[Pancreatic panniculitis with polyarthritis and pathological fracture].
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Arthritis↗
Biomedical subjects
A Mimran
Publications and source records attributed to A Mimran.
Angiotensin-receptor blockers and diuretics--advantages of combination.
Surveys have shown that in as many as half of patients treated for hypertension, blood pressure (BP) is not controlled to target levels; many more persons have undertreated hypertension. Uncontrolled hypertension is a serious risk factor for cardiovascular events such as stroke, heart failure, myocardial infarction and target-organ diseases. Studies have shown that strict BP control significantly reduces the occurrence of these cardiovascular outcomes, in the majority of patients, effective BP control requires two or more antihypertensive agents. The combination of an angiotensin-receptor blocker (ARB) and a thiazide diuretic is appealing, since these agents have complimentary effects on BP reduction, left ventricular hypertrophy and progression of renal diseases. In addition, this combination provide excellent tolerability. The combination of an ARB and a thiazide diuretic may be of particular value in patient populations who tend to have poor BP control on monotherapy, or have additional cardiovascular or renal risk factors.
Angiotensin II Type 1 Receptor Blockers↗
Age-related increase of pulse pressure and plasminogen activator inhibitor-1 I/D gene polymorphism in essential hypertension.
BACKGROUND: Pulse pressure (PP), a marker of cyclic strain on the arterial wall, is a significant predictor of cardiovascular (CV) risk, particularly regarding the incidence of coronary arterial stenosis. Genes related to haemostatic and/or fibrinolytic factors are consistently influenced in vitro by mechanical strain. OBJECTIVE: The goal of the present study was to determine, in the three genotypes of the plasminogen activator inhibitor (PAI)-1 gene polymorphism, the gender-adjusted difference in the relationships between age and PP in subjects with never treated essential hypertension. RESULTS: In the studied population, the genotype deletion (D)/D at position -675 of the PAI-1 insertion (I)/D gene polymorphism was associated with a significant increase in the adjusted slope of the curve relating age to PP by comparison with the two other genotypes. No comparable difference in age-related changes in systolic, diastolic or mean blood pressure was found. CONCLUSION: In subjects with essential hypertension, the PAI-1 I/D gene polymorphism modulates the age-mediated increase of PP, suggesting new insights on the complex interactions between genes, mechanical factors and CV risk.
Adult↗
A population-based European cohort study of persistence in newly diagnosed hypertensive patients.
This study assessed the percentage of patients after 1 year who persisted on initially prescribed antihypertensive therapy. Medical records of 2416 patients with newly diagnosed hypertension who were prescribed initial antihypertensive monotherapy by general practitioners in Germany, France, and the United Kingdom were evaluated. Comparisons were made among the angiotensin II receptor antagonist (AIIRA) irbesartan, all other antihypertensive classes (including AIIRAs other than irbesartan), and the AIIRA losartan. Patients initiated on the AIIRA irbesartan scored highest with a persistence rate of 60.8%, followed by patients who received all other AIIRA agents with a persistence rate of 51.3%. Angiotensin-converting enzyme inhibitors, calcium channel blockers, beta-blockers, and losartan were associated with comparable persistence rates, between 42.0% and 49.7%. Patients who received diuretics scored lowest with a persistence rate of 34.4%. Persistence has emerged as an essential factor for blood pressure control. Prescribing an antihypertensive agent that provides a favourable efficacy and tolerability profile may provide greater persistence with therapy and hence a higher level of blood pressure control.
Adrenergic beta-Antagonists↗
Activation of p53 protein by telomeric (TTAGGG)n repeats.
Genome instability is a primary factor leading to the activation of the p53 tumor suppressor protein. Telomeric repeat (TR) sequences are also responsible for genome integrity. By capping the termini of the chromosomes, TRs prevent them undergoing nucleolytic degradation, ligation or chromosome fusion. Interestingly, telomere shortening was suggested to activate p53, which in turn may cause primary cells to senesce. In order to elucidate the nature of a possible cross talk between the two, we introduced into cells TRs of defined length and investigated their effect on p53 activation and subsequent cellular response. We found that the introduction of a TR into cells leads to stabilization of the p53 protein. This stabilization was specific to TRs and was not observed in response to exposure of cells to plasmids containing non-TR sequences. p53 stabilization requires the presence of an intact p53 oligomerization domain. TR-activated p53 exhibited enhanced transcriptional activity. Eventually, TRs induced p53-dependent growth suppression, measured as a reduction in colony formation.
