cornerstone of renoprotective therapy. Still, the number of patients with end-stage renal disease is increasing worldwide, prompting the search for improved renoprotective strategies.

In spite of proven efficacy at group level, the long-term renoprotective effect of RAAS blockade displays a marked between-patient heterogeneity, which is closely linked to between-patient differences in the intermediate parameters of blood pressure, proteinuria and renal haemodynamics. Of note, the between-patient differences by far exceed the between-regimen differences, and thus may provide a novel target for exploration and intervention.

The responsiveness to RAAS blockade appears to be an individual characteristic — as demonstrated by studies applying a rotation-schedule design. The type and severity of renal disease, obesity, insulin-resistance, glycaemic control, and genetic factors may all be involved in individual differences in responsiveness, as well as dietary factors, such as dietary sodium and protein intake.

Several strategies, such as dietary sodium restriction and diuretic therapy, dose-titration for proteinuria, and dual RAAS blockade with ACE-I and ARB, can improve the response to therapy at a group level. However, when analysed for their effect in individuals, it appears that these measures do not allow poor responders to catch up with the good responders, i.e. in spite of their efficacy at group level, the available measures are usually not sufficient to overcome individual resistance to RAAS blockade.

We conclude that between-patient differences in responsiveness to renoprotective intervention should get specific attention as a target for intervention. Unravelling of the underlying mechanisms may allow development of specific intervention. Based on the currently available data, we propose that response-based treatment schedules, with a multidrug approach titrated and adapted at individual responses rather than fixed treatment schedules, may provide a fruitful strategy for more effective renoprotection.
Local renin-angiotensin systems and their interactions with extra-adrenal corticosteroid production
Authors: MacKenzie Scott M , Fraser Robert , Connell John MC , Davies Eleanor
Published: May 2007

Adrenal aldosterone production is regulated by the renin-angiotensin system (RAS). It is now known that several other tissues are capable of extra-adrenal aldosterone biosynthesis and that these tissues can also generate angiotensin II through local RAS. Therefore, the regulation of local aldosterone production by the local RAS is a distinct possibility. In this review, we present evidence for the existence of such systems in the vascular system, heart and brain. We then discuss the possibility of interactions between the RAS and aldosterone synthesis at the local level and speculate on the possible physiological effects of such systems in these tissues.
Blood pressure and cardiac autonomic function in relation to risk factors and treatment perspectives in Type 1 diabetes
Authors: Poulsen Løgstrup
Published: May 2007

The cumulative incidence of diabetic nephropathy in Type 1 diabetes mellitus is in the order of 25—30%. The recognition that elevated blood pressure (BP) is a major factor in the progression of these patients to end-stage renal failure has led to the widespread use of antihypertensive therapy in order to preserve glomerular filtration rate and ultimately to reduce mortality.

The routine measurement of microalbuminuria allows early identification of the subgroup of patients at increased risk of developing clinical nephropathy.

Microalbuminuric Type 1 diabetic patients show a number of characteristic pathological abnormalities. In addition to elevated BP and abnormal circadian rhythm, there are also associated abnormalities of vagal function, lipid profile and endothelial function, as well as an increased prevalence of retinopathy.

The first section of this two-part review focusses on the early changes associated with renal involvement in Type 1 diabetes. It addresses the associations between urinary albumin excretion, glycaemic control, smoking, BP, circadian BP variation, QT interval abnormalities and autonomic function in three groups of patients; those with normoalbuminuria, those progressing towards microalbuminuria and those with established low-grade microalbuminuria.
Review: The pharmacokinetics and pharmacodynamics of angiotensin-receptor blockers in end-stage renal disease
Authors: Sica Domenic A , Gehr Todd WB
Published: May 2007

