Interpretation of Plasma Renin Concentration in Patients Receiving Aliskiren Therapy
2007; Lippincott Williams & Wilkins; Volume: 51; Issue: 1 Linguagem: Inglês
10.1161/hypertensionaha.107.101287
ISSN1524-4563
Autores Tópico(s)Blood Pressure and Hypertension Studies
ResumoHomeHypertensionVol. 51, No. 1Interpretation of Plasma Renin Concentration in Patients Receiving Aliskiren Therapy Free AccessReview ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessReview ArticlePDF/EPUBInterpretation of Plasma Renin Concentration in Patients Receiving Aliskiren Therapy Duncan J. Campbell Duncan J. CampbellDuncan J. Campbell From the St Vincent's Institute of Medical Research and the Department of Medicine, University of Melbourne, St Vincent's Hospital, Fitzroy, Victoria, Australia. Originally published5 Nov 2007https://doi.org/10.1161/HYPERTENSIONAHA.107.101287Hypertension. 2008;51:15–18Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: November 5, 2007: Previous Version 1 Aliskiren (Tekturna or Rasilez) is an orally active renin inhibitor approved for the treatment of hypertension.1 As with inhibition of the renin-angiotensin system by angiotensin-converting enzyme inhibitors or type 1 angiotensin II (Ang II) receptor blockers, aliskiren therapy is accompanied by a reactive rise in plasma renin concentration, although in contrast to angiotensin-converting enzyme inhibitor and angiotensin receptor blocker therapy, aliskiren reduces enzymatic plasma renin activity (PRA). A direct comparison of aliskiren and angiotensin receptor blocker therapies in hypertensive patients showed differences in the magnitude of the reactive renin response.2,3 In 1 study, 300 mg/d of aliskiren and 320 mg/d of valsartan were similarly hypotensive, whereas plasma renin concentration was 2-fold higher during aliskiren therapy.3 In a second study, 150 mg/d of aliskiren and 150 mg/d of irbesartan were similarly hypotensive, whereas plasma renin concentration was 1.4-fold higher during aliskiren therapy.2,4 Moreover, the renin response to 300 mg of aliskiren was 1.6-fold higher than the response to 320 mg of valsartan in sodium-replete normotensive volunteers.5 Sealey and Laragh6 proposed that the exaggerated renin response may limit aliskiren's ability to reduce blood pressure by counteracting the effect of renin inhibition on Ang II levels and may thereby account for the failure of 600 mg of aliskiren to reduce blood pressure at >300 mg of aliskiren. They also proposed the renin response to aliskiren therapy may paradoxically increase blood pressure in patients with a highly reactive renin concentration (renovascular, advanced, and malignant hypertension).6 Another concern expressed by several authors was the possible action of the increased renin concentrations on the putative renin receptor.2,7–10How should the exaggerated renin response to aliskiren therapy be interpreted? Renin secretion is subject to tonic negative feedback inhibition by Ang II, and the reactive increase in renin concentration provides a valuable, although indirect, measure of the reduction of Ang II levels by aliskiren therapy.2,5,11–14 The renin response may also be due to unloading of the renal and extrarenal baroreceptors, although several studies show that aliskiren is not more hypotensive than angiotensin receptor blocker therapy.2,3,6,15 The kidney is an important site of the uptake of renin inhibitors,16,17 and autoradiographic studies show localization of aliskiren in the renal glomeruli, renal arteries, and capillaries but not in the renal tubules.17 It is, therefore, possible that aliskiren may act directly on the renin-secreting juxtaglomerular cell to influence prorenin processing