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A Jan H Danser - One of the best experts on this subject based on the ideXlab platform.
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multiple ascending dose study with the new Renin Inhibitor vtp 27999 nephrocentric consequences of too much Renin inhibition
Hypertension, 2014Co-Authors: Joanna Balcarek, Michel Azizi, Ingrid M Garrelds, Bruno Seva Pessoa, Catherine Bryson, J Menard, Gerard Mcgeehan, Richard A Reeves, Sue G Griffith, A Jan H DanserAbstract:This study compared the pharmacodynamic/pharmacokinetic profile of the new Renin Inhibitor VTP-27999 in salt-depleted healthy volunteers, administered once daily (75, 150, 300, and 600 mg) for 10 days, versus placebo and 300 mg aliskiren. VTP-27999 was well tolerated with no significant safety issues. It was rapidly absorbed, attaining maximum plasma concentrations at 1 to 4 hours after dosing, with a terminal half-life of 24 to 30 hours. Plasma Renin activity remained suppressed during the 24-hour dosing interval at all doses. VTP-27999 administration resulted in a dose-dependent induction of Renin, increasing the concentration of plasma Renin maximally 350-fold. This induction was greater than with aliskiren, indicating greater intrarenal Renin inhibition. VTP-27999 decreased plasma angiotensin II and aldosterone. At 24 hours and later time points after dosing on day 10 in the 600-mg group, angiotensin II and aldosterone levels were increased, and plasma Renin activity was also increased at 48 and 72 hours, compared with baseline. VTP-27999 decreased urinary aldosterone excretion versus placebo on day 1. On day 10, urinary aldosterone excretion was higher in the 300- and 600-mg VTP-27999 dose groups compared with baseline. VTP-27999 decreased blood pressure to the same degree as aliskiren. In conclusion, excessive intrarenal Renin inhibition, obtained at VTP-27999 doses of 300 mg and higher, is accompanied by plasma Renin rises, that after stopping drug intake, exceed the capacity of extrarenal VTP-27999 to block fully the enzymatic reaction. This results in significant rises of angiotensin II and aldosterone. Therefore, Renin inhibition has an upper limit.
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handle region peptide counteracts the beneficial effects of the Renin Inhibitor aliskiren in spontaneously hypertensive rats
Hypertension, 2011Co-Authors: Joep H.m. Van Esch, Ingrid M Garrelds, Richard Van Veghel, Frank Leijten, Angelique M. Bouhuizen, A Jan H DanserAbstract:To investigate whether the putative (pro)Renin receptor blocker, the handle region peptide (HRP), exerts effects on top of the blood pressure–lowering and cardioprotective effects of the Renin Inhibitor aliskiren, spontaneously hypertensive rats were implanted with telemetry transmitters to monitor heart rate and mean arterial pressure (MAP). After a 2-week recovery period, vehicle, aliskiren, HRP (100 and 1 mg/kg per day, respectively), and HRP+aliskiren were infused for 3 weeks using osmotic minipumps. Subsequently, the heart was removed to study coronary function according to Langendorff. Baseline MAP and heart rate in vehicle-treated rats were 146±3 mm Hg and 326±4 bpm. HRP did not affect MAP, whereas aliskiren and HRP+aliskiren lowered MAP (by maximally 29±2 and 20±1 mm Hg, respectively) without affecting heart rate. Aliskiren significantly reduced MAP throughout the 3-week infusion period, whereas the blood pressure–lowering effect of HRP+aliskiren returned to baseline within 2 weeks of treatment. In comparison with vehicle, aliskiren increased the endothelium-dependent response to bradykinin and decreased the response to angiotensin II in the coronary circulation, whereas these responses were not altered after treatment with HRP or HRP+aliskiren. HRP did not alter plasma Renin activity, plasma angiotensin levels, or the renal angiotensin content, either alone or on top of aliskiren, nor did it alter the aliskiren-induced decrease in renal Ang II type 1 receptor expression. Yet, it did reverse the aliskiren-induced reduction in cardiomyocyte area, without affecting this area when given alone. In conclusion, HRP counteracts the beneficial effects of aliskiren on blood pressure, coronary function, and cardiac hypertrophy in an angiotensin-independent manner.
