angiotensin-i and Kidney-Failure--Chronic

The renin-angiotensin-aldosterone system (RAAS) plays a major role in the regulation of blood pressure and homeostasis. Therefore, it is a commonly used target for pharmacotherapy of cardiovascular diseases in adults. However, the efficacy of this pharmacotherapy can only be limitedly derived into children. Comprehensive knowledge of the humoral parameters acting in the paediatric RAAS (e.g. angiotensin I, angiotensin II, angiotensin 1-7, angiotensin III, and angiotensin IV) might facilitate a more effective and rational pharmacotherapy in children. Therefore, this review aims to provide an overview of the maturing RAAS. Out of 925 identified records, 35 publications were classified as relevant. Physiological and pathophysiological concentrations of angiotensin peptides were compiled and categorised according to European Medicines Agency age groups. Age has a major impact on circulating angiotensin I, angiotensin II, and angiotensin 1-7, which is reflected in an age-dependent decrease during childhood. In contrast to data obtained in adults, no gender-related differences in angiotensin levels were identified. The observed increase in peptide concentrations regarding cardiac- and renal-diseased children is influenced by surgical repair, while evidence for a pharmacological impact is conflicting. A comprehensive set of angiotensin I, angiotensin II, and angiotensin 1-7 values from neonates up to adolescents was compiled. Indicating age as a strong effector. However, evidence about potential promising targets of the RAAS like angiotensin III and angiotensin IV is still lacking in children.

Topics: Adolescent; Age Factors; Angiotensin I; Angiotensin II; Angiotensin III; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Child; Child, Preschool; Female; Humans; Hypertension; Infant; Infant, Newborn; Kidney Failure, Chronic; Male; Peptide Fragments; Renin-Angiotensin System

Enalapril maleate is a prodrug which when administered orally is hydrolysed to release the active converting enzyme inhibitor enalaprilat. Enalapril maleate is 60% absorbed and 40% bioavailable as enalaprilat. Both compounds undergo renal excretion without further metabolism. The functional half-life for accumulation of enalaprilat is 11 h, and this is increased in the presence of a reduction in renal function. Inhibition of converting enzyme inhibition is associated with reductions in plasma angiotensin II and plasma aldosterone, and with increases in plasma renin activity and plasma angiotensin I. Acute and chronic effects have been reviewed. When given with hydrochlorothiazide, enalapril attenuates the secondary aldosteronism and ameliorates the hypokalaemia from diuretics. Both acutely and chronically in patients with essential hypertension, enalapril reduced blood pressure with a rather flat dose-response curve. No evidence of a triphasic response such as seen with captopril has been demonstrated with enalapril, and blood pressure returns smoothly to pretreatment levels when the drug is abruptly discontinued. Once- or twice-daily dosing gives similar results. The antihypertensive effects of enalapril are potentiated by hydrochlorothiazide. Haemodynamically, blood pressure reduction is associated with a reduced peripheral vascular resistance and an increase in cardiac output and stroke volume with little change in heart rate. Renal vascular resistance decreases, and renal blood flow may increase without an increase in glomerular filtration in patients with normal renal function. In patients with essential hypertension and glomerular filtration rates below 80 ml/min/m2, both renal blood flow and glomerular filtration rates may increase.

Topics: Aldosterone; Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Bradykinin; Dipeptides; Drug Administration Schedule; Enalapril; Enalaprilat; Heart Failure; Heart Rate; Humans; Hydrochlorothiazide; Hypertension; Kidney; Kidney Failure, Chronic; Norepinephrine; Prostaglandins; Renal Circulation; Renin

In order to determine whether hypertension would develop in dogs with chronic renal failure, we performed 7/8 renal ablation in 6 healthy dogs and compared pre- and post-ablation blood pressures determined by telemetry. One month after the renal ablation, blood urea nitrogen and creatinine were significantly increased (p<0.05), creatinine clearance was decreased (p<0.05), and blood pressure was increased significantly (p<0.05). Simultaneously, plasma renin activity, angiotensin I and II, and aldosterone were elevated significantly (p<0.05) compared with the values obtained from 11 healthy dogs with intact renal function. The dogs with induced renal failure and hypertension were administered an angiotensin-converting enzyme inhibitor, benazepril hydrochloride, once daily for 2 weeks at 2 mg/kg body weight, and changes in blood pressure and the renin-angiotensin-aldosterone (RAA) system were determined. During the administration of benazepril hydrochloride, blood pressure, angiotensin II and aldosterone decreased significantly (p<0.05) and, upon discontinuation of administration, increased to the pre-administration levels (p<0.05). Plasma renin activity and angiotensin I showed no significant changes throughout the administration study. These results provide experimental evidence that hypertension develops in dogs with chronic renal failure through mechanisms involving the RAA system and demonstrate that benazepril hydrochloride improves renal hypertension in dogs.