and renin release by a mechanism independent of Ang II levels, although there is as yet no evidence for this. The reactive renin response may also reflect an effect of aliskiren on renin clearance,2 but no information is available that addresses this possibility. Finally, aliskiren may interfere with the renin assay by binding to prorenin and causing an overestimation of the renin concentration.2,7,18,19In this brief review, I summarize some of the properties of aliskiren and the mechanisms that may account for the exaggerated renin response to aliskiren therapy. I review evidence that an important contributor to the exaggerated renin response is the interference by the renin inhibitor in the renin assay causing overestimation of the renin concentration.2,7,18,19 Contrary to the suggestion of Sealey and Laragh6 that the reactive renin response may limit the effect of aliskiren therapy on Ang II levels,6 the exaggerated renin response may not represent an increase in enzymatically active renin molecules in plasma. An important consequence of the overestimation of renin concentration is that the impact of the renin inhibitor on angiotensin peptide formation in vivo may be less than that indicated by the renin response.AliskirenAliskiren has the chemical structure 2(S),4(S),5(S),7(S)-N-(2-carbamoyl-2-methylpropyl)-5-amino-4-hydroxy-2,7-diisopropyl-8-(4-methoxy-3-[3-methoxypropoxy-]phenyl)-octanamide and a molecular mass of 551.8 g/mol.20 It is a competitive renin inhibitor with a high species specificity and is reported to have an IC50 of 0.6 nmol/L for both purified human renin and human plasma renin.20 Aliskiren is a rather hydrophilic molecule (log octagonal/water partition coefficient [logPoct/water]=2.45 at pH 7.4) with high aqueous solubility (>350 mg/mL at pH 7.4).20 The distribution volume of intravenously administered aliskiren is reported to be 135 L in normal volunteers, indicating extensive tissue uptake of the drug.21 The absorbed fraction of orally administered aliskiren is estimated to be ≈5%, with 90% of the drug excreted unchanged by the fecal route.22 In contrast to other renin inhibitors with similar affinity for renin,23 aliskiren has a long plasma half life, reported to be 24 to 70 hours.13,14,22,24 Steady-state plasma aliskiren levels are achieved after 5 to 8 days of daily dosing.13 The long plasma half-life and very low urinary excretion ( 1000 nmol/L, whereas the Nichols assay showed artifactual elevation of the renin concentration at 10 to 100 nmol/L of aliskiren (Figure 2). The Nichols IRMA has been shown to overestimate plasma renin concentration in the absence of renin inhibitor therapy. Deinum et al35 showed the Nichols assay, when performed at 22°C for 24 hours, measures ≈5% of plasma prorenin as renin because of unfolding of the prosegment. However, these authors did not detect any evidence for unfolding of the prosegment when the assay was performed at 37°C for 6 hours.35 This overestimation of renin concentration may also be less for the automated Nichols Advantage chemiluminescent immunoassay performed at 37°C,36 although no data have been reported about the effect of renin inhibitors on this assay. Download figureDownload PowerPointFigure 2. Effect of aliskiren concentration on measured renin concentration of 3 plasma samples, measured with either the Cisbio (open symbols) or the Nichols assay (closed symbols). The Cisbio assay was incubated for 3 hours at room temperature; the Nichols assay was incubated for 24 hours at room temperature. ○, •, plasma 1; ▿, ▾, plasma 2; □, ▪, plasma 3. Drawn from data published by Ménard et al.7The studies by Ménard et al7 clearly demonstrate that the conditions of renin