bluuebunny/crossref_metadata_2025_split huggingface dataset:
Role of proteinuria in the regulation of renal renin-angiotensin system components in unilateral proteinuric rats
Authors: Deelman Leo E , Navis Gerjan , de Boer Erik , Wietses Mirian , de Zeeuw Dick , Henning Robert H 
Published: May 2007

Renin-angiotensin system (RAS) overactivity has been implied in progressive renal function loss. We investigated whether changes in the renal expression of RAS components are specifically associated with the proteinuric kidney. Unilateral adriamycin-induced proteinuria was obtained by clamping the left renal artery before injection of adriamycin. In control animals, both left and right renal arteries were clamped. Twelve weeks later, mRNA expression of RAS components was determined in both kidneys. In the affected and non-affected kidney of the unilateral proteinuric rat, we demonstrate up-regulation of angiotensin-converting enzyme (ACE) mRNA (213%±22 and 188%±24 of controls, respectively), up-regulation of transforming growth factor (TGF- ) mRNA (956%±229 and 418%±56) and down-regulation of angiotensin type 2 receptor (AT2-R) mRNA (24%±5 and 20%±5). The expression of angiotensin type 1 receptor (AT1-R) mRNA and inositol 1,4,5-trisphosphate receptor type I (IP3R-I) mRNA were unchanged. In conclusion, renal expression of ACE, AT2-R, and AT1-R mRNA is not mediated by protein leakage. Local intrarenal protein leakage did influence renal TGF- mRNA expression.
Involvement of renal ACE activity in proteinuria-associated renal damage in untreated and treated adriamycin nephrotic rats
Authors: Bos Hendrik , Laverman Gozewijn D , Henning Robert H , Tiebosch Anton TMG , de Jong Paul E , de Zeeuw Dick , Navis Gerjan 
Published: May 2007

Proteinuria is assumed to play a pathogenetic role in progressive renal damage. Angiotensin-converting enzyme (ACE) inhibition reduces proteinuria and provides renoprotection. This suggests that ACE activity might play a pathogenetic role in the development of proteinuria-induced renal structural damage. We investigated this hypothesis in untreated and treated established adriamycin nephrosis, a model of proteinuria-induced renal damage. In a time-course experiment, the development of renal structural damage in untreated adriamycin nephrotic rats was paralleled by a significant rise in renal ACE activity. Moreover, on cross-sectional analysis, a consistent positive correlation between renal, but not plasma, ACE activity and proteinuria, focal glomerulosclerosis and interstitial injury was present. Notably, these associations were present, not only in the untreated condition, but also during intervention with either ACE inhibition or AT1-receptor antagonism. Interestingly, we found that higher renal ACE activity is associated with more severe renal damage for a given amount of proteinuria, suggesting that renal ACE activity may be either a permissive or a promoting factor in the processes by which proteinuria eventually leads to renal structural damage. This relationship was abolished by renin-angiotensin system (RAS)-blockade, suggesting that RAS-mediated effects are involved in the relationship between renal ACE activity and proteinuria-induced renal damage. In conclusion, in untreated as well as treated adriamycin nephrotic rats, renal ACE activity is closely associated with renal outcome. This association appears to be independent of the specific mode of blockade of the RAS. Renal ACE activity is a consistent marker of individual differences in proteinuria-associated renal damage: further studies are needed to investigate a possible pathogenetic role in renal damage.
Ramipril improves nitric oxide availability in hypertensive rats with failing hearts after myocardial infarction
Authors: Linz Wolfgang , Itter Gabi , Dobrucki Lawrence W , Malinski Tadeusz , Wiemer Gabriele 
Published: May 2007