Topics: Aldosterone; Angiotensin I; Angiotensin II; Animals; Antihypertensive Agents; Benzazepines; Blood Pressure; Dog Diseases; Dogs; Female; Hypertension; Kidney Failure, Chronic; Male; Renin

Genes of the renin-angiotensin system (RAS) are involved in the progression of renal failure. Among them, the angiotensin-converting enzyme (ACE), angiotensinogen (AGT) and angiotensin II type 1 receptor (AT1R) genes are of particular interest. We examined polymorphisms of these three genes for association with the development of interstitial nephritis and progression to end-stage renal failure. The allele frequency and genotype distribution were compared in 90 patients with interstitial nephritis and 200 healthy controls. DNA samples were genotyped by polymerase chain reaction (PCR). We did not find statistically significant differences between groups in the insertion/deletion polymorphism of the ACE gene. An involvement of M235T polymorphism of the AGT gene in renal disease was observed in our study. The frequency of the T allele was higher in patients than in controls (32% vs. 24%). In the A1166C AT1R polymorphism the homozygous CC genotype was also more frequent in interstitial nephritis patients (7% vs. 3.5%). In patients carrying the C allele, an average time to ESRD was significantly shorter than in subjects with the AA genotype. Our study shows the association of the AGT and AT1R gene polymorphisms with the development and progression of interstitial nephritis. The C allele of the A1166C polymorphism appears to be a risk factor for faster disease progression.

Topics: Adult; Angiotensin I; Angiotensinogen; Disease Progression; Female; Gene Expression Regulation; Genetic Predisposition to Disease; Genetic Variation; Humans; Kidney Failure, Chronic; Male; Middle Aged; Nephritis, Interstitial; Polymorphism, Genetic; Receptor, Angiotensin, Type 1; Renin-Angiotensin System; Risk Assessment; Statistics as Topic

Recent reports support a protective role for angiotensin-converting enzyme 2 (ACE2) against glomerular diseases, especially by decreasing of extracellular matrix (ECM) proteins. However, the mechanism regulating this effect appears to be complex and poorly understood. Our aim was to investigate whether or not ACE2 ameliorates the profibrotic effects of Ang II-mediated, Akt-dependent pathways in the mouse mesangial cell line, MES-13.Gene transfer of ACE2 suppressed Ang II-activated Akt-phosphorylation, accompanied by a decreased level of collagen type I in cells. In addition, Ang II-induced collagen type I synthesis in MES-13s by activating the Ang II/AT-1R-PI3K pathway. This transactivation was dependent on cAMP/Epac but not on PKA. TGF-βRI played a pivotal role in this signaling pathway inducing collagen deposition effects which could be reversed by ACE2 gene transfer in MES-13 cells. The results revealed that gene transfer of ACE2 regulated Ang II-mediated AT1R-TGFβRI-PI3K-Akt signaling and involved the synthesis of collagen. The beneficial effect of ACE2 overexpression appeared to result mainly from blocking phosphorylation of Akt in mesangial cells, suggesting that the ACE2 gene might be a novel therapeutic target for glomerular diseases.

Topics: Adenylyl Cyclase Inhibitors; Angiotensin I; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme 2; Animals; Cell Line; Collagen Type I; Collagen Type I, alpha 1 Chain; Kidney Failure, Chronic; Mesangial Cells; Mice; Molecular Targeted Therapy; Peptide Fragments; Peptidyl-Dipeptidase A; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Phosphorylation; Protein Kinase Inhibitors; Protein Processing, Post-Translational; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins c-akt; Receptor, Angiotensin, Type 1; Receptor, Transforming Growth Factor-beta Type I; Receptors, Transforming Growth Factor beta; RNA, Messenger; Signal Transduction; Transcriptional Activation