Base Sequence↗
The relevance of tissue angiotensin-converting enzyme: manifestations in mechanistic and endpoint data.
Angiotensin-converting enzyme (ACE) is primarily localized (>90%) in various tissues and organs, most notably on the endothelium but also within parenchyma and inflammatory cells. Tissue ACE is now recognized as a key factor in cardiovascular and renal diseases. Endothelial dysfunction, in response to a number of risk factors or injury such as hypertension, diabetes mellitus, hypercholesteremia, and cigarette smoking, disrupts the balance of vasodilation and vasoconstriction, vascular smooth muscle cell growth, the inflammatory and oxidative state of the vessel wall, and is associated with activation of tissue ACE. Pathologic activation of local ACE can have deleterious effects on the heart, vasculature, and the kidneys. The imbalance resulting from increased local formation of angiotensin II and increased bradykinin degradation favors cardiovascular disease. Indeed, ACE inhibitors effectively reduce high blood pressure and exert cardio- and renoprotective actions. Recent evidence suggests that a principal target of ACE inhibitor action is at the tissue sites. Pharmacokinetic properties of various ACE inhibitors indicate that there are differences in their binding characteristics for tissue ACE. Clinical studies comparing the effects of antihypertensives (especially ACE inhibitors) on endothelial function suggest differences. More comparative experimental and clinical studies should address the significance of these drug differences and their impact on clinical events.
Angiotensin-Converting Enzyme Inhibitors↗
Autoimmunity to the p53 protein is a feature of systemic lupus erythematosus (SLE) related to anti-DNA antibodies.
The induction of anti-DNA autoantibodies in systemic lupus erythematosus (SLE) patients is problematic because mammalian DNA is poorly immunogenic at best. Here we demonstrate a chain of connected antibodies in SLE patient sera that could account for the induction of anti-DNA antibody, and possibly for some of the pathogenic features of SLE. We now report that SLE patients, in addition to anti-DNA, produce antibodies to the carboxy-terminal domain of the tumour suppressor molecule p53; this p53 domain recognizes damaged DNA. Hence, these anti-p53 antibodies could mimic damaged DNA immunologically. Indeed, SLE sera do contain anti-idiotypic antibodies to a prototypic anti-p53 antibody. Moreover, SLE anti-DNA antibodies also recognize this type of anti-p53 antibody. Indeed, binding of affinity-purified anti-DNA both to DNA and to the anti-p53 antibody could be blocked by a p53 peptide derived from the DNA-binding domain. This mimicry of the p53 DNA-binding domain by the SLE anti-DNA antibodies is functional: activation of the p53 molecule could be inhibited by such anti-DNA antibodies. Thus, anti-DNA antibodies may arise in SLE patients by a chain of idiotypic autoimmunity centered around p53 autoimmunity. The SLE anti-DNA and anti-p53 antibodies can functionally block p53 activation, and so could affect apoptosis.
Antibodies, Antinuclear↗
Endothelin gene variants and aortic and cardiac structure in never-treated hypertensives.
