Salt-dependent renal effects of an angiotensin II antagonist in healthy subjects.

This study was designed to evaluate in healthy volunteers the renal hemodynamic and tubular effects of the orally active angiotensin II receptor antagonist losartan (DuP 753 or MK 954). Losartan or a placebo was administered to 23 subjects maintained on a high-sodium (200 mmol/d) or a low-sodium (50 mmol/d) diet in a randomized, double-blind, crossover study. The two 6-day diet periods were separated by a 5-day washout period. On day 6, the subjects were water loaded, and blood pressure, renal hemodynamics, and urinary electrolyte excretion were measured for 6 hours after a single 100-mg oral dose of losartan (n = 16) or placebo (n = 7). Losartan induced no significant changes in blood pressure, glomerular filtration rate, or renal blood flow in these water-loaded subjects, whatever the sodium diet. In subjects on a low-salt diet, losartan markedly increased urinary sodium excretion from 115 +/- 9 to 207 +/- 21 mumol/min (P < .05). The fractional excretion of endogenous lithium was unchanged, suggesting no effect of losartan on the early proximal tubule in our experimental conditions. Losartan also increased urine flow rate (from 10.5 +/- 0.4 to 13.1 +/- 0.6 mL/min, P < .05); urinary potassium excretion (from 117 +/- 6.9 to 155 +/- 11 mumol/min); and the excretion of chloride, magnesium, calcium, and phosphate. In subjects on a high-salt diet, similar effects of losartan were observed, but the changes induced by the angiotensin II antagonist did not reach statistical significance. In addition, losartan demonstrated significant uricosuric properties with both sodium diets.(ABSTRACT TRUNCATED AT 250 WORDS)

Bioavailability of repeated oral administration of MDL 100,240, a dual inhibitor of angiotensin-converting enzyme and neutral endopeptidase in healthy volunteers.

BACKGROUND: MDL 100,240 (pyrido[2,1-a] [2]benzazepine-4-carboxylic acid,7-[[2-(acetylthio)-1-oxo-3-phenylpropyl]amino]-1,2,3,4,6,7,8, 12b-octahydro-6-oxo, [4S-[4alpha,7alpha(R(*)),12bbeta]]-) is a molecule possessing an inhibiting ability on both angiotensin converting enzyme (ACE) and neutral endopeptidase, the enzyme responsible for atrial natriuretic peptide (ANP) degradation. Such a dual mechanism of action presents a potential clinical interest for the treatment of hypertension and congestive heart failure. OBJECTIVES: To evaluate the bioavailability of MDL 100,240 and its accumulation over repeated oral administration, using ACE inhibition as a surrogate for plasma drug level and determining its profile after oral and i.v. administration. METHODS: First, in an open, one-period, single-dose study, the ACE inhibition profile was characterised following a 12.5 mg MDL 100,240 i.v. infusion. Second, in a three-group, parallel, randomised, double-blind study, each group of four subjects received q.d., over 8 days, 2.5, 10 or 20 mg of MDL 100,240 orally. The ACE inhibition profile was determined on day 1 and day 8. Trough plasma ACE was measured on days 2, 3 and 4. The recovery of ACE activity was monitored up to 72 h after the last dose of MDL 100,240. RESULTS: ACE inhibition profile was similar on day 1 and day 8, and trough inhibition remained unchanged after the 8 days of treatment with 10 mg or 20 mg. Following repeated 2.5-mg ingestion, trough inhibition increased from 33% to 44% after the eighth dose. The oral bioavailability of MDL 100,240 was estimated at 85%, not statistically different from 100%. The accumulation ratio at steady state was estimated at 112%. Expressing the accumulation ratio in terms of half-life, a t(1/2) of 0.31 days or 7. 5 h was estimated. CONCLUSION: MDL 100,240 (oral solution) has a good bioavailability, as estimated by ACE inhibition, and no drug accumulation seems to occur over 8 days with the 10-mg and 20-mg doses, but a slight rise in the trough level is observed with the 2. 5-mg dose.

Stability and robustness of blood variables in an antidoping context.