IRMA may lead to overestimation of plasma renin concentration when plasma contains a renin inhibitor. Although direct comparison of the 2 assays showed that the Nichols IRMA gave higher renin levels than the Cisbio IRMA for patients receiving aliskiren therapy,7 the exaggerated renin response to aliskiren therapy cannot be attributed solely to the use of the Nichols IRMA for renin measurement. The use of the Nichols IRMA may have contributed to the exaggerated renin response observed by Oparil et al,3 but an exaggerated renin response was also observed in studies that used the Cisbio IRMA.2,5 Other aspects of the renin IRMA methodology, other than the manufacturer of the assay, may contribute to overestimation of the renin concentration. For example, the methods of handling and centrifugation of blood and freezing and thawing of plasma may contribute to the overestimation of the renin concentration by promoting binding of a renin inhibitor to prorenin.An important question is whether aliskiren binds to prorenin in vivo. Evidence against the binding of aliskiren to prorenin in vivo includes the observation by Deinum et al35 that the prosegment does not unfold during 6 hours at 37°C. Moreover, Ménard et al7 found that aliskiren concentrations of 1000 nmol/L did not influence the measured renin concentration during a 3-hour incubation at room temperature with the Cisbio assay. Peak plasma aliskiren levels after dosing for 8 days at 160 and 640 mg/d were ≈25 (≈45 nmol/L) and ≈300 ng/mL (≈554 nmol/L), respectively, and had fallen by ≈80% at 24 hours after dosing.13 Given that peak plasma aliskiren concentrations are much less than 1000 nmol/L,13 it is unlikely that appreciable binding of aliskiren to prorenin occurs in vivo. Importantly, as mentioned earlier, the free aliskiren concentration is likely to be much less than the measured concentration because of the extensive binding of aliskiren to nonrenin proteins.The question of whether aliskiren binds to prorenin in vivo is unlikely to be answered by the addition of aliskiren to plasma because of the difficulty in reproducing the kinetics of binding to renin, prorenin, and nonrenin proteins that occurs after oral administration. One possible approach to examining the contribution of its binding to prorenin in vitro and in vivo is to administer aliskiren to anephric subjects, who have nearly normal prorenin levels and markedly suppressed renin levels that should not respond to renin inhibition.26,37,38 Measurement of the time course of plasma renin concentration in plasma samples assayed immediately and plasma samples stored frozen before assay from anephric subjects administered aliskiren would help reveal whether aliskiren binds to prorenin in vivo and also during storage and freeze-thaw cycles of plasma.In summary, the most reliable measure of renin inhibition in vivo is the change in plasma levels of Ang I and Ang II. Although the antibody-capture method of PRA assay provides a useful measure of renin inhibition, it may overestimate renin inhibition in vivo, as indicated by plasma angiotensin levels.5,11 The increase in plasma renin concentration is an indirect measure of renin inhibition in patients receiving aliskiren therapy, and it may be overestimated because of binding of aliskiren to prorenin. When interpreting plasma renin concentrations in patients receiving aliskiren therapy it is necessary to consider the type of assay, its manufacturer, whether it is automated or manual, and the time and temperature of incubation. It is also necessary to consider whether appropriate precautions were taken during the collection and centrifugation of blood, during storage of plasma, and during any