Angiotensin-converting enzyme (ACE) inhibitors and more recently angiotensin-receptor blockers (ARBs) have become popular therapies in the end-stage renal disease (ESRD) patient. The ability of either of these drug classes to reduce blood pressure in the ESRD patient is well accepted; however, there is considerably less information available to guide the clinician in the safe and effective use of these drugs in the ESRD patient with congestive heart failure and/or coronary artery disease. Head-to-head studies in the ESRD patient are lacking for both drug classes. Several pharmacokinetic factors can influence the selection of these drugs, including dialysability and the propensity for systemic accumulation. ACE inhibitors (ACE-Is) and ARBs are recognised as having a range of nonpressor effects that are pertinent to patients with ESRD. Such effects include their ability to decrease both thirst drive and erythropoiesis. These drug classes, though, are distinguishable by the unique adverse effect profile for ACE-Is. As is the case in patients without renal failure, ESRD patients can experience cough and, less frequently, angioneurotic oedema with ACE-Is. In the ESRD population, so-called anaphylactoid dialyser reactions can occur in conjunction with ACE-I use. The use of a drug from within the ARB class carries both less risk and permits a compound with a preferred pharmacokinetic profile — limited dialysability and minimal systemic accumulation — to be administered. These attributes would favour the increased use of ARBs in this population.
Review: Salt, blood pressure and the renin-angiotensin system
Authors: He Feng J , MacGregor Graham A
Published: May 2007

Much evidence from epidemiological, migration, intervention, animal and genetic studies suggests that salt intake plays an important role in regulating blood pressure (BP). At the same time, many clinical trials have shown that reducing salt intake lowers BP. However, the magnitude of the fall in BP for a given reduction in salt intake varies with age, ethnic group and BP levels. This difference has been suggested to be related to the responsiveness of the renin-angiotensin system (RAS). However, the sympathetic nervous system, the kallikrein-kinin system, the nitric oxide system, and many eicosanoids may also play a role. In this article, we address the important role of the RAS in determining the fall in BP with salt reduction.
Review: Early renal involvement in Type 1 diabetes mellitus — Part 2: ACE inhibitor intervention in Type 1 diabetes with low grade microalbuminuria
Authors: Poulsen Løgstrup
Published: May 2007

Several clinical trials have consistently shown that antihypertensive treatment, particularly with angiotensin-converting enzyme inhibitors (ACE-I) reduces albuminuria in Type 1 diabetic patients. More recently, data on the beneficial effects of ACE-I on the preservation of glomerular filtration rate and renal ultrastructure have emerged. However, in general, these trials have recruited a wide spectrum of diabetics, including some patients with severe albuminuria. Thus, the question of the ideal stage at which to instigate what is likely to be lifelong therapy in young people still remains unanswered.

Exercise is known to significantly increase both blood pressure (BP) and urinary albumin excretion (UAE), both of which are important determinants of progression of nephropathy in diabetes. Thus, it is possible that exercise may have an adverse effect on diabetic renal disease. The effects of ACE-I on exercise-BP and exercise-UAE in microalbuminuric Type 1 diabetic patients has not been examined in long-term placebo-controlled studies.

In the second part of this two-part review, we examine the effects of the ACE-I, lisinopril, 20 mg o.d. for two years, in comparison with placebo, on UAE, 24-hour ambulatory BP, exercise-BP, exercise-UAE and renal haemodynamics in 22 patients with Type 1 diabetes and low-grade microalbuminuria. We further discuss the effects of ACE-I on nephropathy and other complications of diabetes.
Interaction of -blockers and angiotensin receptor blockers/ACE inhibitors in heart failure
Authors: Cohn Jay N
Published: May 2007