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activity assays and immunoassays for plasma Renin and proRenin information provided and precautions necessary for accurate measurement
Clinical Chemistry, 2009Co-Authors: Duncan J. Campbell, Juerg Nussberger, Michael Stowasser, A Jan H Danser, Alberto Morganti, E Frandsen, Joël MénardAbstract:Background: Measurement of plasma Renin is important for the clinical assessment of hypertensive patients. The most common methods for measuring plasma Renin are the plasma Renin activity (PRA) assay and the Renin immunoassay. The clinical application of Renin Inhibitor therapy has thrown into focus the differences in information provided by activity assays and immunoassays for Renin and proRenin measurement and has drawn attention to the need for precautions to ensure their accurate measurement. Content: Renin activity assays and immunoassays provide related but different information. Whereas activity assays measure only active Renin, immunoassays measure both active and inhibited Renin. Particular care must be taken in the collection and processing of blood samples and in the performance of these assays to avoid errors in Renin measurement. Both activity assays and immunoassays are susceptible to Renin overestimation due to proRenin activation. In addition, activity assays performed with peptidase Inhibitors may overestimate the degree of inhibition of PRA by Renin Inhibitor therapy. Moreover, immunoassays may overestimate the reactive increase in plasma Renin concentration in response to Renin Inhibitor therapy, owing to the Inhibitor promoting conversion of proRenin to an open conformation that is recognized by Renin immunoassays. Conclusions: The successful application of Renin assays to patient care requires that the clinician and the clinical chemist understand the information provided by these assays and of the precautions necessary to ensure their accuracy.
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renal and hormonal responses to direct Renin inhibition with aliskiren in healthy humans
Circulation, 2008Co-Authors: Naomi D L Fisher, A Jan H Danser, William P Dole, J Nussberger, Norman K HollenbergAbstract:Background— Pharmacological interruption of the Renin-angiotensin system focuses on optimization of blockade. As a measure of intrarenal Renin activity, we have examined renal plasma flow (RPF) responses in a standardized protocol. Compared with responses with angiotensin-converting enzyme inhibition (rise in RPF ≈95 mL · min−1 · 1.73 m−2), greater renal vasodilation with angiotensin receptor blockers (≈145 mL · min−1 · 1.73 m−2) suggested more effective blockade. We predicted that blockade with the direct oral Renin Inhibitor aliskiren would produce renal vascular responses exceeding those induced by angiotensin-converting enzyme Inhibitors and angiotensin receptor blockers. Methods and Results— Twenty healthy normotensive subjects were studied on a low-sodium (10 mmol/d) diet, receiving separate escalating doses of aliskiren. Six additional subjects received captopril 25 mg as a low-sodium comparison and also received aliskiren on a high-sodium (200 mmol/d) diet. RPF was measured by clearance of para-am...
Deborah L Keefe - One of the best experts on this subject based on the ideXlab platform.
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safety and tolerability of the direct Renin Inhibitor aliskiren in combination with angiotensin receptor blockers and thiazide diuretics a pooled analysis of clinical experience of 12 942 patients
Journal of Clinical Hypertension, 2011Co-Authors: William B White, Robert S Bresalier, Allen P Kaplan, Biff F Palmer, Robert H Riddell, Anastasia Lesogor, William Chang, Deborah L KeefeAbstract:Combinations of the direct Renin Inhibitor aliskiren with angiotensin receptor blockers (ARBs) or diuretics are effective therapeutic regimens for the treatment of hypertension. A large database of safety information has become available during the past several years with aliskiren in combination trials. Data were pooled from 9 short-term (8-week) and 4 longer-term (26- to 52-week) randomized controlled trials of aliskiren in patients with hypertension. Adverse event (AE) rates were assessed for aliskiren combination therapy compared with component monotherapies. In short-term studies, overall AE rates were similar for patients receiving aliskiren/valsartan or aliskiren/diuretic combinations (32.2%-39.8%) and those receiving the component monotherapies (30.0%-39.6%). In longer-term studies, AE rates with aliskiren/losartan (55.5%) and aliskiren/diuretic (45.0%) combination therapy were similar to those with losartan (53.9%) and diuretic (48.9%) alone. Angioedema and hyperkalemia occurred in similar proportions of patients taking combination therapies vs monotherapy. The safety and tolerability profile of aliskiren in combination with the ARBs valsartan or losartan, or diuretic, is similar to aliskiren, ARBs, or diuretics alone.