Introduction:  With the setting up of the newly Athlete's Biological Passport antidoping programme, novel guidelines have been introduced to guarantee results beyond reproach. We investigated in this context, the effect of storage time on the variables commonly measured for the haematological passport. We also wanted to assess for these variables, the within and between analyzer variations. Methods:  Blood samples were obtained from top level male professional cyclists (27 samples for the first part of the study and 102 for the second part) taking part to major stage races. After collection, they were transported under refrigerated conditions (2 °C < T < 12 °C), delivered to the antidoping laboratory, analysed and then stored at approximately 4 °C to conduct analysis at different time points up to 72 h after delivery. A mixed-model procedure was used to determine the stability of the different variables. Results:  As expected haemoglobin concentration was not affected by storage and showed stability for at least 72 h. Under the conditions of our investigation, the reticulocytes percentage showed a much better stability than previous published data (> 48 h) and the technical comparison of the haematology analyzer demonstrated excellent results. Conclusion:  In conclusion, our data clearly demonstrate that as long as the World Anti-Doping Agency's guidelines are followed rigorously, all blood results reach the quality level required in the antidoping context.

Blood pressure modifies the association between serum adiponectin and uric acid, in a sex-dependent manner

Purpose: Plasma adiponectin and serum uric acid (SUA) levels are negatively correlated. To better understand the possible mechanisms linking adiponectin and uric acid, we analyzed whether the association between adiponectin and SUA differed by hypertension status (or blood pressure level) and by sex. Methods and materials: We analyzed data from the populationbased CoLaus study (Switzerland). Fasting plasma adiponectin levels were assessed by ELISA and SUA by uricase-PAP. Blood pressure (BP) was measured using a validated automated device and hypertension was defined as having office BP 140/90 mm Hg or being on current antihypertensive treatment. Results: In the 2897 men and 3181 women, aged 35-74, BMI (mean ± SD) was 26.6 ± 4.0 and 25.1 ± 4.8 Kg/m2, systolic blood pressure (SBP) was 132.2 ± 16.6 and 124.8 ± 18.3 mm Hg, median (interquartile range) plasma adiponectin was 6.2 (4.1-9.2) and 10.6 (6.9-15.4) mg/dL, and hypertension prevalence was 42.0% and 30.2%, respectively. The age- and BMI- adjusted partial correlation coefficients between log-adiponectin and SUA were 0.09 and 0.06 in normotensive men and women (P <0.01), and 0.004 (P = 0.88) and 0.15 (P <0.001) in hypertensive men and women, respectively. In median regression adjusted for BMI, insulin, smoking, alcohol consumption, menopausal status and HDL-cholesterol, there was a significant three-way interaction between SUA, SBP and sex for their effect on adiponectin (dependent variable, P = 0.005), as well as interactions between SBP and sex (P = 0.014) and between SUA and sex (P = 0.033). Conclusion: Plasma adiponectin and SUA are negatively associated, independently of BMI and insulin, in a population-based study in Caucasians. However, BP modifies this inverse relationship, as it was significant mainly in women with elevated BP. This observation suggests that the link between adiponectin and SUA may be mediated by sex hormones and the hypertension status.

Toxic substances in blood: an analysis of current recommendations under a Bayesian (decision) approach

This article extends existing discussion in literature on probabilistic inference and decision making with respect to continuous hypotheses that are prevalent in forensic toxicology. As a main aim, this research investigates the properties of a widely followed approach for quantifying the level of toxic substances in blood samples, and to compare this procedure with a Bayesian probabilistic approach. As an example, attention is confined to the presence of toxic substances, such as THC, in blood from car drivers. In this context, the interpretation of results from laboratory analyses needs to take into account legal requirements for establishing the 'presence' of target substances in blood. In a first part, the performance of the proposed Bayesian model for the estimation of an unknown parameter (here, the amount of a toxic substance) is illustrated and compared with the currently used method. The model is then used in a second part to approach-in a rational way-the decision component of the problem, that is judicial questions of the kind 'Is the quantity of THC measured in the blood over the legal threshold of 1.5 μg/l?'. This is pointed out through a practical example.