The renin-angiotensin-aldosterone system contributes to the progression of heart failure and its inhibition slows ventricular remodelling and favourably affects morbidity and mortality. -blockers exert a remarkably favourable effect on progression that may be mediated at least in part by renin inhibition. Although earlier trials suggested a possible adverse interaction when an angiotensin receptor blocker was added to an angiotensin-converting enzyme inhibitor and a -blocker, a recent study and newly analysed mechanistic data indicate that the triple combination provides modest additional inhibition of angiotensin that can further slow progression of disease.
Elevated intracardiac angiotensin II leads to cardiac hypertrophy and mechanical dysfunction in normotensive mice
Authors: Huggins Catherine E , Domenighetti Andrea A , Pedrazzini Thierry , Pepe Salvatore , Delbridge Lea MD
Published: May 2007

Introduction

Angiotensin II (Ang II) is known to induce cardiac growth and modulate myocardial contractility. It has been reported that elevated levels of endogenous Ang II contribute to the development of cardiac hypertrophy in hypertensives. However, the long-term functional effects of cardiac exposure to Ang II in normotensives is unclear.

A recently developed transgenic mouse (TG1306/1R), in which cardiac-specific overproduction of Ang II produces primary hypertrophy, provides a new experimental model for investigation of this phenotype. The aim of the present study was to use this model to investigate whether there is a functional deficit in primary hypertrophy that may predispose to cardiac failure and sudden death. We hypothesised that primary cardiac hypertrophy is associated with mechanical dysfunction in the basal state.

Methods

Normotensive heterozygous TG1306/1R mice harbouring multiple copies of a cardiac-specific rat angiotensinogen gene were studied at age 30—40 weeks and compared with age-matched wild-type littermates. Left ventricular function was measured ex vivo in bicarbonate buffer-perfused, Langendorffmounted hearts ( at a perfusion pressure of 80 mmHg, 37°C) using a fluid-filled PVC balloon interfaced to a pressure transducer and digital data acquisition system.

Results

There was no difference in the mean (±SEM) intrinsic heart rate of TG1306/1R and wild-type control mice (357.4±11.8 vs. 367.5±20.9 bpm, n=9 & 7). Under standardised end-diastolic pressure conditions, TG1306/1R hearts exhibited a significant reduction in peak developed pressure (132.2±9.4 vs. 161.5±3.1 mmHg, n=9 & 7, p<0.05) and maximum rate of pressure development (3566.7±323.7 vs. 4486.3±109.4 mmHg, n=9 & 7, p<0.05). TG1306/1R mice show a significant correlation between incidence of arrhythmia and increasing heart size (Spearman's correlation coefficient 0.61).

Conclusion

These data demonstrate that chronic in vivo exposure to elevated levels of intra-cardiac Ang II is associated with significant contractile abnormalities evident in the ex vivo intact heart. Our findings suggest that endogenous overproduction of cardiac Ang II, independent of changes in blood pressure, is sufficient to induce ventricular remodelling that culminates in impaired cardiac function which may precede failure.
Dietary sodium restriction specifically potentiates left ventricular ACE inhibition by zofenopril, and is associated with attenuated hypertrophic response in rats with myocardial infarction
Authors: Westendorp Bart , Schoemaker Regien G , Buikema Hendrik , de Zeeuw Dick , van Veldhuisen Dirk J , van Gilst Wiek H
Published: May 2007

Introduction In patients with myocardial infarction (MI)-induced heart failure, angiotensin-converting enzyme (ACE) inhibitors are proven effective therapy in inhibiting the progression towards overt heart failure. However, the prognosis in these patients is still very poor, and optimisation of therapy is warranted. The antihypertensive and renoprotective effects of ACE inhibitors (ACE-Is) can be substantially enhanced by dietary sodium restriction. In line with the latter, the aim of the present study was to explore whether dietary sodium restriction enhances the efficacy of ACE-I after MI.

Methods Rats with MI-induced left ventricular (LV) dysfunction received ACE-I therapy with zofenopril (5.5 mg/kg/day orally), with or without dietary sodium restriction. ACE activity was measured in non-infarcted LV tissue, kidneys and plasma. Effects on cardiac hypertrophy were examined by means of organ weight/body weight ratios. After blood pressure (BP) measurements, functional consequences of therapy were evaluated as LV pressure development in isolated perfused hearts.