freeze-thaw cycles. Unfortunately, this information is usually not provided in published reports. Finally, it is necessary to consider the aliskiren dose and whether blood levels achieved are likely to bind to prorenin in vivo. In those studies reporting an exaggerated renin response to aliskiren therapy,2,3,5,6 it is likely that the reactive renin response was overestimated and the effect of aliskiren on angiotensin levels in vivo was less than that indicated by the renin response.Source of FundingD.J.C. is recipient of a senior research fellowship from the National Health and Medical Research Council of Australia (grant no. 395508).DisclosuresD.J.C. has had research contracts with Solvay Pharmaceutical Company and Novartis in the last 5 years and has been a member of an advisory board for Novartis.FootnotesCorrespondence to Duncan J. Campbell, St Vincent's Institute of Medical Research, 41 Victoria Parade, Fitzroy, Victoria 3065, Australia. E-mail [email protected] References 1 Traynor K. Novartis hypertension drug approved. Am J Health-Syst Pharm. 2007; 64: 796.MedlineGoogle Scholar2 Nussberger J, Gradman AH, Schmieder RE, Lins RL, Chiang Y, Prescott MF. Plasma renin and the antihypertensive effect of the orally active renin inhibitor aliskiren in clinical hypertension. Int J Clin Pract. 2007; 61: 1461–1468.CrossrefMedlineGoogle Scholar3 Oparil S, Yarows SA, Patel S, Fang H, Zhang J, Satlin A. Efficacy and safety of combined use of aliskiren and valsartan in patients with hypertension: a randomised, double-blind trial. Lancet. 2007; 370: 221–229.CrossrefMedlineGoogle Scholar4 Gradman AH, Schmieder RE, Lins RL, Nussberger J, Chiang Y, Bedigian MP. Aliskiren, a novel orally effective renin inhibitor, provides dose-dependent antihypertensive efficacy and placebo-like tolerability in hypertensive patients. Circulation. 2005; 111: 1012–1018.LinkGoogle Scholar5 Azizi M, Menard J, Bissery A, Guyene TT, Bura-Riviere A. Hormonal and hemodynamic effects of aliskiren and valsartan and their combination in sodium-replete normotensive individuals. Clin J Am Soc Nephrol. 2007; 2: 947–955.CrossrefMedlineGoogle Scholar6 Sealey JE, Laragh JH. Aliskiren, the first renin inhibitor for treating hypertension: reactive renin secretion may limit its effectiveness. Am J Hypertens. 2007; 20: 587–597.CrossrefMedlineGoogle Scholar7 Ménard J, Guyene TT, Peyrard S, Azizi M. Conformational changes in prorenin during renin inhibition in vitro and in vivo. J Hypertens. 2006; 24: 529–534.CrossrefMedlineGoogle Scholar8 Nguyen G, Delarue F, Burckle C, Bouzhir L, Giller T, Sraer JD. Pivotal role of the renin/prorenin receptor in angiotensin II production and cellular responses to renin. J Clin Invest. 2002; 109: 1417–1427.CrossrefMedlineGoogle Scholar9 Huang Y, Noble NA, Zhang J, Xu C, Border WA. Renin-stimulated TGF-beta1 expression is regulated by a mitogen-activated protein kinase in mesangial cells. Kidney Int. 2007; 72: 45–52.CrossrefMedlineGoogle Scholar10 Schefe JH, Menk M, Reinemund J, Effertz K, Hobbs RM, Pandolfi PP, Ruiz P, Unger T, Funke-Kaiser H. A novel signal transduction cascade involving direct physical interaction of the renin/prorenin receptor with the transcription factor promyelocytic zinc finger protein. Circ Res. 2006; 99: 1355–1366.LinkGoogle Scholar11 Nussberger J, Delabays A, de Gasparo M, Cumin F, Waeber B, Brunner HR, Ménard J. Hemodynamic and biochemical consequences of renin inhibition by infusion of CGP 38560A in normal volunteers. Hypertension. 1989; 13: 948–953.LinkGoogle Scholar12 Jeunemaitre X, Menard J, Nussberger J, Guyenne TT, Brunner HR, Corvol P. Plasma angiotensins, renin, and blood pressure during acute renin inhibition by CGP 38 560A in hypertensive patients. Am J Hypertens. 