A markedly decreased aortic nitric oxide (NO) availability, probably due to impaired endothelial nitric oxide synthase activity with enhanced O2- and peroxynitrite production, seems to be attributable to endothelial dysfunction in spontaneously hypertensive rats (SHR) with severe congestive heart failure (CHF). In this study, we investigated the chronic effect of the angiotensin-converting enzyme inhibitor, ramipril (RA) and the loop diuretic, frusemide (FU), as well as the combination of both on endothelial NO, O2- and peroxynitrite production in aortae from SHR with failing hearts after myocardial infarction (MI). Heart failure was induced by permanent occlusion of the left coronary artery. SHR were randomised to receive either placebo, RA, (1 mg/kg/day), FU (4 mg/kg/day) or RA+FU (1 and 4 mg/kg/day, respectively). Treatments were started two weeks following MI and continued for six weeks. Reduced aortic and coronary flow indices in the working heart, which can be considered as markers for endothelial function, were significantly normalised and improved, respectively, by RA, FU or RA+FU-treatment. Similarly, all three treatment regimens significantly enhanced the reduced calcium ionophore (CaI)-induced NO-release (assessed by a NO-sensitive microsensor) from aortic endothelial cells of placebo- treated animals with CHF. Concomitantly, the increased CaI-stimulated O 2production (assessed by an electrochemical sensor) in aortic endothelial cells of placebo-treated animals with CHF was significantly reduced by RA and RA+FUtreatment. Treatment with RA and RA+FU also attenuated the dramatic increase in endothelial peroxynitrite concentration (chemiluminescence method), which was observed in placebo-treated rats with CHF. FU did not counteract improved haemo- and cardiodynamic parameters by RA. Thus, RA and FU act synergistically to enhance bioavailability of endothelium-derived NO, and this may contribute to the clinical usefulness of the combination of these drugs in treatment of heart failure.
Effects of ACE inhibition and AT1-receptor antagonism on endothelial function and insulin sensitivity in essential hypertensive patients
Authors: Yavuz Dilek , Koç Mehmet , Toprak Ahmet , Akpιnar Ihsan , Velioğlu Ayliz , Deyneli Oguzhan , Haklar Goncagül , Akalln Sema 
Published: May 2007

Objective Disturbed endothelial function is closely associated with hyperinsulinaemia and insulin resistance in essential hypertension. The aims of this study were: 1) to evaluate whether the two alternative drugs, angiotensin-converting enzyme (ACE) inhibitors and Angiotensin II (Ang II) antagonists, had comparable effects on glucose metabolism and endothelial function. 2) to determine whether they improve endothelial dysfunction through modulating insulin resistance and oxidative stress. Study design and methods Study design and methods Essential hypertensive patients were randomised into two groups: Twelve (nine patients in final analysis) patients were given enalapril (enalapril group), and twelve (nine patients in final analysis) were given losartan (losartan group). Twelve sex- and age-matched normotensive volunteers were included as controls. Before and after six months of treatment, endothelial function, insulin sensitivity and lipid peroxidation (TBARs) and NO metabolites (NOx) were evaluated. Results Endothelial function, measured as flow mediated dilatation (FMD), was improved in both of the treatment groups (p=0.0001). Calculated insulin sensitivity index also improved in the enalapril-treated group (p=0.05) but not in the losartan-treated group, compared with baseline levels. TBARS values decreased significantly in the enalapril group compared with baseline levels (p<0.001). FMD was positively correlated with insulin sensitivity index (r=0.32, p<0.05) and NOx levels (r=0.39, p=0.01) and negatively correlated with TBARS levels (r=-0.53, p=0.0002) in hypertensive patients. Conclusion Inhibition of the renin-angiotensin system, either with ACE inhibitors or AT1-receptor blockers improves endothelial dysfunction. ACE inhibition has prominent effects on improving insulin sensitivity and decreasing oxidative stress in essential hypertensive patients.
Combined renin-angiotensin system blockade and dietary sodium restriction impairs cardiomyocyte contractility
Authors: Trongtorsak Petcharat , Morgan Trefor O , Delbridge Lea MD 
Published: May 2007