Discordant secular trends in elevated blood pressure and obesity in children and adolescents in a rapidly developing country

BACKGROUND: The effect of the increasing prevalence of obesity on blood pressure (BP) secular trends is unclear. We analyzed BP and body mass index secular trends between 1998 and 2006 in children and adolescents of the Seychelles, a rapidly developing island state in the African region. METHODS AND RESULTS: School-based surveys were conducted annually between 1998 and 2006 among all students in 4 school grades (kindergarten and 4th, 7th, and 10th years of compulsory school). We used the Centers for Disease Control and Prevention criteria to define obesity and elevated BP. The same methods and instruments were used in all surveys. Some 25 586 children and adolescents 4 to 18 years of age contributed 43 867 observations. Although the prevalence of obesity in boys and girls increased from 5.1% and 6.0%, respectively, in 1998 to 2000 to 8.0% and 8.7% in 2004 to 2006, the prevalence of elevated BP decreased from 8.4% and 9.8% to 6.9% and 7.8%. During the interval, mean age-adjusted body mass index increased by 0.57 kg/m(2) in boys and 0.58 kg/m(2) in girls. Mean age- and height-adjusted systolic BP decreased by -3.0 mm Hg in boys and -2.8 mm Hg in girls, whereas mean diastolic BP did not change substantially in boys (-0.2 mm Hg) and increased slightly in girls (0.4 mm Hg). CONCLUSIONS: At a population level, the marked increase in the prevalence of obesity in children and adolescents in the Seychelles was not associated with a commensurate secular rise in mean BP.

Traitement chronique de l'hypertension arterielle par un inhibiteur de l'enzyme de conversion de l'angiotensine. [Chronic treatment of hypertension by an inhibitor of angiotensin converting enzyme]

Captopril, or SQ 14,225 an orally active inhibitor of angiotensin-converting enzyme, produced a significant blood pressure reduction in 26 hypertensives. This new drug, alone or combined with a diuretic, has normalized the blood pressure of the 22 patients on long-term treatment.

Changes in Aortic Pulse Wave Velocity in Hypertensive Postmenopausal Women: Comparison Between a Calcium Channel Blocker vs Angiotensin Receptor Blocker Regimen.

J Clin Hypertens (Greenwich). 2012;14:773-778. ©2012 Wiley Periodicals, Inc. Postmenopausal women are at greater risk for hypertension-related cardiovascular disease. Antihypertensive therapy may help alleviate arterial stiffness that represents a potential modifiable risk factor of hypertension. This randomized controlled study investigated the difference between an angiotensin receptor blocker and a calcium channel blocker in reducing arterial stiffness. Overall, 125 postmenopausal hypertensive women (age, 61.4±6 years; systolic blood pressure/diastolic blood pressure [SBP/DBP], 158±11/92±9 mm Hg) were randomized to valsartan 320 mg±hydrochlorothiazide (HCTZ) (n=63) or amlodipine 10 mg±HCTZ (n=62). The primary outcome was carotid-to-femoral pulse wave velocity (PWV) changes after 38 weeks of treatment. Both treatments lowered peripheral blood pressure (BP) (-22.9/-10.9 mm Hg for valsartan and -25.2/-11.7 mm Hg for amlodipine, P=not significant) and central BP (-15.7/-7.6 mm Hg for valsartan and -19.2/-10.3 mm Hg for amlodipine, P<.05 for central DBP). Both treatments similarly reduced the carotid-femoral PWV (-1.9 vs -1.7 m/s; P=not significant). Amlodipine was associated with a higher incidence of peripheral edema compared with the valsartan group (77% vs 14%, P<.001). BP lowering in postmenopausal women led to a reduction in arterial stiffness as assessed by PWV measurement. Both regimens reduced PWV to a similar degree after 38 weeks of treatment despite differences in central BP lowering, suggesting that the effect of valsartan on PWV is mediated through nonhemodynamic effects.