1989; 2: 819–827.CrossrefMedlineGoogle Scholar13 Nussberger J, Wuerzner G, Jensen C, Brunner HR. Angiotensin II suppression in humans by the orally active renin inhibitor Aliskiren (SPP100): comparison with enalapril. Hypertension. 2002; 39: e1–e8.LinkGoogle Scholar14 Azizi M, Menard J, Bissery A, Guyenne TT, Bura-Riviere A, Vaidyanathan S, Camisasca RP. Pharmacologic demonstration of the synergistic effects of a combination of the renin inhibitor aliskiren and the AT1 receptor antagonist valsartan on the angiotensin II-renin feedback interruption. J Am Soc Nephrol. 2004; 15: 3126–3133.CrossrefMedlineGoogle Scholar15 Stanton A, Jensen C, Nussberger J, O'Brien E. Blood pressure lowering in essential hypertension with an oral renin inhibitor, aliskiren. Hypertension. 2003; 42: 1137–1143.LinkGoogle Scholar16 Richter WF, Whitby BR, Chou RC. Distribution of remikiren, a potent orally active inhibitor of human renin, in laboratory animals. Xenobiotica. 1996; 26: 243–254.CrossrefMedlineGoogle Scholar17 Feldman DL, Persohn E, Schutz H, Jin L, Miserendino-Molteni R, Xuan H, Zhuang S, Zhou W. Renal localization of the renin inhibitor aliskiren (abstract). J Clin Hypertens. 2006; 8 (suppl. A): A80.Google Scholar18 Danser AH, Deinum J. Renin, prorenin and the putative (pro)renin receptor. Hypertension. 2005; 46: 1069–1076.LinkGoogle Scholar19 Ménard J, Azizi M. The difficult conception, birth and delivery of a renin inhibitor: controversies around aliskiren. J Hypertens. 2007; 25: 1775–1782.CrossrefMedlineGoogle Scholar20 Wood JM, Maibaum J, Rahuel J, Grutter MG, Cohen NC, Rasetti V, Ruger H, Goschke R, Stutz S, Fuhrer W, Schilling W, Rigollier P, Yamaguchi Y, Cumin F, Baum HP, Schnell CR, Herold P, Mah R, Jensen C, O'Brien E, Stanton A, Bedigian MP. Structure-based design of aliskiren, a novel orally effective renin inhibitor. Biochem Biophys Res Commun. 2003; 308: 698–705.CrossrefMedlineGoogle Scholar21 Azizi M, Webb R, Nussberger J, Hollenberg NK. Renin inhibition with aliskiren: where are we now, and where are we going? J Hypertens. 2006; 24: 243–256.CrossrefMedlineGoogle Scholar22 Waldmeier F, Glaenzel U, Wirz B, Oberer L, Schmid D, Seiberling M, Valencia J, Riviere GJ, End P, Vaidyanathan S. Absorption, distribution, metabolism, and elimination of the direct renin inhibitor aliskiren in healthy volunteers. Drug Metab Dispos. 2007; 35: 1418–1428.CrossrefMedlineGoogle Scholar23 Staessen JA, Li Y, Richart T. Oral renin inhibitors. Lancet. 2006; 368: 1449–1456.CrossrefMedlineGoogle Scholar24 Vaidyanathan S, Reynolds C, Yeh CM, Bizot MN, Dieterich HA, Howard D, Dole WP. Pharmacokinetics, safety, and tolerability of the novel oral direct renin inhibitor aliskiren in elderly healthy subjects. J Clin Pharmacol. 2007; 47: 453–460.CrossrefMedlineGoogle Scholar25 Campbell DJ. The site of angiotensin production. J Hypertens. 1985; 3: 199–207.CrossrefMedlineGoogle Scholar26 Campbell DJ, Kladis A, Skinner SL, Whitworth JA. Characterization of angiotensin peptides in plasma of anephric man. J Hypertens. 1991; 9: 265–274.CrossrefMedlineGoogle Scholar27 Derkx FH, Schalekamp MP, Schalekamp MA. Two-step prorenin-renin conversion. Isolation of an intermediary form of activated prorenin. J Biol Chem. 1987; 262: 2472–2477.CrossrefMedlineGoogle Scholar28 Sealey JE, Moon C, Laragh JH, Alderman M. Plasma prorenin: cryoactivation and relationship to renin substrate in normal subjects. Am J Med. 1976; 61: 731–738.CrossrefMedlineGoogle Scholar29 Osmond DH, Cooper RM. Cryoactivation and tryptic activation of blood 'prorenin' in normal man and animals. Can J Physiol Pharmacol. 