Introduction Blockade of the renin-angiotensin system (RAS) by combined angiotensin-converting enzyme inhibitor and angiotensin type 1 receptor (AT1) antagonist treatment with reduced dietary sodium intake produces suppression of cardiac growth and regression of cardiac hypertrophy. The purpose of this study was to investigate whether cardiac growth suppression by combined RAS blockade under conditions of dietary sodium restriction is associated with cardiomyocyte atrophy and contractile dysfunction and whether this intervention modifies cardiomyocyte inotropic responsiveness to angiotensin II (Ang II).Methods Rats were fed a high (4% w/w) or low (0.2% w/w) NaCl diet for six days. Both groups were then given a combined intraperitoneal injection of perindopril (6 mg/kg/day) and losartan (10 mg/kg/day) with maintained dietary treatment for another seven days. At the end of the treatment period, animals were anaesthetised and their hearts were removed and weighed. Left ventricular cardiomyocytes were isolated by enzymatic dissociation and cell dimensions were evaluated. A line scan camera and digital imaging technique were used to assess cardiomyocyte contraction and inotropic responses to exogenous Ang II (10-10to 10-8M).Results Dietary treatment alone had no effect on body growth, whereas combined RAS blockade suppressed somatic growth in the low sodium (LS) group, compared with the high sodium (HS) group. This growth suppression in the LS group was also evident in the heart at the organ and cellular level. Studies of cardiomyocyte contraction showed that myocytes from the LS group exhibited contractile instability and depression of contractile performance. Compared with the HS group, myocytes from the LS group showed a significant reduction in maximum cell shortening (6.40±0.17 vs. 7.32±0.16% resting length, p<0.05), and maximum rate of shortening (3.85±0.14 vs. 4.29±0.11 cell length/ms, p<0.05). Myocytes of the HS group exhibited negative inotropic responses to Ang II at all concentrations tested, with a significant reduction in maximum cell shortening by 11—16% after 12 minutes peptide exposure (p<0.05 vs. non-treated control). In comparison, Ang II elicited both positive and negative responses in myocytes from the LS group, with a predominant negative inotropic effect.Conclusions This study provides evidence that combined RAS blockade treatment under restricted sodium intake conditions can impair cardiomyocyte contractile function in association with cardiomyocyte growth suppression. Chronic RAS blockade qualitatively alters the intrinsic inotropic status and responsiveness of ventricular cardiomyocytes, and this shift is further modulated by dietary sodium intake conditions.
Review: Blood pressure in haemodialysis patients: The importance of the relationship between the renin-angiotensin-aldosterone system, salt intake and extracellular volume
Authors: Doulton Timothy WR , MacGregor Graham A 
Published: May 2007

This review outlines the major mechanisms for control of blood pressure (BP) in individuals with renal failure on haemodialysis. Dietary salt stimulates thirst and, thereby, greater fluid intake with excessive fluid gain between dialysis sessions and chronic expansion of extracellular volume. At the same time, this volume expansion often fails to suppress the renin-angiotensin system (RAS) appropriately and this inevitably leads to high BP in the majority of individuals on haemodialysis. A greater understanding of the mechanisms involved leads to more rational treatment and better BP control. This can be achieved by careful measurement of BP before and after dialysis, allowing time for the equilibration of extracellular fluid shifts that occur after dialysis, combined with measurements of plasma renin activity. It is relatively easy to then decide how the high BP should be treated either by removal of excess volume by gradual ultrafiltration combined with restriction of salt intake to help prevent thirst and excessive fluid gain between dialyses, or by inhibition of the RAS, or by a combination of both. In those individuals who are unable to adequately reduce their dietary salt intake and still continue to gain large amounts of weight between dialysis, and are resistant to reducing their pre-dialysis weight, calcium antagonists may help to lower BP, either alone or in combination with RAS blockade. However, the BP often remains resistant to treatment unless they can be persuaded to reduce their salt intake.
Neurohumoral mechanism in the natriuretic action of intracerebroventricular administration of renin
Authors: Zavala Lida , Barbella Yarisma , Israel Anita 
Published: May 2007

Introduction Intracerebroventricular (IVT) administration of renin (R) decreases urinary volume and increases urinary sodium excretion. We investigated whether IVT-R-induced natriuresis could be associated with the release of atrial natriuretic peptide (ANP), its interaction with renal ANP-A receptors (ANPR-A) and the subsequent increase of urinary cyclic 3'-5' guanosine monophosphate (cGMP). Methods In IVT cannulated rats, the left carotid artery was catheterised with PE-50 tubing for blood collection, renin was injected IVT and arterial blood samples were collected at 0, 2, 5, 10 and 15 minutes of injection, and urinary sodium and cGMP excretion at 1-, 3- and 6-hour periods of urine collection. Plasma ANP levels and urinary cGMP were determined by radioimmunoassay, and each urine sample was analysed for sodium concentration using a flame photometer. Results Our results demonstrate that IVT-R administration increases plasma ANP levels after two minutes of injection and urinary cGMP concentration at 1-, 3-and 6 hour period of urine collection. The natriuretic action induced by IVT-R was blunted by peripheral administration of anantin, an ANPR-A antagonist. We assessed the role of brain angiotensin II (Ang II) AT1-receptors on the IVT-induced antidiuresis, natriuresis and cGMP urinary excretion, the last as an indirect index of ANP secretion. Blockade of brain Ang II AT 1-receptors with losartan (LOS; 120 µg/3 µl, IVT), inhibited the antidiuretic action and blocked the increased urinary sodium and cGMP excretion induced by IVT-R (7.14 mGU/5 µl). The increase in urinary cGMP was independent of nitric oxide synthase stimulation, since L-NAME pre-treatment did not alter the renal actions induced by IVT-R. Conclusions Our results suggest that there is a link between the brain and the kidney. The activation of brain angiotensinergic neurons and stimulation of AT1 receptors may stimulate the release of ANP to the circulation. The released ANP circulates to the kidneys where it acts through renal ANPR-As and the consequent increase in cGMP to produce natriuresis.
Macroarray analysis in the hypertrophic left ventricle of renin-dependent hypertensive rats: identification of target genes for renin
Authors: Kurdi Mazen , Cerutti Catherine , Randon Jacques , McGregor Lilian , Bricca Giampiero 
Published: May 2007