Results Dietary sodium restriction alone had no effect on any of the measured parameters, whereas zofenopril alone significantly reduced plasma and kidney ACE activity, but not LV ACE activity, nor LV weight/body weight ratio. However, only when ACE-I therapy was combined with dietary sodium restriction was LV ACE activity significantly reduced. This effect was paralleled by inhibition of LV hypertrophy. BP was reduced after infarction, and further reduced by zofenopril, but not affected by dietary sodium. Neither treatment was associated with effects on the MI-induced reduction of LV function in vitro.

Conclusions Effects of ACE inhibition with zofenopril can be potentiated by additional dietary sodium restriction. However, these effects were tissue-specific, since LV, but not kidney or plasma, ACE activity was affected by the additional dietary sodium restriction. Effects on LV ACE activity were paralleled by reduced LV hypertrophy. Since the measured parameters did not indicate any adverse side-effects, dietary sodium restriction may provide a safe strategy to improve ACE-I efficacy in patients with infarction-induced LV dysfunction.
Effects of ACE inhibition and AT1-receptor blockade on haemodynamic responses to L-arginine in Type 1 diabetes
Authors: Komers Radko , Simkova Renata , Kazdova Ludmila , Ruzickova Jana , Pelikanova Terezie
Published: May 2007

Introduction Angiotensin-converting enzyme (ACE) inhibitors have been shown to improve endothelial function in Type 1 diabetes. However, the potential of ACE inhibitors (ACE-I) to enhance the haemodynamic effects of L-arginine (L-arg), the precursor of nitric oxide (NO), has not been evaluated. Furthermore, angiotensin receptor blockers (ARBs), another group of inhibitors of the renin-angiotensin system (RAS), have not been studied in this context.

Methods Using a randomised, crossover design, the acute effects of L-arg (200 mg/kg) on blood pressure (BP) and renal haemodynamics were determined in uncomplicated Type 1 diabetic patients before and after three weeks of treatment with the ACE-I ramipril (5 mg/day) or the ARB losartan (50 mg/day).

Results L-arg alone did not influence BP or renal haemodynamics. BP responses to L-arg were not modulated by ACE-I or ARB. In contrast to the systemic responses, L-arg induced significant renal vasodilation after treatment with ramipril (p<0.05). Unlike ramipril, losartan did not modulate renal haemodynamic responses to L-arg. L-arg administration was paralleled by increments in plasma L-citrulline levels, determined as a measure of L-arg-induced systemic NO production. These responses were not influenced by RAS inhibitors. No changes in other indicators of the systemic and renal NO production, such as plasma and urinary nitrates/nitrites, were detected in response to L-arg alone or after treatment with RAS inhibitors.

Conclusions ACE-Is have greater potential than ARBs to enhance L-arg effects in the kidney in uncomplicated Type 1 diabetes. Neither RAS inhibitor influenced the systemic effects of L-arg. The lack of changes in renal NO indicators parallelling the haemodynamic responses, suggests that the effects of ACE-I on L-arg-induced renal haemodynamic changes could be also attributable to NO-independent mechanisms.
Regulation of renal proximal fluid uptake by luminal and peritubular angiotensin II
Authors: Hiranyachattada Siriphun , Harris Peter J
Published: May 2007

Introduction

Angiotensin II (Ang II), when administered to either tubular lumen or peritubular capillary, exerts a biphasic action on proximal fluid uptake rate. At low concentrations, (10-12—10-10M) Ang II stimulates fluid transport, whereas higher doses (> 10-9 M) inhibit. Ang II is secreted into the lumen in the proximal tubule and the concentration of Ang II in the proximal lumen has been reported to be in the nanomolar range, 100—1,000 times higher than in peritubular blood. We investigated the regulation of renal proximal fluid transport by luminal (predominantly locally produced) and peritubular capillary (circulatory) Ang II in anaesthetised rats, using a selective AT1-receptor antagonist, candesartan.
Review: Arterial stiffness and the renin-angiotensin-aldosterone system
Authors: Mahmud Azra , Feely John
Published: May 2007