1978; 56: 792–805.CrossrefMedlineGoogle Scholar30 Leckie BJ, McGhee NK. Reversible activation-inactivation of renin in human plasma. Nature. 1980; 288: 702–705.CrossrefMedlineGoogle Scholar31 Heinrikson RL, Hui J, Zurcher-Neely H, Poorman RA. A structural model to explain the partial catalytic activity of human prorenin. Am J Hypertens. 1989; 2: 367–380.CrossrefMedlineGoogle Scholar32 Pitarresi TM, Rubattu S, Heinrikson R, Sealey JE. Reversible cryoactivation of recombinant human prorenin. J Biol Chem. 1992; 267: 11753–11759.CrossrefMedlineGoogle Scholar33 Derkx FHM, Van den Meiracker AH, Fischli W, Admiraal PJJ, Man In'T Veld AJ, Van Brummelen P, Schalekamp MADH. Nonparallel effects of renin inhibitor treatment on plasma renin activity and angiotensins I and II in hypertensive subjects: An assay-related artifact. Am J Hypertens. 1991; 4: 602–609.CrossrefMedlineGoogle Scholar34 Derkx FHM, Deinum J, Lipovski M, Verhaar M, Fischli W, Schalekamp MADH. Nonproteolytic "activation" of prorenin by active site-directed renin inhibitors as demonstrated by renin-specific monoclonal antibody. J Biol Chem. 1992; 267: 22837–22842.CrossrefMedlineGoogle Scholar35 Deinum J, Derkx FH, Schalekamp MA. Improved immunoradiometric assay for plasma renin. Clin Chem. 1999; 45: 847–854.CrossrefMedlineGoogle Scholar36 Iervasi A, Zucchelli GC, Turchi S, Emdin M, Passino C, Ripoli A, Clerico A. Analytical and clinical performance of an automated chemiluminescent immunoassay for direct renin measurement: comparison with PRA and aldosterone assays. Immuno-anal Biol Spécial. 2005; 20: 257–262.Google Scholar37 Man In'T Veld AJ, Wenting GJ, Schalekamp MADH. Does captopril lower blood pressure in anephric patients? BMJ. 1979; 2: 1110.CrossrefGoogle Scholar38 Leslie BR, Case DB, Sullivan JF, Vaughan ED Jr. Absence of blood-pressure lowering effect of captopril in anephric patients. BMJ. 1980; 280: 1067–1068.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Antlanger M, Bernhofer S, Kovarik J, Kopecky C, Kaltenecker C, Domenig O, Poglitsch M and Säemann M (2017) Effects of direct renin inhibition versus angiotensin II receptor blockade on angiotensin profiles in non-diabetic chronic kidney disease, Annals of Medicine, 10.1080/07853890.2017.1313447, 49:6, (525-533), Online publication date: 18-Aug-2017. Gralinski M, Neves L and Tiniakova O (2016) Renin–Angiotensin System Drug Discovery and Evaluation: Pharmacological Assays, 10.1007/978-3-319-05392-9_141, (665-707), . Fehlhammer W and Beck W (2015) Azide Chemistry - An Inorganic Perspective, Part II [‡] [3+2]-Cycloaddition Reactions of Metal Azides and Related Systems , Zeitschrift für anorganische und allgemeine Chemie, 10.1002/zaac.201500165, 641:10, (1599-1678), Online publication date: 1-Aug-2015. Biswas K, Nabi A, Ebihara A, Nakagawa T, Iddamalgoda A and Suzuki F (2014) RENIN ANGIOTENSIN SYSTEM-DEPENDENT AND -INDEPENDENT FUNCTIONS OF (PRO)RENIN RECEPTOR AND THE ROLES OF ITS BLOCKERS, Reviews in Agricultural Science, 10.7831/ras.2.37, 2:0, (37-47), . Juutilainen A, Savolainen K, Romppanen J, Turpeinen U, Hämäläinen E, Kemppainen J, Moilanen L and Pulkki K (2014) Combination of LC–MS/MS aldosterone and automated direct renin in screening for primary aldosteronism, Clinica Chimica Acta, 10.1016/j.cca.2014.03.015, 433, (209-215), Online publication date: 1-Jun-2014. Gralinski M, Neves L and Tiniakova O (2015) Renin–Angiotensin System Drug Discovery and Evaluation: Pharmacological Assays, 10.1007/978-3-642-27728-3_141-1, (1-51), . Harrison D and Luther J (2013) Vascular Pharmacology Vascular Medicine: A Companion to Braunwald's Heart Disease, 10.1016/B978-1-4377-2930-6.00006-9, (75-93), . Riccioni G (2013) The role of direct renin inhibitors in the treatment of the