Introduction The aim of this work was to identify new renin target genes in left ventricular hypertrophy during hypertension. Materials and methods We compared left ventricle gene expression from four transgenic TGR(mRen2)27 (TG+/-) rats and four non-transgenic littermates (TG-/-) using cDNA macroarray. Hybridisation signals were quantified with a phosphorimager, and normalised to an external scale. Data analysis was performed with Statistical Analysis for Microarrays (SAM 1.21) software. The mRNA levels of candidate genes were determined by semi-quantitative RT-PCR in three different hypertensive rats: TG+/-, spontaneously hypertensive (SHR) and genetically Lyon hypertensive (LH) rats, compared to their respective controls (TG-/-, Wistar-Kyoto, Lyon low blood pressure rats). Results Out of 1,200 genes present on the macroarray, 233 were reliably measured and only three were overexpressed (Biglycan, β1-adenosine monophosphate-activated protein kinase [AMPK] and amyloid precursor like protein 2 [APLP2]) and 19 were underexpressed in the left ventricle of TG+/compared with TG-/-. APLP2 is a member of the amyloid precursor protein (APP) family. APLP2 and APP mRNA levels were increased in TGR(mRen2)27 but significantly decreased in LH rats, while only APP was increased in SHR rats. Conclusions We report new genes associated with renin-dependent left ventricular hypertrophy. Moreover, this work shows for the first time that the APP family gene expression could be altered in response to high renin activity and this effect is independent of cardiac remodelling and hypertension.
Losartan may prevent the elevation of plasma glucose, corticosterone and catecholamine levels induced by chronic stress
Authors: Üresin Yağiz , Erbas Bahar , Özek Mehmet , Özkök Elif , Gürol Ali Osman 
Published: May 2007

Introduction Stress is a stimulus that activates the hypothalamic pituitary adrenal (HPA) axis and sympathetic nervous system (SNS). Increased activity of the SNS causes to increment or impairment in blood pressure, heart rate, body temperature and plasma glucose and adrenocorticotrophic hormone (ACTH) levels. Angiotensin II (Ang II), which is a product of the renin-angiotensin system (RAS), is an important factor affecting the activity of the SNS and responses to stress. We suggest that the blockade of Ang II may be worthwhile in the prevention and treatment of diabetes mellitus and cardiovascular diseases affected by stress. Therefore, we investigated the effects of immobilisation stress on blood glucose, norepinephrine (NE), epinephrine (E) and corticosterone levels and the effects of an Ang II receptor antagonist, losartan, on these parameters. Materials and methods The rats were kept in small cylindrical cages for 60 min/day for 10 consecutive days to perform chronic immobilisation stress. Losartan (10 mg/kg) was given daily by gavage to Losartan (L) and Losartan + Chronic Stress (L+CS) groups. Control (C) and Chronic Stress (CS) P groups received an equal volume of saline daily by gavage for 10 days. After the last stress regimen, blood samples were collected for plasma glucose, NE, E and corticosteroid measurements. Results Plasma glucose, NE, E and corticosterone levels in the CS Group increased significantly compared with the C group. In Group L+CS, the plasma glucose, NE, E and corticosterone levels decreased significantly vs. Group CS. In Group L there was no significant difference vs. Group C. Conclusion It can be speculated that chronic blockade of RAS may decrease the excess sympathetic responses to stress in cardiovascular diseases and prevent the likely development of Type II diabetes mellitus.
Current guidelines in the pharmacological management of chronic heart failure
Authors: Metra Marco , Nodari Savina , Cas Livio Dei 
Published: May 2007