Arterial stiffness has recently been recognised as an independent risk factor for cardiovascular morbidity and mortality in hypertension. Many of the complications seen with angiotensin II (Ang II) excess or hyperaldosteronism — an increased event rate, left ventricular hypertrophy, endothelial dysfunction and target organ damage — are also associated with arterial stiffness. It is possible that reduced arterial compliance may be one mechanism whereby increased activity of the renin-angiotensin-aldosterone system (RAAS) produces adverse vascular effects. Common pathophysiological processes, altered collagen turnover and increased fibrosis may underlie both arterial stiffness and RAAS-associated vascular damage. While it is recognised that patients with hyperaldosteronism have increased arterial stiffness, the role of the RAAS in modulating arterial compliance in essential hypertension and in normotensive subjects is less clear cut. There is, however, more consistent data which show that drugs that interfere with Ang II or aldosterone, namely angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs) and aldosterone antagonists, all reduce arterial stiffness. In many cases, this is to a greater extent than predicted from the extent of reduction in blood pressure (BP), suggesting a role for RAAS in vascular stiffness in hypertensive subjects. There is also evidence that combined ACE inhibitors (ACE-Is) and ARBs may have an additive effect in reducing stiffness. The reduction in cardiovascular mortality in end-stage renal disease patients treated with ACE-Is was preferentially seen in those who had reduced arterial stiffness. These data suggest that, in addition to regulation of vascular biology and BP, the RAAS is an important determinant of arterial stiffness in health and, more particularly, in disease.
BNP and ANP as diagnostic and predictive markers in heart failure with left ventricular systolic dysfunction
Authors: Menezes Falcão Luiz , Pinto Fausto , Ravara Luciano , van Zwieten Peter Adriaan
Published: May 2007

Background

The prevalence of chronic heart failure (CHF) with systolic dysfunction is increasing. Plasma natriuretic peptides have been envisaged as diagnostic and predictive markers.

Aims

To investigate the relationship between the levels of B-type natriuretic peptide (BNP) and A-type natriuretic peptide (ANP) and the clinical and functional parameters of CHF in outpatients with CHF at baseline, compared with normal healthy controls; to find out the differences in a randomised controlled trial between patients treated with an angiotensin-converting enzyme (ACE) inhibitor, captopril, or an angiotensin receptor blocker (ARB), irbesartan. These differences were assessed throughout the six-month treatment period and at the sixth month.

Methods Plasma BNP (pmol/L) and ANP (pmol/L) were

determined in 68 hypertensive patients with dilated cardiomyopathy, NYHA class III-IV and ejection fraction (EF) <40%, and in 26 normal controls. Statistical analysis for BNP and ANP was done by Student's t-test. The patient group was randomly subdivided into two subgroups of 34 patients, each treated with either an ARB, irbesartan, or an ACE inhibitor (ACE-I), captopril. BNP and ANP were measured in both subsamples and correlated with clinical, functional and neurohormonal parameters throughout a follow-up period of six months and at the sixth month.

Results

The mean EF in the patient sample was 33.43±6.52% and in the controls was 61.96 ±3.53% (p=0.000). The mean BNP (pmol/L) in patients was 44.78±54.36 and in the controls was 7.12±8.28 (p=0.000) and the mean ANP (pmol/L) was 30.32±25.97 in patients and 11.18±7.92 in controls (p=0.000). A statistically significant difference was found between patients and healthy controls. Significant correlations were found between natriuretic peptides and EF. Between the baseline phase and the sixth month, BNP and ANP decreased significantly in the ARB group. At the sixth month, both BNP and ANP were lower in the ARB group. Evidence of clinical benefit was found with both ARB or ACE-I treatment throughout the six months, with patients moving from classes III and IV to class II NYHA. Improvement of EF was also found, with transition of patients with lower EF (even <30%) to higher values. EF was higher in the ARB group at the sixth month.