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safety and tolerability of the direct Renin Inhibitor aliskiren a pooled analysis of clinical experience in more than 12 000 patients with hypertension
Journal of Clinical Hypertension, 2010Co-Authors: William B White, Robert S Bresalier, Allen P Kaplan, Biff F Palmer, Robert H Riddell, Anastasia Lesogor, William Chang, Deborah L KeefeAbstract:While the safety of Renin-angiotensin system (RAS)-blocking drugs such as angiotensin-converting enzyme (ACE) Inhibitors and angiotensin receptor blockers is well known, less is known about the new direct Renin Inhibitor aliskiren. The authors pooled data from 12 randomized controlled trials of aliskiren in patients with hypertension and analyzed the incidence and types of adverse events (AEs) and laboratory abnormalities. Studies were characterized as short-term (≤2 months) placebo-controlled or long-term (>2 months) active-controlled. Relative risks for AEs of particular interest for RAS blockers were calculated. In short-term studies, AEs occurred in similar proportions of aliskiren 150 mg and 300 mg (33.6% and 31.6%, respectively) and placebo treatment groups (36.8%). In long-term studies, a lower proportion of patients treated with aliskiren 150 mg and 300 mg had AEs (33.7% and 43.2%, respectively) than those treated with ACE Inhibitors (60.1%), angiotensin receptor blockers (53.9%), and thiazide diuretics (48.9%). Events of special interest, including angioedema, hyperkalemia, and diarrhea occurred in similar proportions of patients taking aliskiren, placebo, and comparator agents. In studies of up to 36 weeks, patients treated with aliskiren were significantly less likely to develop cough than those treated with ACE Inhibitors. At the registered doses of 150 mg and 300 mg daily, aliskiren has safety and tolerability profiles similar to placebo, other RAS blockers, and diuretics. Cough rates are lower with aliskiren compared with ACE Inhibitors.
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Effects of the direct Renin Inhibitor aliskiren and atenolol alone or in combination in patients with hypertension.
Journal of the renin-angiotensin-aldosterone system : JRAAS, 2008Co-Authors: Rainer Dietz, Margaret F Prescott, Ralf Dechend, Manesh Bheda, Jessica Ford, Deborah L KeefeAbstract:Introduction. Aliskiren is the first in a new class of direct Renin Inhibitors to be approved for the treatment of hypertension.Patients and methods. In this double-blind, multicentre trial, 694 patients with hypertension (mean sitting diastolic blood pressure [BP] ≥ 95 and < 110 mmHg) were randomised to once-daily aliskiren 150 mg (n=231), atenolol 50 mg (n=231) or the combination (150/50 mg; n=232) for six weeks, followed by a further six weeks on double the initial doses of aliskiren and atenolol. Efficacy (reduction from baseline in mean sitting systolic and diastolic BP) and tolerability of study treatments were assessed; plasma Renin activity (PRA) was measured in a subset of patients.Results. At Week 12 endpoint, aliskiren, atenolol and aliskiren/atenolol lowered systolic and diastolic BP from baseline by 14.3/11.3, 14.3/13.7 and 17.3/14.1 mmHg, respectively. Systolic BP reductions with aliskiren/atenolol were significantly greater than those with aliskiren (p=0.039) or atenolol (p=0.034) alone, an...
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effects of the oral direct Renin Inhibitor aliskiren in patients with symptomatic heart failure
Circulation-heart Failure, 2008Co-Authors: John J V Mcmurray, Scott D Solomon, Anil Verma, Deborah L Keefe, Jessica Ford, Bertram Pitt, Roberto Latini, Aldo P Maggioni, James D LewseyAbstract:Background— Loss of negative feedback inhibition of Renin release during chronic treatment with an angiotensin-converting enzyme (ACE) Inhibitor leads to a compensatory rise in Renin secretion and downstream components of the Renin-angiotensin-aldosterone (RAAS) cascade. This may overcome ACE inhibition but should be blocked by a direct Renin Inhibitor. We studied the effects of adding the direct Renin Inhibitor aliskiren to an ACE Inhibitor in patients with heart failure. Methods and Results— Patients with New York Heart Association class II to IV heart failure, current or past history of hypertension, and plasma brain natriuretic peptide (BNP) concentration >100 pg/mL who had been treated with an ACE Inhibitor (or angiotensin receptor blocker) and β-blocker were randomized to 3 months of treatment with placebo (n=146) or aliskiren 150 mg/d (n=156). The primary efficacy outcome was the between-treatment difference in N-terminal pro-BNP (NT-proBNP). Patients’ mean age was 68 years, mean ejection fraction ...