hypertensive diabetic patient, Therapeutic Advances in Endocrinology and Metabolism, 10.1177/2042018813490779, 4:5, (139-145), Online publication date: 1-Oct-2013. Taylor A and Pool J (2012) Clinical Role of Direct Renin Inhibition in Hypertension, American Journal of Therapeutics, 10.1097/MJT.0b013e3182068da5, 19:3, (204-210), Online publication date: 1-May-2012. Makówka A, Olejniczak-Fortak M and Nowicki M A Comparison of the Antihypertensive and Anti-Inflammatory Effects of Aliskiren and Ramipril Add-On Therapy in Peritoneal Dialysis Patients – A Pilot Open Label Study, Kidney and Blood Pressure Research, 10.1159/000339023, 36:1, (18-25) Boschmann M, Nussberger J, Engeli S, Danser A, Yeh C, Prescott M, Dahlke M and Jordan J (2012) Aliskiren penetrates adipose and skeletal muscle tissue and reduces renin–angiotensin system activity in obese hypertensive patients, Journal of Hypertension, 10.1097/HJH.0b013e32834f6b43, 30:3, (561-566), Online publication date: 1-Mar-2012. Rashikh A, Ahmad S, Pillai K and Najmi A (2011) Aliskiren as a novel therapeutic agent for hypertension and cardio-renal diseases, Journal of Pharmacy and Pharmacology, 10.1111/j.2042-7158.2011.01414.x, 64:4, (470-481), Online publication date: 15-Mar-2012. Gruson D, Maisin D, Lison P, Maiter D and Persu A (2011) Two-site automated chemiluminescent assay for measurement of immunoreactive renin, Biomarkers, 10.3109/1354750X.2011.614015, 16:7, (605-609), Online publication date: 1-Nov-2011. Campbell D, Zhang Y, Kelly D, Gilbert R, McCarthy D, Shi W and Smyth G (2011) Aliskiren increases bradykinin and tissue kallikrein mRNA levels in the heart, Clinical and Experimental Pharmacology and Physiology, 10.1111/j.1440-1681.2011.05572.x, 38:9, (623-631), Online publication date: 1-Sep-2011. Wilkinson-Berka J, Tan G, Binger K, Sutton L, McMaster K, Deliyanti D, Perera G, Campbell D and Miller A (2011) Aliskiren reduces vascular pathology in diabetic retinopathy and oxygen-induced retinopathy in the transgenic (mRen-2)27 rat, Diabetologia, 10.1007/s00125-011-2239-9, 54:10, (2724-2735), Online publication date: 1-Oct-2011. Mizuno Y, Jacob R and Mason R (2011) Combined use of calcium channel blockers and inhibitors of the renin–angiotensin system for treating hypertension, Therapy, 10.2217/thy.11.17, 8:3, (247-260), Online publication date: 1-May-2011. Ahmed T, Karalis I and Jukema J (2011) Emerging drugs for coronary artery disease. From past achievements and current needs to clinical promises, Expert Opinion on Emerging Drugs, 10.1517/14728214.2011.549606, 16:2, (203-233), Online publication date: 1-Jun-2011. Gosse P, Coulon P, Brossaud J and Corcuff J (2011) A simple test to appreciate compliance to aliskiren treatment, Journal of Hypertension, 10.1097/HJH.0b013e32834acb17, 29:10, (2038), Online publication date: 1-Oct-2011. Morganti A (2010) A comparative study on inter and intralaboratory reproducibility of renin measurement with a conventional enzymatic method and a new chemiluminescent assay of immunoreactive renin, Journal of Hypertension, 10.1097/HJH.0b013e32833857ad, 28:6, (1307-1312), Online publication date: 1-Jun-2010. Funke-Kaiser H, Zollmann F, Schefe J and Unger T (2009) Signal transduction of the (pro)renin receptor as a novel therapeutic target for preventing end-organ damage, Hypertension Research, 10.1038/hr.2009.206, 33:2, (98-104), Online publication date: 1-Feb-2010. Rabbia F, Testa E, Totaro S, Leotta G, Berra E, Covella M, Milazzo V, Di Stefano C and Veglio F (2010) Effects of Antihypertensive Drugs on the Renin-Angiotensin System in Essential Hypertension, High Blood Pressure & Cardiovascular Prevention, 10.2165/11311870-000000000-00000, 17:3, (109-115), Online