BACKGROUND: The polymorphism of several candidate genes has been studied in relation to essential hypertension and cardiovascular complications. Target organ damage in essential hypertension is a complex disorder influenced by multiple genetic and environmental factors. The possible contribution of endothelin gene variants to target organ damage in hypertension in humans has not been studied in depth. PROCEDURE: We assessed the influence of genetic variants of components of the endothelin system ETAR -231A/G, 1363C/T, ETBR 30G/A and endothelin-1 (ET-1) 138insertion/deletion (I/D) on aortic stiffness, left ventricular geometric, and radial artery parameters in 528 never-treated hypertensive subjects of European origin. The study population included 314 men and 214 women with a mean age of 48+/-0.5 years (+/-SEM). In samples of patients, aortic stiffness was assessed with carotid-femoral pulse wave velocity (PWV). Radial artery thickness was measured with an echotracking angiometer and left ventricular geometric parameter with standard echographic procedures. RESULTS: The main results showed that the ETAR-231A/G (P = .022) and the ETBR 30G/A (P = .026) receptor gene variants influenced PWV level in women. The -231G and 30G alleles were associated with a codominant increase in PWV, explaining 18.6% of its variability (P = .005). In men, the ETBR 30G/A receptor gene variant was also related to the level of radial artery parameters (P = .02). No association between the 138I/D polymorphism of the ET-1 gene and left ventricular and radial artery parameters was observed in either men or women. CONCLUSIONS: These results indicate that the influence of endothelin system genes can be detected first on arterial parameters.
Adult↗
Endothelin blockade in angiotensin II hypertension: prevention and treatment studies in the rat.
1. The participation of endothelin (ET) in the development and maintenance of hypertension induced by angiotensin (Ang) II was assessed using the non-specific ET receptor antagonist bosentan (30 mg/kg per day). 2. In the prevention study, bosentan was given 24 h prior to and during the 17 day period of AngII infusion (200 ng/kg per min, s.c., osmotic pump), whereas in the treatment study, bosentan was administered from day 10 to day 17. Tail-cuff pressure (TCP) was measured before and on days 10 and 17 of AngII infusion. At the end of studies, heart weight index was calculated as the ratio of heart to bodyweight (HWI) and the wall thickness of the carotid artery (perfusion/fixation at 120 mmHg) was measured. Tail-cuff pressure increased from 129 +/- 3 to 179 +/- 7 and 189 +/- 9 mmHg on days 10 and 17 of AngII infusion, respectively. 3. Final TCP was markedly lowered in rats pretreated with bosentan, whereas TCP remained comparable with untreated hypertensive rats when bosentan was given from day 10 of AngII infusion (177 +/- 9 mmHg). 4. The increase in cardiac mass associated with AngII hypertension was similarly attenuated in the two groups receiving bosentan. 5. The HWI was 3.49 +/- 0.12 mg/g in untreated hypertensive rats and 3.18 +/- 0.08 and 3.11 +/- 0.09 mg/g in rats pretreated with bosentan and those receiving the antagonist from day 10. 6. The increase in carotid wall thickness induced by AngII was prevented, but not reversed, by bosentan. 7. These results support the hypothesis that endogenous ET participates only in the initial phase of AngII hypertension. In addition, the beneficial effect of bosentan of cardiac mass but not on arterial wall thickness is in favour of a role of ET as a local mediator of the cardiac hypertrophic effect of AngII, independently of the level of blood pressure and duration of hypertension.
Angiotensin II↗
Influence of irbesartan and enalapril on changes of renal function associated with the established phase of l-NAME hypertension.
OBJECTIVE: Reversibility of the systemic and renal alterations induced by N(omega)-nitro-L-arginine-methyl ester(L-NAME) was assessed by treatment with irbesartan and enalapril (30 and 10 mg/kg per 24 h, respectively) alone or in combination. DESIGN: L-NAME (20 mg/kg per 24 h) was given to rats for 6 weeks and treatments were administered during the last 2 weeks. Glomerular filtration rate and renal plasma flow [GFR and RPF per g of kidney weight (KW)] were determined using the clearance technique. RESULTS: Arterial pressure was similarly reduced by treatments. GFR was lower in L-NAME-treated rats than in controls (552 +/- 52 versus 1106 +/- 78 microl/min per g KW), whereas RPF was reduced to a larger extent, thus resulting in an increase in filtration fraction. GFR was normalized by irbesartan but not enalapril or the combination (1042 +/- 50, 790 +/- 79 and 725 +/- 38 microl/min per g KW, respectively). RPF returned to normal and filtration fraction fell markedly with the combination. All treatments reduced the lesions of preglomerular vessels and reversed L-NAME-induced albuminuria and cardiovascular hypertrophy. At a dose of 3 mg/kg per 24 h, irbesartan only reduced the lesions of the afferent arteriole. CONCLUSIONS: Through its effects on AT1 receptors, angiotensin II may play an important role in the maintenance of L-NAME hypertension and associated alterations. The lower GFR and filtration fraction observed with enalapril in the presence of irbesartan suggests the intervention of non-angiotensin II-mediated mechanism, and at the postglomerular level, in the effect of angiotensin-converting enzyme (ACE) inhibitors.