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comparative efficacy and safety of aliskiren an oral direct Renin Inhibitor and ramipril in hypertension a 6 month randomized double blind trial
Journal of Hypertension, 2008Co-Authors: Karl Andersen, Myron H Weinberger, Brent M Egan, Christian M Constance, Mohammed Atif Ali, James Jin, Deborah L KeefeAbstract:OBJECTIVES: This double-blind study compared long-term efficacy, safety and tolerability of the oral direct Renin Inhibitor aliskiren and the angiotensin-converting enzyme Inhibitor ramipril alone and combined with hydrochlorothiazide in patients with hypertension. METHODS: After a 2-4-week placebo run-in, 842 patients [mean sitting diastolic blood pressure (msDBP) 95-109 mmHg] were randomized to aliskiren 150 mg (n = 420) or ramipril 5 mg (n = 422). Dose titration (to aliskiren 300 mg/ramipril 10 mg) and subsequent hydrochlorothiazide addition (12.5 mg, titrated to 25 mg if required) were permitted at weeks 6, 12, 18 and 21 for inadequate blood pressure control. Patients completing the 26-week active-controlled treatment period were re-randomized to their existing regimen or placebo for a 4-week double-blind withdrawal phase. RESULTS: Six hundred and eighty-seven patients (81.6%) completed the active treatment period. At week 26, aliskiren-based therapy produced greater mean reductions in mean sitting systolic blood pressure (17.9 versus 15.2 mmHg, P = 0.0036) and msDBP (13.2 versus 12.0 mmHg, P = 0.025), and higher rates of systolic blood pressure control (< 140 mmHg; 72.5 versus 64.1%, P = 0.0075) compared with ramipril-based therapy. During withdrawal, blood pressure increased more rapidly after stopping ramipril than aliskiren-based therapy; median blood pressure reached 140/90 mmHg after 1 and 4 weeks, respectively. Blood pressure reductions were maintained with continued active treatment. Aliskiren therapy was well tolerated. Overall adverse event rates were similar with aliskiren (61.3%) and ramipril (60.4%); cough was more frequent with ramipril (9.5%) than aliskiren (4.1%). CONCLUSIONS: Aliskiren-based therapy was well tolerated and produced sustained blood pressure reductions in patients with hypertension over 6 months, greater than those with ramipril-based therapy.
David Louis Feldman - One of the best experts on this subject based on the ideXlab platform.
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angiotensinogen exerts effects independent of angiotensin ii
Arteriosclerosis Thrombosis and Vascular Biology, 2016Co-Authors: Deborah A Howatt, David Louis Feldman, Anju Balakrishnan, Jessica J Moorleghen, Xiaofeng Chen, Mingming Zhao, Mark Graham, Adam E Mullick, Rosanne M Crooke, Lisa A CassisAbstract:Objective—This study determined whether angiotensinogen (AGT) has angiotensin II–independent effects using multiple genetic and pharmacological manipulations. Approach and Results—All study mice were in low-density lipoprotein receptor −/− background and fed a saturated fat–enriched diet. In mice with floxed alleles and a neomycin cassette in intron 2 of the AGT gene (hypoAGT mice), plasma AGT concentrations were >90% lower compared with their wild-type littermates. HypoAGT mice had lower systolic blood pressure, less atherosclerosis, and diminished body weight gain and liver steatosis. Low plasma AGT concentrations and all phenotypes were recapitulated in mice with hepatocyte-specific deficiency of AGT or pharmacological inhibition of AGT by antisense oligonucleotide administration. In contrast, inhibition of AGT cleavage by a Renin Inhibitor, aliskiren, failed to alter body weight gain and liver steatosis in low-density lipoprotein receptor −/− mice. In mice with established adiposity, administration of...
