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Published ahead of print on August 8, 2007
Clin J Am Soc Nephrol 2: 947-955, 2007
© 2007 American Society of Nephrology
doi: 10.2215/CJN.00360107
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Clinical Pharmacology

Hormonal and Hemodynamic Effects of Aliskiren and Valsartan and Their Combination in Sodium-Replete Normotensive Individuals

Michel Azizi*,{dagger},{ddagger}, Joël Ménard*,{dagger},{ddagger}, Alvine Bissery{dagger}, Than-Tam Guyene{dagger}, and Alessandra Bura-Rivière{dagger},{ddagger}

* Université Paris Descartes, Faculté de Médecine, {dagger} Assistance Publique Hôpitaux de Paris, Hôpital Européen Georges Pompidou, and {ddagger} INSERM, CIC 9201, Paris, France

Address correspondence to: Dr. Michel Azizi, Centre d'Investigations Cliniques, Hôpital Européen Georges Pompidou, 20–40 rue Leblanc, 75908 Paris cedex 15, France. Phone: +33-1-5609-2911; Fax: +33-1-5609-2929; E-mail: michel.azizi{at}egp.ap-hop-paris.fr


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 Conclusions
 Disclosures
 References
 
Background and Objectives: An AT1 receptor antagonist induces a counterregulatory renin release whose intensity and duration reflect the magnitude of the renin-angiotensin blockade. We investigated whether a renin inhibitor may neutralize this counterregulation and amplify the effects of AT1 receptor antagonists.

Design, Setting, Participants, & Measurements: In 12 normotensive male individuals who were on a high-sodium diet, a double-blind, placebo-controlled, randomized, crossover design was used to study the hormonal and BP effects of single oral administrations of 300 mg of the renin inhibitor aliskiren, 320 mg of valsartan, and a combination of these two drugs, each at half dosage (150 mg of aliskiren and 160 mg of valsartan).

Results: Valsartan (320 mg) increased plasma renin activity and angiotensin I and angiotensin II levels, but 300 mg of aliskiren decreased them for 48 h. Aliskiren (300 mg) stimulated immunoreactive renin release more strongly than 320 mg of valsartan, decreased urinary aldosterone excretion for longer than 320 mg of valsartan, and had a similar BP-lowering effect as 320 mg of valsartan. In combination, 150 mg of aliskiren neutralized the valsartan (160 mg)-induced increase in plasma angiotensins for 48 h. The renin and aldosterone effects of the combination of 150 mg of aliskiren and 160 mg of valsartan were similar to those of 300 mg of aliskiren and greater than those of 320 mg of valsartan. When plasma drug concentrations were taken into account, the combination of 150 mg of aliskiren and 160 mg of valsartan had a synergistic effect on renin release. The BP-lowering effect of 150 mg of aliskiren and 160 mg of valsartan was similar to that of 300 mg of aliskiren and 320 mg of valsartan at peak but was more prolonged.

Conclusion: The stronger and longer lasting effects on plasma active renin and urinary aldosterone of aliskiren, alone or in combination, demonstrate a more effective blockade of the renin-angiotensin system than that obtained with 320 mg of valsartan alone.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 Conclusions
 Disclosures
 References
 
Studies of the changes in plasma immunoreactive active renin in sodium-deplete normotensive individuals initially demonstrated that the renin-angiotensin system (RAS) blockade was reinforced by the combination of an angiotensin I (AngI)-converting enzyme (ACE) inhibitor with an AT1 receptor antagonist (1). Another potential pharmacologic approach to reinforce RAS blockade is to combine a renin inhibitor with an AT1 receptor antagonist (2). Indeed, in sodium-depleted normotensive individuals, the rise in the plasma concentration of immunoreactive active renin as a result of the interruption of the AngII–renin feedback by a single oral dose of an AT1 receptor antagonist, valsartan, was synergistically enhanced by the concomitant inhibition of renin activity by the co-administration of an orally active renin inhibitor, aliskiren, which also neutralized the valsartan-induced increase in plasma AngII concentration (2,3). These proof-of-concept studies have subsequently been confirmed by investigations of the BP-lowering effect of combined RAS blockade in experimental and clinical hypertension studies. In telemetered spontaneously hypertensive rats, the decrease in BP after treatment with a submaximal dose of benazeprilat (3 mg/kg per d) or valsartan (3 mg/kg per d) is more pronounced when aliskiren (30 mg/kg per d) is co-administered by osmotic minipumps (4). In a factorial design study that included 1123 patients with mild to moderate hypertension, an 8-wk treatment with a combination of 75 mg of aliskiren and 80 mg of valsartan induced a decrease in BP similar to that achieved with doses four times higher of each monotherapy (aliskiren 300 mg or valsartan 320 mg), even though the BP effects of 75 mg of aliskiren or 80 mg of valsartan alone were not significantly greater than placebo (5).