Treatment of heart failure has undergone major changes in the last two decades. European and US guidelines have absorbed these major changes and set the new standards. It is therefore mandatory that treatment of heart failure is based on this knowledge. According to these guidelines, patients with chronic symptomatic heart failure should be treated with a diuretic and sometimes digoxin and vasodilators, to relieve symptoms, in addition to an angiotensin-converting enzyme inhibitor and/or an angiotensin receptor blocker (ARB) and a β-blocker to improve prognosis. An aldosterone antagonist should be added in patients with more advanced heart failure. Prevention of heart failure has also become a major goal. We summarise here the major issues regarding the pharmacological treatment of chronic heart failure as indicated by the European and US guidelines.
Aldosterone blockade in heart failure
Authors: Struthers Allan D 
Published: May 2007

Aldosterone plays a key role in the pathophysiology of heart failure. Angiotensin converting enzyme inhibitors and angiotensin II receptor blockers may not suppress aldosterone production in the long term. This allows aldosterone to exert its effects on myocardial fibrosis and cardiac remodelling, endothelial function, electrolytes and baroreceptor response. The Randomized Aldactone Evaluation Study (RALES) tested spironolactone against placebo in patients with severe heart failure. The study found a 30% reduction in the risk of death among patients treated with spironolactone and a 31% reduction in the risk of death from cardiac causes. Patients in the spironolactone group had significantly lower risks of death from progression of heart failure and sudden cardiac death. The Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) investigated the effects of eplerenone against placebo in patients with myocardial infarction complicated by left ventricular dysfunction. Compared to placebo, the relative risk of death from any cause was 0.85 in eplerenone-treated patients, and the relative risk of death or hospitalisation for cardiovascular events was 0.87. The reduction in the risk of sudden death from cardiac causes was statistically significant. In conclusion, aldosterone blockade should form part of optimal therapy for patients with heart failure.
Effect of bestatin on angiotensin I-, II- and III-induced collagen gel contraction in cardiac fibroblasts
Authors: Lijnen Paul , Petrov Victor , Diaz-Araya Guillermo , Fagard Robert 
Published: May 2007

Objective The purpose of this investigation was to determine whether the aminopeptidase inhibitor with broad specificity, bestatin, affects angiotensin I (Ang I)-, angiotensin II (Ang II)- or angiotensin III (Ang III)-stimulated collagen gel contraction in cardiac fibroblasts. Design and methods Cardiac fibroblasts (from normal male adult rats) were cultured to confluency in Dulbecco's modified Eagle's medium (DMEM) with 10% foetal bovine serum (FBS). These fibroblasts (100,000 cells) were then further incubated in a floating collagen gel lattice with the test products Ang I (1 µmol/L), Ang II (100 nmol/L), Ang III (100 nmol/L) and bestatin (100 µmol/L) for three days in DMEM without FBS. The area of the collagen gels embedded with cardiac fibroblasts was determined by a densitometric analysis. Aminopeptidase activity was estimated by spectrophotometric determination of the liberation of p-nitroaniline from alanine- or arginine-p-nitroanilide, Results p-nitroaniline from alanine- or arginine-p-nitroanilide. Results Ang I, II and III stimulated (p <0.05) collagen gel contraction by 30.4±4.8 (SEM)%, 27.1±3.1% and 15.4±3.6% respectively. Ang I- and II-induced stimulation of collagen gel contraction was of the same order but more pronounced (p<0.05) than Ang III-stimulated collagen gel contraction. The Ang I-, II- and III-stimulated collagen contraction was reduced by bestatin. Bestatin, however, did not affect basal collagen gel contraction in cardiac fibroblasts. Bestatin dose-dependently inhibited the hydrolysis of arginine- and alanine-p-nitroanilide in cardiac fibroblasts. When a neutralising antibody to transforming growth factor TGF-β 1 was added to the collagen gel simultaneously with the angiotensins, the stimulated collagen contraction was not affected. Beta-aminoproprionitrile, an inhibitor of lysyl oxidase, completely abolished basal as well as Ang I-, II- and III-stimulated collagen contraction in cardiac fibroblasts. Results Our data suggest that aminopeptidases are involved in the Ang I-, II- and III-induced stimulation of collagen contraction in cardiac fibroblasts.