Conclusions

BNP and ANP can be useful diagnostic tools in hypertensive CHF patients with moderate-to-severe LV dysfunction. The decrease in BNP and ANP in the ARB group throughout six months, as well as the lower value at the sixth month, suggest a prognostic value of these parameters.
Renin-angiotensin system blockade prevents the increase in plasma transforming growth factor β1, and reduces proteinuria and kidney hypertrophy in the streptozotocin-diabetic rat
Authors: Erman Arie , Veksler Semyon , Gafter Uzi , Boner Geoffrey , Wittenberg Clara , van Dijk David Jonathan
Published: May 2007

Introduction

Combination therapy with angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) is used to improve renal outcome achieved by monotherapy in diabetic patients. In addition, interference with the renin-angiotensin system (RAS) reduced expression and excretion of transforming growth factor β1 (TGF-β1) in diabetic nephropathy. The aim of this study was to investigate the effects of interrupting the RAS by ACE inhibitor (ACE-I) or ARB monotherapy or by combination therapy on proteinuria, kidney hypertrophy and plasma TGF-β1 in diabetic rats.

Materials and methods

Forty-one male Wistar rats were allocated to five groups: 1 = control rats, 2 = diabetic rats (streptozotocin [STZ] 55 mg/kg), 3 = diabetic rats as above receiving enalapril (20 mg/kg/day), 4 = diabetic rats receiving losartan (80 mg/kg/day), 5 = diabetic rats receiving both losartan and enalapril. The study lasted 60 days.

Results

Urinary protein excretion, kidney weight, serum ACE activity and plasma TGF-β1 increased significantly in untreated diabetic rats compared with controls. Administration of losartan, enalapril, or both for 60 days prevented these changes. Furthermore, combined therapy for 30 days normalised urinary protein excretion, while monotherapy did not. Losartan inhibited serum ACE activity both in vivo and in vitro. Plasma TGF-β1 levels were positively correlated with blood glucose levels (r=0.4059) and with urinary protein excretion (r=0.3558).

Conclusions

Combination therapy with losartan and enalapril was more effective than monotherapy with either drug in achieving an early antiproteinuric response. Long-term treatment with losartan was as effective as the combined treatment, possibly due to a dual inhibitory effect on the RAS. The antiproteinuric effect may be related, in part, to reduced TGF-β1.
The VALUE trial: a commentary
Authors: Sever Peter
Published: May 2007

The Valsartan Antihypertensive Long-Term Use Evaluation (VALUE) Trial compared coronary heart disease outcome in two anti-hypertensive treatment strategies based on either an angiotensin receptor blocker, valsartan, or a calcium channel blocker (CCB), amlodipine. In both patient groups a diuretic was added, if necessary, in an attempt to achieve blood pressure (BP) goals. Follow-up of over 15,000 patients was maintained for 4.2 years. There were no differences in the primary composite endpoint of cardiac morbidity and mortality (which included interventional procedures, hospitalised heart failure, non-fatal myocardial infarction and fatal coronary heart disease, however myocardial infarction and stroke events occurred less commonly on amlodipine than on valsartan — the former achieving statistical significance [p=0.02 and p=0.08 respectively]). There was a non-significant excess of hospitalised heart failure on amlodipine (p=0.012). However, lower BPs early in the trial probably accounted for most of the observed benefits in favour of the CCB. The angiotensin receptor blocker arm was associated with less new onset diabetes.