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effects of aliskiren on blood pressure albuminuria and pro Renin receptor expression in diabetic tg mren 2 27 rats
Hypertension, 2008Co-Authors: David Louis Feldman, Liang Jin, Hong Xuan, Aurelie Contrepas, Yinong Zhou, Randy Lee Webb, Dominik N Mueller, Sandra Feldt, Frederick Cumin, Wieslawa ManiaraAbstract:The aim of this study was to explore the effects of the Renin Inhibitor aliskiren in streptozotocin-diabetic TG(mRen-2)27 rats. Furthermore, we investigated in vitro the effect of aliskiren on the interactions between Renin and the (pro)Renin receptor and between aliskiren and proRenin. Aliskiren distributed extensively to the kidneys of normotensive (non)diabetic rats, localizing in the glomeruli and vessel walls after 2 hours exposure. In diabetic TG(mRen-2)27 rats, aliskiren (10 or 30 mg/kg per day, 10 weeks) lowered blood pressure, prevented albuminuria, and suppressed renal transforming growth factor-beta and collagen I expression versus vehicle. Aliskiren reduced (pro)Renin receptor expression in glomeruli, tubules, and cortical vessels compared to vehicle (in situ hybridization). In human mesangial cells, aliskiren (0.1 micromol/L to 10 micromol/L) did not inhibit binding of (125)I-Renin to the (pro)Renin receptor, nor did it alter the activation of extracellular signal-regulated kinase 1/2 by Renin (20 nmol/L) preincubated with aliskiren (100 nmol/L) or affect gene expression of the (pro)Renin receptor. Evidence was obtained that aliskiren binds to the active site of proRenin. The above results demonstrate the antihypertensive and renoprotective effects of aliskiren in experimental diabetic nephropathy. The evidence that aliskiren can reduce in vivo gene expression for the (pro)Renin receptor and that it may block proRenin-induced angiotensin generation supports the need for additional work to reveal the mechanism of the observed renoprotection by this Renin Inhibitor.
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effects of aliskiren on blood pressure albuminuria and pro Renin receptor expression in diabetic tg mren 2 27 rats
Hypertension, 2008Co-Authors: David Louis Feldman, Liang Jin, Hong Xuan, Aurelie Contrepas, Yinong Zhou, Randy Lee Webb, Dominik N Mueller, Sandra Feldt, Frederick Cumin, Wieslawa ManiaraAbstract:The aim of this study was to explore the effects of the Renin Inhibitor aliskiren in streptozotocin-diabetic TG(mRen-2)27 rats. Furthermore, we investigated in vitro the effect of aliskiren on the interactions between Renin and the (pro)Renin receptor and between aliskiren and proRenin. Aliskiren distributed extensively to the kidneys of normotensive (non)diabetic rats, localizing in the glomeruli and vessel walls after 2 hours exposure. In diabetic TG(mRen-2)27 rats, aliskiren (10 or 30 mg/kg per day, 10 weeks) lowered blood pressure, prevented albuminuria, and suppressed renal transforming growth factor-β and collagen I expression versus vehicle. Aliskiren reduced (pro)Renin receptor expression in glomeruli, tubules, and cortical vessels compared to vehicle (in situ hybridization). In human mesangial cells, aliskiren (0.1 μmol/L to 10 μmol/L) did not inhibit binding of 125 I-Renin to the (pro)Renin receptor, nor did it alter the activation of extracellular signal-regulated kinase 1/2 by Renin (20 nmol/L) preincubated with aliskiren (100 nmol/L) or affect gene expression of the (pro)Renin receptor. Evidence was obtained that aliskiren binds to the active site of proRenin. The above results demonstrate the antihypertensive and renoprotective effects of aliskiren in experimental diabetic nephropathy. The evidence that aliskiren can reduce in vivo gene expression for the (pro)Renin receptor and that it may block proRenin-induced angiotensin generation supports the need for additional work to reveal the mechanism of the observed renoprotection by this Renin Inhibitor.