Angiotensin Receptor Antagonists↗
Glucose tolerance and age-associated decline in renal function of hypertensive patients.
BACKGROUND: Renal function is thought to decrease with age in the general population, but the determinants of this age-associated evolution are poorly understood. Hypertension and diabetes mellitus, two leading causes of chronic renal failure in the elderly, may accelerate this decline. PATIENTS AND METHODS: Urinary clearances of [99mTc]diethylene triaminopentaacetic acid (DTPA) (glomerular filtration rate) and [131I]hippuran (effective renal plasma flow) were assessed in 227 never-treated essential hypertensives aged 20-69 years. Based on the oral glucose tolerance test, the study population consisted of 4% patients with previously unknown diabetes mellitus, 24% with impaired glucose tolerance and 72% with normal glucose tolerance. RESULTS: When the population of 218 non-diabetic subjects was considered, glomerular filtration rate was inversely correlated with age and arterial blood pressure, and positively correlated with effective renal plasma flow, filtration fraction and fasting plasma glucose. In multivariate analysis, age and blood pressure were independent determinants of renal plasma flow, whereas renal plasma flow, age and fasting plasma glucose were independent determinants of glomerular filtration rate. The slope of the regression line relating glomerular filtration rate to age was steeper in patients with impaired glucose tolerance than in those with normal glucose tolerance (-1.52 +/- 0.28 versus -0.65 +/- 0.12, P < 0.01). CONCLUSIONS: These results suggest that impaired glucose tolerance, which is seldom searched for in patients with essential hypertension, may be an important determinant of the age-associated decline in renal function.
Adult↗
Inhibition of the acute effects of angiotensin II by the receptor antagonist irbesartan in normotensive men.
Irbesartan (SR 47436, BMS 186295) is an imidazole derivative that specifically binds to the angiotensin type 1 receptor. The purpose of this study was to assess the inhibitory effect of irbesartan on the pressor action of exogenous angiotensin II in healthy subjects, to evaluate the dose dependency and duration of this inhibition, and to determine the effect of irbesartan on plasma components of the renin-angiotensin system. Forty-two healthy male volunteers maintained on ad libitum sodium intake were enrolled in a randomized, double-blind, placebo-controlled, parallel-design, dose-ranging study. On 2 study days 1 week apart, volunteers were given either a placebo or the active drug at one of the chosen doses (5, 25, 50, 75, 100, 150, or 300 mg). The pressor effects of an individually titrated test dose of exogenous angiotensin II as well as plasma levels of angiotensin II, active renin, aldosterone, and treatment drug were determined before and throughout the 24 h after drug administration. The inhibitory effect of irbesartan on the pressor response to angiotensin II was observed within 1 h after dosing, peaked between 2 and 4 h, and lasted more than 24 h for doses of 25 mg and more. The effect was clearly dose related. Two and 24 h after administration of irbesartan, 300 mg, the response of arterial blood pressure (systolic and diastolic) to a given dose of angiotensin II was reduced by approximately 100% and 60%, respectively. Plasma concentrations of angiotensin II and active renin increased markedly after irbesartan administration, whereas plasma concentrations of aldosterone decreased. No evidence was found that the high levels of circulating angiotensin II observed after irbesartan administration could override the inhibitory effect of irbesartan on any of the measured parameters up to 24 h after dose. In conclusion, irbesartan appears to be a well-tolerated, orally active, potent antagonist of the renin-angiotensin system in men.
Adult↗
Nitric oxide inhibition and renal alterations.