publication date: 1-Sep-2010. Ruddy M (2015) Unmet Needs in Managing Hypertension: Potential Role of Direct Renin Inhibition, Postgraduate Medicine, 10.3810/pgm.2010.05.2159, 122:3, (203-212), Online publication date: 1-May-2010. Pöss J, Werner C, Lorenz D, Gensch C, Böhm M and Laufs U (2010) The renin inhibitor aliskiren upregulates pro-angiogenic cells and reduces atherogenesis in mice, Basic Research in Cardiology, 10.1007/s00395-010-0120-5, 105:6, (725-735), Online publication date: 1-Nov-2010. Campbell D (2009) Aliskiren Therapy Will Have Minimal Effect on Intracellular Renin of Renin-Producing Cells, Hypertension, 53:2, (e17-e17), Online publication date: 1-Feb-2009. Pinto R and Gradman A (2009) Direct renin inhibition: An update, Current Hypertension Reports, 10.1007/s11906-009-0077-7, 11:6, (456-462), Online publication date: 1-Dec-2009. Campbell D, Nussberger J, Stowasser M, Danser A, Morganti A, Frandsen E and Ménard J (2009) Activity Assays and Immunoassays for Plasma Renin and Prorenin: Information Provided and Precautions Necessary for Accurate Measurement, Clinical Chemistry, 10.1373/clinchem.2008.118000, 55:5, (867-877), Online publication date: 1-May-2009. Trimarchi H and Orías M (2014) Aliskiren and the Kidney: Beyond Hypertension, Nephrology Research & Reviews, 10.4081/nr.2009.e1, 1:1, (1-4), Online publication date: 1-Jan-2009. Sealey J and Laragh J (2009) Aliskiren Fails to Lower Blood Pressure in Patients Who Have Either Low PRA Levels or Whose PRA Falls Insufficiently or Reactively Rises, American Journal of Hypertension, 10.1038/ajh.2008.275, 22:1, (112-121), Online publication date: 1-Jan-2009. Cappuccio F and Stranges S (2008) Response to Gender-Specific Associations of Short Sleep Duration With Prevalent Hypertension, Hypertension, 51:3, (e17-e17), Online publication date: 1-Mar-2008.Danser A, Charney A, Feldman D, Nussberger J, Fisher N and Hollenberg N (2008) The Renin Rise With Aliskiren: It's Simply Stoichiometry, Hypertension, 51:4, (e27-e28), Online publication date: 1-Apr-2008.Campbell D (2008) Response to the Renin Rise With Aliskiren: It's Simply Stoichiometry, Hypertension, 51:4, (e29-e29), Online publication date: 1-Apr-2008.Verma S and Gupta M (2008) Aliskiren Improves Nitric Oxide Bioavailability and Limits Atherosclerosis, Hypertension, 52:3, (467-469), Online publication date: 1-Sep-2008. Han G, Wang G, Zhu C, Cai Y and Xiong R (2008) Trapping and crystallographic characterization of Valsartan intermediate (tetrazole–zinc complex), Inorganic Chemistry Communications, 10.1016/j.inoche.2008.02.031, 11:6, (652-654), Online publication date: 1-Jun-2008. Sica D (2008) Direct Renin Inhibition- Commonly Asked Questions, The Journal of Clinical Hypertension, 10.1111/j.1751-7176.2008.00039.x, 10:11, (871-875), Online publication date: 1-Nov-2008. Azizi M (2008) Direct renin inhibition: clinical pharmacology, Journal of Molecular Medicine, 10.1007/s00109-008-0329-z, 86:6, (647-654), Online publication date: 1-Jun-2008. Schefe J, Neumann C, Goebel M, Danser J, Kirsch S, Gust R, Kintscher U, Unger T and Funke-Kaiser H (2008) Prorenin engages the (pro)renin receptor like renin and both ligand activities are unopposed by aliskiren, Journal of Hypertension, 10.1097/HJH.0b013e3283060f2e, 26:9, (1787-1794), Online publication date: 1-Sep-2008. January 2008Vol 51, Issue 1 Advertisement Article InformationMetrics https://doi.org/10.1161/HYPERTENSIONAHA.107.101287PMID: 17984367 Manuscript receivedSeptember 13, 2007Manuscript acceptedOctober 17, 2007Originally publishedNovember 5, 2007 PDF download Advertisement SubjectsClinical StudiesDiagnostic TestingPharmacology
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