bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cardiac, renal and vascular complications in the diabetic patient
Authors: Zanchetti Alberto 
Published: May 2007

Summary Type 2 diabetes has long been known to be associated with an increased risk of cardiovascular disease. Patients with type 2 diabetes have also been shown to benefit more from antihypertensive therapy than do non-diabetics with hypertension. The benefits of aggressive antihypertensive therapy are reflected in the recent reduction of blood pressure (BP) targets in international guidelines. Drugs acting on the renin-angiotensin-aldosterone system (RAAS) have well-documented efficacy, and results from large-scale trials with highly selective angiotensin II (Ang II) receptor blockers (ARBs), such as valsartan, are awaited. The VALUE trial will provide the largest body of information yet on the comparative benefits of using an ARB or calcium channel blocker in hypertensive patients with diabetes.
New clinical investigations with selective angiotensin II receptor blocker therapy in diabetes and renal disease
Authors: Ruilope Luis M 
Published: May 2007

Summary Halting the reduction in glomerular filtration rate (GFR) is the primary aim of any treatment of patients presenting with progressive chronic renal failure, a very common corollary to diabetes. To improve GFR, the high blood pressure (BP) and proteinuria often seen in these patients must both be controlled. These symptoms lead not only to progressive loss of renal function, but also to an increase in cardiovascular risk. Use of angiotensin-converting enzyme (ACE) inhibitors in these patients has been reported to control BP and reduce protein excretion and cardiovascular risk. Complete blockade of angiotensin II (Ang II) action with the highly selective Ang II receptor blocker (ARB) valsartan, both as monotherapy and in combination with ACE inhibitors, is well-tolerated and efficacious in patients with renal failure. Unlike ACE inhibition, ARB treatment leads to no initial reduction in GFR, thus valsartan may be a better agent for the control of BP, with greater renal protection.
Pathological involvement of chymase-dependent angiotensin II formation in the development of cardiovascular disease
Authors: Urata Hidenori 
Published: May 2007

Summary Chymase is a potent and specific angiotensin II (Ang II)-forming enzyme in vitro. There is also strong evidence to suggest its importance in vivo. Recent clinical studies have suggested that high serum cholesterol levels are associated with increased vascular chymase activity and this may assist in the development of atherosclerosis. This clinical finding has been reproduced in hamster models. Studies with transgenic mice overexpressing the human chymase gene suggest a direct association between vascular chymase upregulation and atherogenesis. There is also increased chymase activity following various cardiac diseases such as myocardial ischaemia, volume overload cardiac failure, cardiomyopathy and viral myocarditis, suggesting that increased cardiac chymase activity appears to be involved in cardiac remodelling.
Should the use of short acting angiotensin-converting enzyme inhibitors be abandoned?
Authors: Erman Arie , Boner Geoffrey , van Dijk David J 
Published: May 2007

Background Angiotensin-converting enzyme inhibitors (ACE-I) have different modes of action and different durations of inhibition. The effects of ACE-I on the various components of the renin-angiotensin system (RAS) at trough hours were studied in patients with diabetes mellitus receiving long-term ACE-I treatment. Methods Out of 86 Type 1 and 2 diabetic patients, 49 were untreated, 25 received captopril and 12 received enalapril as chronic treatment. Blood for the determination of plasma renin activity (PRA), serum ACE activity and plasma angiotensin II (Ang II) was drawn in the morning (0700—0900 hours) after an overnight fast, about 12 hours after the last dose. PRA and Ang II were measured by RIA and serum ACE activity was assayed by a radiometric assay using 3H-hippuryl-glycyl-glycine as a substrate. Results Mean age was significantly greater in the enalapril-treated patients. Systolic and diastolic blood pressures were not different between the captopril-treated and untreated groups. Serum ACE activity in the captopril-treated diabetic patients was 101.5±42.5 nmol/mL/min, values obtained in untreated diabetic patients (101.4±25.2 nmol/mL/min). In contrast, ACE activity in the enalapril-treated patients was significantly reduced (5.5±7.5 nmol/mL/min) compared with untreated and captopril-treated patients (p<0.00001). PRA values in the ACE-I treated patients were significantly increased. Plasma Ang II levels were significantly increased in the captopril-treated vs. untreated patients (65.1±50.2 vs. 36.2±31.7 pg/mL, p=0.006), whereas the values in the enalapril-treated patient were slightly, but not significantly, reduced (23.8±21.4 pg/mL). Conclusion Trough serum ACE activity is not suppressed in diabetic patients receiving captopril, compared with those receiving enalapril and we thus question the use of short acting ACE-I in these patients.
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.
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.
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.
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: 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.
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.