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aliskiren a human Renin Inhibitor ameliorates cardiac and renal damage in double transgenic rats
Hypertension, 2005Co-Authors: Bernhard Pilz, David Louis Feldman, Ralf Dechend, Erdenechimeg Shagdarsuren, Maren Wellner, Anette Fiebeler, Petra Gratze, Silke Meiners, Randy L Webb, Ingrid M GarreldsAbstract:We tested the hypothesis that the Renin Inhibitor aliskiren ameliorates organ damage in rats transgenic for human Renin and angiotensinogen genes (double transgenic rat [dTGR]). Six-week-old dTGR were matched by albuminuria (2 mg per day) and divided into 5 groups. Untreated dTGR were compared with aliskiren (3 and 0.3 mg/kg per day)-treated and valsartan (Val; 10 and 1 mg/kg per day)-treated rats. Treatment was from week 6 through week 9. At week 6, all groups had elevated systolic blood pressure (BP). Untreated dTGR showed increased BP (202±4 mm Hg), serum creatinine, and albuminuria (34±5.7 mg per day) at week 7. At week 9, both doses of aliskiren lowered BP (115±6 and 139±5 mm Hg) and albuminuria (0.4±0.1 and 1.6±0.6 mg per day) and normalized serum creatinine. Although high-dose Val lowered BP (148±4 mm Hg) and albuminuria (2.1±0.7 mg per day), low-dose Val reduced BP (182±3 mm Hg) and albuminuria (24±3.8 mg per day) to a lesser extent. Mortality was 100% in untreated dTGR and 26% in Val (1 mg/kg per day) treated rats, whereas in all other groups, survival was 100%. dTGR treated with low-dose Val had cardiac hypertrophy (4.4±0.1 mg/g), increased left ventricular (LV) wall thickness, and diastolic dysfunction. LV atrial natriuretic peptide and β-myosin heavy chain mRNA, albuminuria, fibrosis, and cell infiltration were also increased. In contrast, both aliskiren doses and the high-dose Val lowered BP to a similar extent and more effectively than low-dose Val. We conclude that in dTGR, equieffective antihypertensive doses of Val or aliskiren attenuated end-organ damage. Thus, Renin inhibition compares favorably to angiotensin receptor blockade in reversing organ damage in dTGR.
Randy Lee Webb - One of the best experts on this subject based on the ideXlab platform.
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effects of aliskiren on blood pressure albuminuria and pro Renin receptor expression in diabetic tg mren 2 27 rats
Hypertension, 2008Co-Authors: David Louis Feldman, Liang Jin, Hong Xuan, Aurelie Contrepas, Yinong Zhou, Randy Lee Webb, Dominik N Mueller, Sandra Feldt, Frederick Cumin, Wieslawa ManiaraAbstract:The aim of this study was to explore the effects of the Renin Inhibitor aliskiren in streptozotocin-diabetic TG(mRen-2)27 rats. Furthermore, we investigated in vitro the effect of aliskiren on the interactions between Renin and the (pro)Renin receptor and between aliskiren and proRenin. Aliskiren distributed extensively to the kidneys of normotensive (non)diabetic rats, localizing in the glomeruli and vessel walls after 2 hours exposure. In diabetic TG(mRen-2)27 rats, aliskiren (10 or 30 mg/kg per day, 10 weeks) lowered blood pressure, prevented albuminuria, and suppressed renal transforming growth factor-beta and collagen I expression versus vehicle. Aliskiren reduced (pro)Renin receptor expression in glomeruli, tubules, and cortical vessels compared to vehicle (in situ hybridization). In human mesangial cells, aliskiren (0.1 micromol/L to 10 micromol/L) did not inhibit binding of (125)I-Renin to the (pro)Renin receptor, nor did it alter the activation of extracellular signal-regulated kinase 1/2 by Renin (20 nmol/L) preincubated with aliskiren (100 nmol/L) or affect gene expression of the (pro)Renin receptor. Evidence was obtained that aliskiren binds to the active site of proRenin. The above results demonstrate the antihypertensive and renoprotective effects of aliskiren in experimental diabetic nephropathy. The evidence that aliskiren can reduce in vivo gene expression for the (pro)Renin receptor and that it may block proRenin-induced angiotensin generation supports the need for additional work to reveal the mechanism of the observed renoprotection by this Renin Inhibitor.