The results of VALUE add further support to the evidence that blood pressure control is the major determinant in outcome in trials of antihypertensive therapy.
Lectin chromatography of extrarenal renin protein in human plasma and tissues: Potential endocrine function via the renin receptor
Authors: Stubbs Anthony JM , Skinner Sandford L
Published: May 2007

Secretion of prorenin from extrarenal tissues comprises approximately half of the renin protein in plasma; its origin is unknown. The discovery of a prorenin/renin receptor that activates vascular tissue kinases raises interest in this otherwise inactive component. We have studied its glycosylation as this may distinguish it from renal renin. The binding of renin protein (active and prorenin) in human plasma and tissues to concanavalin (Con A) and wheat germ lectins was deployed. Immunoradiometric and enzyme kinetic assays were applied to column fractions. Mannosylated renin protein binds to Con A and has been shown to be taken up by human vascular and hepatic cells on mannose-6-phosphate receptors, possibly as a clearance mechanism. But the other binding sites of prorenin/renin that elicit a cellular phosphorylation response are apparently independent of glycosylation. The tissues examined (kidney, adrenal, ovary) each contain high proportions of Con A binding renin, but the plasma of normal resting males and females contain mainly non-binding renin, the proportion increasing as renal renin secretion decreases. The extreme of this relationship is seen in anephric patients and in some normal women on oral contraceptives with suppressed renal renin, in whom plasma renin is entirely non-binding to Con A. Conversely, when renal renin secretion was stimulated, the increased plasma active renin bound to Con A. However, extrarenal tissues containing exclusively Con A non-binding renin protein, and hence potential sources of anephric plasma renin protein, were not identified, but are unlikely to include adrenal or female reproductive tract. The findings are consistent with the view that normal human plasma contains a considerable amount of amannosylated prorenin of extrarenal origin that escapes hepatic clearance and has a longer half-life than renal renin. This plasma renin form would be expected to be activated in association with the recently described renin/prorenin aspartyl protease receptor and to participate in local pathophysiological processes.
Renin-angiotensin system gene polymorphisms and premature coronary heart disease
Authors: Sekuri Cevad , Cam F Sirri , Ercan Ertugrul , Tengiz Istemihan , Sagcan Abdi , Eser Erhan , Berdeli Afig , Akin Mustafa
Published: May 2007

Introduction

Experimental and clinical studies demonstrated that the renin-angiotensin system (RAS) affects the pathogenesis of atherosclerosis and prognosis of coronary heart disease (CHD). The aim of this study was to investigate the genotype distribution and the allele frequencies of three RAS genes polymorphisms and their effects on premature CHD in a Turkish population.

Materials and methods

One-hundred and fifteen Turkish patients with premature CHD and 128 controls were included into the study. Angiotensin-converting enzyme (ACE), angiotensin II type 1 (AT1) receptor and angiotensinogen (AGT) gene polymorphisms were analysed by polymerase chain reaction (PCR ) and restriction fragment length polymorphism (RFLP).

Results

The patients group showed an increased frequency of the ACE D allele compared with controls (65% vs. 35%, p=0.0001). There was a significant association between the DD genotype and premature CHD (ACE DD vs. ID and II; odds ratio [OR]=2.82 [CI 95% 1.33—2.91, p=0.002]). Also, we observed increased premature CHD risk associated with higher frequencies of the AGT MM genotype in patients when compared with controls (AGT MM vs. TT and MT, OR=1.92 [CI 95% 1.11—3.33, p=0.018]). We found a significant association between AT1-receptor AA genotype and decreased risk of premature CHD (AT1R AA vs. AC and CC, OR= 0.57[CI 95% 0.34—0.95, p=0.03]).

Conclusions

We demonstrated that increased premature CHD risk is associated with higher frequencies of the ACE DD and AGT MM genotypes. These findings indicate a synergistic contribution of ACE DD and AGT MM polymorphisms to the development of premature CHD. Also, our results suggest that family history, smoking, diabetes, hypertension, obesity and ACE DD genotype were independent risk factors for premature CHD.