Ambulatory blood pressure monitoring to assess antihypertensive therapy in private practice

Non-invasive ambulatory blood pressure monitoring has proved to be very useful in evaluating hypertensive patients. However, most previous studies were performed in specialised centres. Here the results of two trials are presented in which private physicians used ambulatory BP monitoring to assess the efficacy of antihypertensive drugs. The results were very similar to those observed previously in specialised clinics. In the individual patient, the level of ambulatory recorded pressure could not be predicted based on BP readings taken at the doctor's office. Also, the BP response to antihypertensive therapy was more reproducible when evaluated by ambulatory BP monitoring than by the doctor. Thus, the use of noninvasive ambulatory BP monitoring is also very appropriate in everyday practice for the management of hypertensive patients.

Complementary effects of adenosine and angiotensin II in hypoxemia-induced renal dysfunction in the rabbit.

The acute renal effects of hypoxemia and the ability of the co-administration of an angiotensin converting enzyme inhibitor (perindoprilat) and an adenosine receptor antagonist (theophylline) to prevent these effects were assessed in anesthetized and mechanically-ventilated rabbits. Renal blood flow (RBF) and glomerular filtration rate (GFR) were determined by the clearances of para-aminohippuric acid and inulin, respectively. Each animal acted as its own control. In 8 untreated rabbits, hypoxemia induced a significant drop in mean blood pressure (-12 +/- 2%), GFR (-16 +/- 3%) and RBF (-12 +/- 3%) with a concomitant increase in renal vascular resistance (RVR) (+ 18 +/- 5%), without changes in filtration fraction (FF) (-4 +/- 2%). These results suggest the occurrence of both pre- and postglomerular vasoconstriction during the hypoxemic stress. In 7 rabbits pretreated with intravenous perindoprilat (20 microg/kg), the hypoxemia-induced changes in RBF and RVR were prevented. FF decreased significantly (-18 +/- 2%), while the drop in GFR was partially blunted. These results could be explained by the inhibition of the angiotensin-mediated efferent vasoconstriction by perindoprilat. In 7 additional rabbits, co-administration of perindoprilat and theophylline (1 mg/kg) completely prevented the hypoxemia-induced changes in RBF (+ 11 +/- 3%) and GFR (+ 2 +/- 3%), while RVR decreased significantly (-14 +/- 3%). Since adenosine and angiotensin II were both shown to participate, at least in part, in the renal changes induced by hypoxemia, the beneficial effects of perindoprilat and theophylline in this model could be mediated by complementary actions of angiotensin II and adenosine on the renal vasculature.

An angiotensin II- and NF-kappaB-dependent mechanism increases connexin 43 in murine arteries targeted by renin-dependent hypertension.

AIMS: Connexins (Cxs) play a role in the contractility of the aorta wall. We investigated how connexins of the endothelial cells (ECs; Cx37, Cx40) and smooth muscle cells (SMCs; Cx43, Cx45) of the aorta change during renin-dependent and -independent hypertension. METHODS AND RESULTS: We subjected both wild-type (WT) mice and mice lacking Cx40 (Cx40(-/-)), to either a two-kidney, one-clip procedure or to N-nitro-l-arginine-methyl-ester treatment, which induce renin-dependent and -independent hypertension, respectively. All hypertensive mice featured a thickened aortic wall, increased levels of Cx37 and Cx45 in SMC, and of Cx40 in EC (except in Cx40(-/-) mice). Cx43 was up-regulated, with no effect on its S368 phosphorylation, only in the SMCs of renin-dependent models of hypertension. Blockade of the renin-angiotensin system of Cx40(-/-) mice normalized blood pressure and prevented both aortic thickening and Cx alterations. Ex vivo exposure of WT aortas, carotids, and mesenteric arteries to physiologically relevant levels of angiotensin II (AngII) increased the levels of Cx43, but not of other Cx. In the aortic SMC line of A7r5 cells, AngII activated kinase-dependent pathways and induced binding of the nuclear factor-kappa B (NF-kappaB) to the Cx43 gene promoter, increasing Cx43 expression. CONCLUSION: In both large and small arteries, hypertension differently regulates Cx expression in SMC and EC layers. Cx43 is selectively increased in renin-dependent hypertension via an AngII activation of the extracellular signal-regulated kinase and NF-kappaB pathways.