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effects of aliskiren on blood pressure albuminuria and pro Renin receptor expression in diabetic tg mren 2 27 rats
Hypertension, 2008Co-Authors: David Louis Feldman, Liang Jin, Hong Xuan, Aurelie Contrepas, Yinong Zhou, Randy Lee Webb, Dominik N Mueller, Sandra Feldt, Frederick Cumin, Wieslawa ManiaraAbstract:The aim of this study was to explore the effects of the Renin Inhibitor aliskiren in streptozotocin-diabetic TG(mRen-2)27 rats. Furthermore, we investigated in vitro the effect of aliskiren on the interactions between Renin and the (pro)Renin receptor and between aliskiren and proRenin. Aliskiren distributed extensively to the kidneys of normotensive (non)diabetic rats, localizing in the glomeruli and vessel walls after 2 hours exposure. In diabetic TG(mRen-2)27 rats, aliskiren (10 or 30 mg/kg per day, 10 weeks) lowered blood pressure, prevented albuminuria, and suppressed renal transforming growth factor-β and collagen I expression versus vehicle. Aliskiren reduced (pro)Renin receptor expression in glomeruli, tubules, and cortical vessels compared to vehicle (in situ hybridization). In human mesangial cells, aliskiren (0.1 μmol/L to 10 μmol/L) did not inhibit binding of 125 I-Renin to the (pro)Renin receptor, nor did it alter the activation of extracellular signal-regulated kinase 1/2 by Renin (20 nmol/L) preincubated with aliskiren (100 nmol/L) or affect gene expression of the (pro)Renin receptor. Evidence was obtained that aliskiren binds to the active site of proRenin. The above results demonstrate the antihypertensive and renoprotective effects of aliskiren in experimental diabetic nephropathy. The evidence that aliskiren can reduce in vivo gene expression for the (pro)Renin receptor and that it may block proRenin-induced angiotensin generation supports the need for additional work to reveal the mechanism of the observed renoprotection by this Renin Inhibitor.
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Renin inhibition with aliskiren where are we now and where are we going
Journal of Hypertension, 2006Co-Authors: Michel Azizi, Juerg Nussberger, Randy Lee Webb, Norman K HollenbergAbstract:With the development of aliskiren, blockade of the Renin-angiotensin-aldosterone system (RAAS) at the level of the interaction of Renin with a substrate has become a clinical reality. This review covers the specific features of the first agent likely to achieve widespread clinical exposure, aliskiren. The potential of Renin inhibition must be viewed in the context of the remarkable efficacy of both angiotensin-converting enzyme (ACE) inhibition and angiotensin receptor blockers (ARBs). The implications of blockade of the Renin system at its rate-limiting step are reviewed, with the therapeutic implications for both the Renin Inhibitor employed alone or the Renin Inhibitor combined with an ACE Inhibitor or ARB. The relevant and necessary studies are ongoing.
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aliskiren a novel orally effective Renin Inhibitor lowers blood pressure in marmosets and spontaneously hypertensive rats
Journal of Hypertension, 2005Co-Authors: Jeanette Marjorie Wood, Joël Ménard, Christian Schnell, Frederic Cumin, Randy Lee WebbAbstract:Objectives Aliskiren is a new Renin Inhibitor of a novel structural class that has recently been shown to be efficacious in hypertensive patients after once-daily oral dosing. We report the results of animal experiments performed in marmosets and rats in order to characterize aliskiren before its recent investigation in humans. Methods The effects of aliskiren were investigated in sodium-depleted marmosets (oral dosing) and in spontaneously hypertensive rats (dosing via subcutaneous osmotic minipumps). Blood pressure (BP) and heart rate were measured by radiotelemetry. Results In sodium-depleted marmosets, single oral doses of aliskiren (1-30 mg/kg) dose-dependently lowered BP. At a dose of 3 mg/kg, peak effects were observed 1 h after dosing (−30 ± 4 mmHg, n = 6) and the response persisted for more than 12 h. A single oral dose of 3 mg/kg aliskiren was more effective than the same dose of either remikiren or zankiren, two orally active Renin Inhibitors previously tested in humans. Aliskiren (10 mg/kg) was at least as effective as equal doses of the AT1-receptor blocker valsartan or the angiotensin-converting enzyme Inhibitor benazepril. In spontaneously hypertensive rats, aliskiren dose-dependently (10-100 mg/kg per day) decreased BP. Aliskiren also potentiated the antihypertensive effects of low doses of valsartan or benazeprilat (1 or 3 mg/kg per day). Conclusions Aliskiren is an orally effective, long-lasting Renin Inhibitor that shows antihypertensive efficacy in animals superior to previous Renin Inhibitors and at least equivalent to angiotensin-converting enzyme Inhibitors and AT1-receptor blockers. Aliskiren may therefore represent an effective, novel approach to the treatment of hypertension and related disorders, alone or in combination with other antihypertensive agents.