Acute and chronic administrations of L-arginine analogues are associated with renal functional and structural alterations that can be prevented or reversed by pharmacological blockade of other vasoactive systems. When given acutely, L-arginine derivatives have an antinatriuretic effect that is overridden by elevation of perfusion pressure and both endothelin and angiotensin II play an important role in the systemic and renal haemodynamic alterations associated with impaired nitric oxide availability. Long-term administration of L-arginine derivatives, mainly NG-nitro-L-arginine methylester (L-NAME), resulted in hypertension, intrarenal vascular, tubular and glomerular lesions and reduction in renal function. In prevention studies, blockade of the renin-angiotensin system markedly reduced hypertension and the renal morphological alterations associated with L-NAME administration. Although improvement in renal function may be achieved when arterial pressure is fully controlled, several reports indicate that the L-NAME-induced renal structural changes were independent of blood pressure and at least partly mediated by endothelin. In intervention studies, blockers of the renin-angiotensin system decreased but did not completely normalize arterial pressure, improved renal function and normalized albuminuria. Both the renin-angiotensin and the sympathetic nervous systems contribute to the sustained phase of chronic nitric oxide synthase inhibition, the adrenergic component being prominent with time. L-NAME hypertension can also be reversed by calcium antagonists, possibly via inhibition of angiotensin II-induced vasoconstriction, and the T-type antagonist had a greater effect than the L-type antagonist in reducing pre-glomerular resistance. The rat model of hypertension induced by chronic inhibition of nitric oxide generation has provided a useful tool to study both the development and the treatment of renal lesions resembling those found in human hypertension, a disease associated with early generalized impairment of endothelial function.
Angiotensin-Converting Enzyme Inhibitors↗
[Simvastatin attenuates cardiovascular effects and oxidative stress induced by angiotensin II].
The effects of an HMG-CoA reductase inhibitor, simvastatin (statin, 60 mg/Kg/24 h by forced feeding), were studied on the development of hypertension, cardiac hypertrophy and oxidating stress induced by chronic perfusion of angiotensin II (ANG II, 200 ng/Kg/min s.c., for 10 days) in the rat. The statin was giver 24 hours before, and during the 10 days of ANG II. At the end of the study, mean blood pressure was measured and blood sampling performed under anaesthesia (sodium pentobarbital). The cardiac mass index was measured (cardiac mass/body weight, mg/Kg). TBARS (thiobarbituric acid reactive substances), representing the index of lipid peroxidation, was assessed by fluorimetry. The statin attenuated the development of hypertension (131 +/- 9 vs 164 +/- 4 mmHg) and the increase in cardiac mass (3.13 +/- 0.09 vs 3.46 +/- 0.09 mg/g) associated with ANG II. The overproduction of TBARS induced by ANG II was partially prevented by simvastatin (598 +/- 40 vs 794 +/- 79 pmol/mL). These results indicate that simvastatin attenuates the cardiovascular effects and lipid peroxidation induced by chronic administration of angiotensin II.
Angiotensin II↗
Systemic lupus erythematosus in mice, spontaneous and induced, is associated with autoimmunity to the C-terminal domain of p53 that recognizes damaged DNA.
The tumor suppressor molecule p53 features a regulatory domain at the C terminus that recognizes damaged DNA. Since damaged DNA might be involved in activating anti-DNA autoantibodies, we tested whether autoimmunity to the C terminus of p53 might mark murine systemic lupus erythematosus (SLE). We now report that MRL / MpJ-Fas(lpr) mice, which spontaneously develop SLE, produce antibodies both to the C terminus of p53 and to a monoclonal antibody (PAb-421) that binds the p53 C terminus. Anti-idiotypic antibodies to PAb-421 (sampled as monoclonal antibodies) could also bind DNA. Thus, the PAb-421 antibody mimics DNA, and the anti-idiotypic antibody to PAb-421 mimics the p53 DNA-binding site. This mimicry was functional; immunization of BALB / c mice to PAb-421 induced anti-DNA antibodies and antibodies to the C terminus of p53, and most of the mice developed an SLE-like disease. Immunization of C57BL / 6 mice to PAb-421 induced antibodies to p53, but not to its C-terminal domain. The C57BL / 6 mice also did not develop anti-DNA antibodies or the SLE-like disease. Thus, network autoimmunity to the domain of p53 that recognizes damaged DNA can be a pathogenic feature in SLE in genetically susceptible strains of mice.