Clinical pharmacology of the angiotensin II receptor antagonist losartan potassium in healthy subjects

INTRODUCTION: The evaluation of a new drug in normotensive volunteers provides important pharmacodynamic and pharmacokinetic information as long as the compound has a specific mechanism of action which can be evaluated in healthy subjects as well as in patients. The purpose of the present paper is to discuss the results that have been obtained in normal volunteers with the specific angiotensin II receptor antagonist, losartan potassium. DOSE-FINDING: Over the last few years, studies in normotensive subjects have demonstrated that the minimal dose of losartan that produces maximal efficacy is 40-80 mg. Losartan has a long duration of action and its ability to produce a sustained blockade of the renin-angiotensin system is due almost exclusively to the active metabolite E3174. HORMONAL EFFECTS: Angiotensin II receptor blockade with losartan induces an expected increase in plasma renin activity and plasma angiotensin II levels. A decrease in plasma aldosterone levels has been found only with a high dose of losartan (120 mg). RENAL AND BLOOD PRESSURE EFFECTS: In normotensive subjects, losartan has little or no effect on blood pressure unless the subjects are markedly salt-depleted. Losartan causes no change in the glomerular filtration rate and either no modification or only a slight increase in renal blood flow. Losartan significantly increases urinary sodium excretion, however, and surprisingly produces a transient rise in urinary potassium excretion. Finally, losartan increases uric acid excretion and lowers plasma uric acid levels. CONCLUSIONS: These results suggest that losartan is an effective angiotensin II receptor antagonist in normal subjects. Its safety and clinical efficacy in hypertensive patients will be addressed in large clinical trials.

Combining blockers of the renin-angiotensin system or increasing the dose of an angiotensin II receptor antagonist in proteinuric patients: a randomized triple-crossover study.

Objective The goal of this study was to investigate whether increasing the dose of an angiotensin II receptor blocker (ARB) provides as much benefits as combining the ARB with an angiotensin-converting enzyme inhibitor (ACEI) in terms of blood pressure (BP) control and urinary albumin excretion (UAE) in hypertensive patients with a proteinuria.Methods We enrolled 20 hypertensive patients with proteinuric nephropathies and a reduced renal function in a randomized, 12-month, triple-crossover, prospective, open-label study to compare the effects of a regular dose of losartan (Los 100mg q.d., LOS100) vs. a high dose of losartan (Los 100mg b.i.d., LOS200) vs. losartan 100mg q.d. associated with lisinopril 20 mg q.d. (LOS100 + LIS20). Each treatment was given for 8 weeks with a 4-week initial run-in period and 2 weeks of washout between each treatment phases. 24 h UAE and ambulatory BP were measured during the running phase and at the end of each treatment period.Results Compared to pretreatment, 24 h SBP and DBP were reduced by 10/5 +/- 7/4 mmHg with LOS100 (P=0.023 vs. baseline) and, respectively, 13/6 +/- 12/5 mmHg with LOS200 (P=0.011) and 19/9 +/- 15/8 mmHg with LOS100+LIS20 (P < 0.01). UAE decreased significantly with LOS100 and to an even greater degree with LOS200 and LOS100+LIS20 (P < 0.01 vs. baseline for both and P=0.032, LOS100+LIS20 vs. LOS200). The combination had a greater impact in patients with a high baseline proteinuria as suggested by a nonparallel leftward shift of the relationship between the changes in UAE induced by the combination and those induced by LOS200. The high dose of losartan was better tolerated than the combination.Conclusion Increasing the dose of losartan from 100mg once daily to 100mg twice a day enables to obtain a greater decrease in BP and proteinuria and is better tolerated than combining the ARB with lisinopril, though the high dose appears to be slightly less effective than the combination in patients with a marked proteinuria. J Hypertens 29: 1228-1235 (C) 2011 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.