The renin-angiotensin system (RAS) plays a critical role in chronic renal failure associated with heart failure. In the past few years, angiotensin (Ang) (1-7) have been reported to counteract the effects of angiotensin II (Ang II) and were even considered as a new therapeutical target in RAS. The purposes of this study were to examine whether the Ang (1-7) improves the heart function and remodeling of the left ventricle (LV) in mice with 5/6 nephrectomy (NC). We used a 5/6 nephrectomy to induce significant renal dysfunction in wildtype mice (WT). Twelve weeks after NC, WT showed high blood pressure, significant left-ventricular dilation and dysfunction, which were accompanied by cardiomyocyte hypertrophy, diffuse interstitial fibrosis and oxidative damage of cardiomyocytes. Exogenous Ang (1-7) injection improved the heart function and remodeling of LV in mice with 5/6 NC accompanied by a reduction in cardiac interstitial fibrosis, inflammatory cytokine expression and oxidative damage levels of cardiomyocytes, decrease in the profibrotic signaling molecule transforming growth factor (TGF)-beta and increase in the collagen degradation signaling molecule matrix metalloproteinase (MMP)-2, -9. However, these beneficial effects did not occur in hydralazine-treated mice. These findings suggest that (1) Exogenous Ang (1-7) injection improve the heart function and remodeling of LV in mice with 5/6 NC. (2) These beneficial effects are independent of its anti-blood pressure effect.

Topics: Angiotensin I; Animals; Antihypertensive Agents; Blood Pressure; Creatinine; Heart Failure; Heart Ventricles; Kidney; Kidney Failure, Chronic; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Mice; Mice, Inbred C57BL; Myocardium; Peptide Fragments; Proto-Oncogene Mas; Proto-Oncogene Proteins; Receptors, G-Protein-Coupled; Transforming Growth Factor beta; Ventricular Dysfunction, Left; Ventricular Remodeling

The aim of the present study was to evaluate plasma renin activity (PRA) and Angiotensin (Ang) levels [Ang I, Ang II and Ang-(1-7)] to examine the circulating Renin-Angiotensin System (RAS) in renal disease among children with different forms and stages of chronic renal failure (CRF). Subjects were divided as follows: 32 normotensive healthy subjects, 23 normotensive CRF subjects, 34 hypertensive CRF subjects and 21 subjects with end-stage renal disease (ESRD). Radioimmunoassays for PRA (ngAngI/mL/h) and angiotensin (pg/mL) measurements were performed on all subjects. PRA, Ang I, Ang II and Ang-(1-7) levels were significantly higher in hypertensive CRF subjects when compared with normotensive CRF and healthy subjects (p < 0.05 for all comparisons). No differences were observed between normotensive CRF and healthy subjects. ESRD subjects exhibited a dramatic increase in Ang-(1-7) (25-fold higher than control values). In hypertensive CRF subjects, treatment with angiotensin-converting enzyme inhibitors (ACEi) increased (1.4-fold) plasma Ang-(1-7) and decreased (2.4-fold) Ang II. In ESRD, the use of ACEi produced a similar (1.5-fold) elevation of Ang-(1-7), but no changes in plasma Ang II. Our data showed different circulating RAS profiles between hypertensive and in normotensive CRF subjects. Marked changes in plasma Ang-(1-7) were associated with the presence of hypertension and progression of kidney dysfunction.

Topics: Adolescent; Angiotensin I; Angiotensin II; Angiotensins; Case-Control Studies; Child; Child, Preschool; Cross-Sectional Studies; Disease Progression; Female; Humans; Hypertension; Kidney Failure, Chronic; Male; Peptide Fragments; Peptidyl-Dipeptidase A; Renin; Renin-Angiotensin System

In two patients with chronic renal failure (CRF) different effects of angiotensin convertase inhibitors (ACEI) and angiotensin receptor 1 blockers (AT1B) were observed. In patient 1 with CRF due to hemolytic-uremic syndrome (HUS), with arterial hypertension (HT) and proteinuria, a switch from AT1B to ACEI led to significant deterioration of renal function. After restitution of AT1B, renal function returned to previous range. The 2nd patient with CRF and severe HT, without proteinuria, due to atypical HUS, was on CAPD. Because of severe HT he received 3-4 hypertensives and ACEI in full dose was the main medication. Despite relatively low urea and creatinine values while on dialysis and high residual diuresis several attempts an end of CAPD was unsuccessful because of hyperkalemia and unacceptable increase of urea and creatinine concentrations after few days. Conversion from ACEI to AT1B enabled withholding CAPD, stabilisation of renal function and good control of HT. It seems that in patients with CRF without hyperfiltration syndrome and sensitive to changes in glomerular hemodynamics, in whom blockade of angiotensin action is needed AT1B may be a better option than ACEI. When using ACEI in patients with CRF, it is important to adjust the dose to renal function.