Animals↗
Nephrotic-range proteinuria in patients with renovascular disease.
PURPOSE: Proteinuria is usually considered a manifestation of glomerular disease. We sought to describe the characteristics of patients with nephrotic-range proteinuria resulting from renovascular disease and to compare them with those of patients who had glomerulonephritis. SUBJECTS AND METHODS: We identified 14 patients with nephrotic-range proteinuria and renovascular disease and compared them with 14 patients who had nephrotic-range proteinuria and biopsy-proven glomerulonephritis, matched for sex, age, and glomerular filtration rate. RESULTS: Patients with renovascular disease were more likely to have known atherosclerotic vascular disease [13 of 14 (93%) vs 3 of 14 (21%), P < 0.0001) and were usually smokers [12 of 14 (85%) vs 3 of 14 (21%), P < 0.0001]. They also had a greater mean (+/- SD) difference between the lengths of their kidneys (29 +/- 10 vs 5 +/- 5 mm, P < 0.001); greater systolic blood pressure (203 +/- 22 vs 174 +/- 25 mm Hg, P < 0.005), plasma renin activity (17 +/- 19 vs 2 +/- 2 ng/mL/h, P = 0.005), and plasma aldosterone concentration (40 +/- 23 vs 11 +/- 10 ng/dL, P = 0.0001); and lower serum potassium levels (3.3 +/- 0.5 vs 3.8 +/- 0.5, P <0.05). Effective renal plasma flow was lower (139 +/- 68 vs 307 +/- 185 mL/min/1.73 m3) and filtration fraction was markedly greater (0.28 +/- 0.04 vs 0.15 +/- 0.07, P = 0.0001) in the patients with renovascular disease. After the oral administration of captopril, blood pressure, effective renal plasma flow, and glomerular filtration rate decreased only among patients with renovascular disease. Of the 14 patients with renovascular disease, 13 had evidence of renal artery thrombosis seen at angiography; 2 patients required dialysis, and 3 others died during follow-up. CONCLUSION: Our findings suggest that the patients with nephrotic-range proteinuria resulting from renovascular disease have distinct characteristics and a poor prognosis.
Aged↗
Antioxidant supplementation and chronic renal transplant dysfunction.
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Antioxidants↗
Left ventricular adaptation to hypertension and plasma renin activity.
Chronic pressure and volume overload result in morphologically and functionally distinct forms of myocardial hypertrophy. In essential hypertension, the respective effect of these factors on the morphology of the left ventricle remains unknown. In the present study, we hypothesised that activity of the renin angiotensin system (assessed by plasma renin activity) may be associated to the variability of the left ventricular adaptation to essential hypertension. To assess this relation, we categorised by echocardiography 333 never-treated hypertensive patients, according to values of left ventricular mass and relative wall thickness. Higher systolic and pulse arterial pressure was strongly associated with concentric left ventricular hypertrophy (27% of hypertensives). When compared to the normal left ventricle group, patients with eccentric left ventricular hypertrophy (15% of hypertensives) had a high cardiac index (5 +/- 1 vs 4 +/- 0.8 L/min/m2; P = 0.0001), a lower basal plasma renin activity (0.81 +/- 0.63 vs 1.45 +/- 1.3 ng/ml/h; P = 0.02) and similar mean values of left ventricular performance and glomerular filtration rate. A tendency for depressed myocardial contractility assessed by the midwall shortening/end-systolic stress was associated with concentric left ventricular remodelling and hypertrophy when compared to hypertensive with a normal left ventricle. In conclusion, at the early phase of essential hypertension, in patients without renal dysfunction, each anatomic pattern of cardiac adaptation to hypertension was associated with a distinct profile of haemodynamics, myocardial function and activity of the renin-angiotensin system. Journal of Human Hypertension (2000) 14, 181-188.
Adaptation, Physiological↗