Deleterious Actions Of Vegf On The Blood Retinal Barrier And Photoreceptor Survival In The Light-damage Model

Purpose: The retinal balance between pro- and anti-angiogenic factors is critical for angiogenesis control, but is also involved in cell survival. We previously reported upregulation of VEGF and photoreceptor (PR) cell death in the Light-damage (LD) model. Preliminary results showed that anti-VEGF can rescue PR from cell death. Thus, we investigated the role of VEGF on the retina and we herein described the effect of anti-VEGF antibody delivered by lentiviral gene transfer in this model.Methods: To characterize the action of VEGF during the LD, we exposed Balb/c mice subretinally injected with LV-anti-VEGF, or not, to 5'000 lux for 1h. We next evaluated the retinal function, PR survival and protein expression (VEGF, VEGFR1/2, Src, PEDF, p38MAPK, Akt, Peripherin, SWL-opsin) after LD. We analyzed Blood retinal barrier (BRB) integrity on flat-mounted RPE and cryosections stained with β-catenin, ZO-1, N-cadherin and albumin.Results: Results indicate that the VEGF pathway is modulated after LD. LD leads to extravascular albumin leakage and BRB breakdown: β-catenin, ZO-1 and N-cadherin translocate to the cytoplasm of RPE cells showing loss of cell cohesion. This phenomenon is in adequacy with the VEGF time-course expression. Assessment of the retinal function reveals that PR rescue correlates with the level of LV-anti-VEGF expression. Rhodopsin content was higher in the LV-anti-VEGF group than in controls and measures of the ONL thickness indicate that LV-anti-VEGF preserves by 82% the outer nuclear layer from degeneration. Outer segments (OS) appeared well organized with an appropriate length in the LV-anti-VEGF group compared to controls, and the expression of SWL-opsin is maintained in the OS without being mislocalized as in the LV-GFP group. Finally, LV-anti-VEGF treatment prevents BRB breakdown and maintained RPE cell integrity.Conclusions: This study involves VEGF in LD and highlights the prime importance of the BRB integrity for PR survival. Taken together, these results show that anti-VEGF is neuroprotective in this model and maintains functional PR layer in LD-treated mice.

Low adiponectin is associated with increased ambulatory pulse pressure and activation of the renin-angiotensin system in subjects of African descent

Purpose: Adiponectin, arterial stiffness, as well components of the renin-angiotensin system are associated with cardiovascular risk. This study was aimed to investigate whether plasma adiponectin was directly linked with pulse pressure (PP), as a marker for arterial stiffness, and the renin-angiotensin system (RAS). Methods and materials: A family-based study in subjects of African descent enriched with hypertensive patients was carried out in the Seychelles. Fasting plasma adiponectin was determined by ELISA, plasma renin activity according to the antibody-trapping principle and plasma aldosterone by radioimmunoassay. Daytime ambulatory blood pressure (BP) was measured using Diasys Integra devices. PP was calculated as the difference between systolic and diastolic BP. The association of adiponectin with PP, plasma renin activity and plasma aldosterone were analyzed using generalized estimating equations with a gaussian family link and an exchangeable correlation structure to account for familial aggregation. Results: Data from 335 subjects from 73 families (152 men, 183 women) were available. Men and women had mean (SD) age of 45.4 ± 11.1 and 47.3 ± 12.4 years, BMI of 26.3 ± 4.4 and 27.8 ± 5.1 kg/m2, daytime systolic/diastolic BP of 132.6 ± 15.4 / 86.1 ± 10.9 and 130 ± 17.6 / 83.4 ± 11.1 mmHg, and daytime PP of 46.5 ± 9.9 and 46.7 ± 10.7 mmHg, respectively. Plasma adiponectin was 4.4± 3.04 ng/ml in men and 7.39 ± 5.44 ng/ml in women (P <0.001). After adjustment for age, sex and BMI, log-transformed adiponectin was negatively associated with daytime PP (-0.009 ± 0.003, P = 0.004), plasma renin activity (-0.248 ± 0.080, P = 0.002) and plasma aldosterone (-0.004 ± 0.002, P = 0.014). Conclusion: Low adiponectin is associated with increased ambulatory PP and RAS activation in subjects of African descent. Our data are consistent with the observation that angiotensin II receptor blockers increase adiponectin in humans.