Topics: Adolescent; Angiotensin I; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Child, Preschool; Drug Administration Schedule; Humans; Hypertension; Kidney; Kidney Failure, Chronic; Male

Renin activity appears to be present in low concentrations in the plasma of anephric humans but could be artifactual secondary to inadvertent activation of prorenin during specimen collection and handling or from a renin-like enzyme. We studied the effects of specimen collection, storage, different assay conditions, trypsin activation, and the renin inhibitor EMD 56133 (E Merck, Darmstadt) on plasma renin activity (PRA) in anephric man. PRA was detectable in all seven bilaterally nephrectomized (BNX) patients (0.2 +/- 0.1 ng AI/ml/hr, range 0.1-0.7) but was significantly lower than normals (2.4 +/- 0.3 ng AI/ml/hr, range 1.5-3.1, p = 0.001). PRA was not different in BNX whether blood samples were collected on ice or at room temperature and assayed immediately or whether samples were frozen and assayed several days later. Prolonged cold storage of samples and five freeze-thaw cycles over six to seven months did not significantly increase PRA in normals or anephrics. However, deliberate repeated freezing and thawing over the period of a single day increased PRA 4.1-fold in BNX and 1.6-fold in normals. Renin-like activity was also detected in BNX individuals using renin concentration determinations with either excess human or sheep angiotensinogen. The inhibition of renin activity (IC-50% = 3.16 x 10(-9) molar) by EMD 56133 was not different between BNX and normals. Thus, active renin is present in the plasma of anephric humans and does not result from the inadvertent activation of prorenin due to sample handling. Although the source of PRA in BNX is unknown, the enzyme appears functionally normal as evidenced by the dose-response to a single renin inhibitor.

Topics: Adult; Angiotensin I; Angiotensinogen; Enzyme Activation; Enzyme Precursors; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Nephrectomy; Oligopeptides; Renal Dialysis; Renin; Trypsin

In a patient with periarteritis nodosa failure of antihypertensive treatment with beta-blockers and diuretics encouraged the authors to use captopril in doses of 150 mg per day. Blood pressure rapidly returned to normal levels. The hypotensive effect of captopril is ascribable to its action on the renin-angiotensin system, since plasma renin activity was particularly high in this patients.

Topics: Angiotensin I; Captopril; Humans; Hypertension; Kidney Failure, Chronic; Male; Middle Aged; Polyarteritis Nodosa; Proline; Renin

We have previously reported that the in vitro enzymatic activity of exogenous renin, plasma renin reactivity (PRR), is increased in plasma of patients with chronic renal failure, possibly due to the deficiency of a renin inhibitor. To determine whether increases PRR is related to renal failure per se or to hyperlipidemia, PRR was measured in 10 control subjects, 10 patients with renal failure, and 10 hyperlipidemic patients with normal renal function. Compared to that in control subjects (52.6 ng angiotensin I generated per ml/h +/- 3.8 SE) PRR was increased (P < 0.05) in plasma of uremic patients (65.1 +/- 4.3) and hyperlipidemic patients (71.4 +/- 10.7). Renin substrate concentration did not differ among groups, and after denaturation of endogenous substrate by acidification of plasma, PRR was still increased. A "protein-free" extract of plasma from normal subjects inhibited renin, whereas little or no inhibition occurred with a comparable extract from uremic patients and hyperlipidemic patients. Thus, alterations in lipid metabolism may account for the increased enzymatic activity of renin in uremic plasma. Increased PRR may be related to the deficiency of a normally occurring renin inhibitor.

Topics: Angiotensin I; Cholesterol; Humans; Hyperlipidemias; Kidney Failure, Chronic; Renin; Triglycerides

Topics: Adult; Angiotensin I; Animals; Cholesterol Esters; Fatty Acids, Nonesterified; Humans; Kidney Failure, Chronic; Kidney Transplantation; Kinetics; Male; Middle Aged; Phospholipids; Prednisone; Renin; Transplantation, Homologous; Triglycerides