Wieslawa Maniara - One of the best experts on this subject based on the ideXlab platform.
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effects of aliskiren on blood pressure albuminuria and pro Renin receptor expression in diabetic tg mren 2 27 rats
Hypertension, 2008Co-Authors: David Louis Feldman, Liang Jin, Hong Xuan, Aurelie Contrepas, Yinong Zhou, Randy Lee Webb, Dominik N Mueller, Sandra Feldt, Frederick Cumin, Wieslawa ManiaraAbstract:The aim of this study was to explore the effects of the Renin Inhibitor aliskiren in streptozotocin-diabetic TG(mRen-2)27 rats. Furthermore, we investigated in vitro the effect of aliskiren on the interactions between Renin and the (pro)Renin receptor and between aliskiren and proRenin. Aliskiren distributed extensively to the kidneys of normotensive (non)diabetic rats, localizing in the glomeruli and vessel walls after 2 hours exposure. In diabetic TG(mRen-2)27 rats, aliskiren (10 or 30 mg/kg per day, 10 weeks) lowered blood pressure, prevented albuminuria, and suppressed renal transforming growth factor-beta and collagen I expression versus vehicle. Aliskiren reduced (pro)Renin receptor expression in glomeruli, tubules, and cortical vessels compared to vehicle (in situ hybridization). In human mesangial cells, aliskiren (0.1 micromol/L to 10 micromol/L) did not inhibit binding of (125)I-Renin to the (pro)Renin receptor, nor did it alter the activation of extracellular signal-regulated kinase 1/2 by Renin (20 nmol/L) preincubated with aliskiren (100 nmol/L) or affect gene expression of the (pro)Renin receptor. Evidence was obtained that aliskiren binds to the active site of proRenin. The above results demonstrate the antihypertensive and renoprotective effects of aliskiren in experimental diabetic nephropathy. The evidence that aliskiren can reduce in vivo gene expression for the (pro)Renin receptor and that it may block proRenin-induced angiotensin generation supports the need for additional work to reveal the mechanism of the observed renoprotection by this Renin Inhibitor.
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effects of aliskiren on blood pressure albuminuria and pro Renin receptor expression in diabetic tg mren 2 27 rats
Hypertension, 2008Co-Authors: David Louis Feldman, Liang Jin, Hong Xuan, Aurelie Contrepas, Yinong Zhou, Randy Lee Webb, Dominik N Mueller, Sandra Feldt, Frederick Cumin, Wieslawa ManiaraAbstract:The aim of this study was to explore the effects of the Renin Inhibitor aliskiren in streptozotocin-diabetic TG(mRen-2)27 rats. Furthermore, we investigated in vitro the effect of aliskiren on the interactions between Renin and the (pro)Renin receptor and between aliskiren and proRenin. Aliskiren distributed extensively to the kidneys of normotensive (non)diabetic rats, localizing in the glomeruli and vessel walls after 2 hours exposure. In diabetic TG(mRen-2)27 rats, aliskiren (10 or 30 mg/kg per day, 10 weeks) lowered blood pressure, prevented albuminuria, and suppressed renal transforming growth factor-β and collagen I expression versus vehicle. Aliskiren reduced (pro)Renin receptor expression in glomeruli, tubules, and cortical vessels compared to vehicle (in situ hybridization). In human mesangial cells, aliskiren (0.1 μmol/L to 10 μmol/L) did not inhibit binding of 125 I-Renin to the (pro)Renin receptor, nor did it alter the activation of extracellular signal-regulated kinase 1/2 by Renin (20 nmol/L) preincubated with aliskiren (100 nmol/L) or affect gene expression of the (pro)Renin receptor. Evidence was obtained that aliskiren binds to the active site of proRenin. The above results demonstrate the antihypertensive and renoprotective effects of aliskiren in experimental diabetic nephropathy. The evidence that aliskiren can reduce in vivo gene expression for the (pro)Renin receptor and that it may block proRenin-induced angiotensin generation supports the need for additional work to reveal the mechanism of the observed renoprotection by this Renin Inhibitor.