RAS inhibitor dosage and dosing interval must be carefully considered when interpreting the short-term effects on BP (6,7) and long-term effects on target organ protection (8) of combination of different RAS blockers. We therefore repeated our initial clinical investigation of renin release in conditions of high sodium intake and low plasma renin, which mimic the RAS profile of some subgroups of patients with hypertension especially because daily sodium intake remains large in most industrialized countries (9). We used the same experimental design as in the previous study of sodium-depleted individuals and the same single oral dosage of aliskiren (300 mg [A300]) given alone but a higher dosage of valsartan alone (320 mg rather than 160 mg [V320]) and in the combination with 150 mg of aliskiren (160 rather than 80 mg of valsartan [A150+V160]).


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 Conclusions
 Disclosures
 References
 
Twelve healthy normotensive white male individuals were recruited for the study. Their clinical characteristics were as follows: Age 25.3 ± 2.7 yr, body mass index 23.5 ± 2.38 kg/m2, systolic BP 123 ± 6 mmHg, diastolic BP 66 ± 9 mmHg, and heart rate 64 ± 10 bpm. The study design (double-blind, double-dummy, placebo-controlled, randomized, four-period, crossover study with 2-wk washout intervals) has been reported previously for sodium-depleted normotensive volunteers (1,2). The main difference in this study of sodium replete individuals was the following. For induction of sodium repletion, participants were given slow-release sodium tablets (6 g/d) for 9 d (from day –5 to day 3) and were instructed to eat high-sodium foods preferentially. Urinary sodium excretion was measured before each study drug intake and showed that a similar sodium balance was achieved in all participants. Urinary sodium excretion measured 12 h before the intake of placebo, A300, V320, and A150+V160 combination was 129 ± 30, 133 ± 57, 129 ± 48, and 135 ± 42 mmol/12 h, respectively.

At 9 a.m. on the study day (day 1), 12 participants received A300, V320, a combination of A150+V160, or matched placebos, according to a Latin square design, after a 1-h period of rest in a semirecumbent position. All participants remained in the fasting state from 12 h before to 6 h after drug intake to prevent drug bioavailability being affected by food intake. Fluid intake was unrestricted on the study days (1500 to 2000 ml/24 h). Blood was sampled before and at various times up to 48 h after drug intake for plasma renin activity (PRA), immunoreactive active renin, AngI, AngII, and aldosterone and circulating drug determinations. Mean arterial pressure (MAP; mean of 10 measurements performed at 2-min intervals) was determined at the same time points, with an automatic validated BP recorder (Press Mate BP 8800; Colin Co., Komaki-City, Japan). For BP and hormone determinations performed after the first 6 h, participants were again placed in the semirecumbent position 1 h before sampling and BP determination. Urine volume and free aldosterone extractable at pH 1 were measured for each fractionated urine sample.

The protocol was approved by the Comité Consultatif de Protection des Personnes se prêtant à des Recherches Biomédicales (Paris-Cochin, France) and the procedures followed were in accordance with the Declaration of Helsinki. Informed, written consent was obtained from all participants before inclusion.

Rationale for Dosage Selection
Aliskiren (film-coated tablet), valsartan, and placebo were placed in capsules identical in appearance. We used a dosage of 300 mg of aliskiren because this was the highest dosage used in most phase II and phase III trials during its clinical development in hypertensive patients (10–12). The dosage of 320 mg of valsartan was chosen because it was the highest daily dosage currently recommended for the treatment of hypertension. We used a half dosage of aliskiren and valsartan in the combination to test pharmacologically the additivity of two RAS inhibitors acting on different steps of the pathway, renin and AT1 receptors. The additive or synergistic effects of such combinations are more evident at low dosages than at high dosages because of the physiologic limits of both the rise in renin release and the renin-dependent fall in BP (13).

Laboratory Methods
The methods used to determine plasma active renin (immunoradiometric assay), PRA (AngI trapping assay), plasma AngI and AngII (RIA), and plasma and urine aldosterone (RIA) concentrations and those used for blood and urine sampling were as described for previous investigations of RAS inhibitors and their combinations (1,2,14). Circulating levels of aliskiren (molecular weight 609.8 and 551.8 for free base) and of valsartan (molecular 435.5) were determined as described previously (2).

Pharmacokinetic Calculations
The area under the curve up to 24 and 48 h after dose (AUC0 to 24 and AUC0 to 48, respectively) and extrapolated to infinity (AUC0 to {infty}) and the plasma terminal half-life were determined for each individual concentration-time profile by a noncompartmental method using WinNonlin Pro 4.0 software (Mountain View, CA). The renin/pharmacokinetic index (RPI), expressed in pg active renin/ml per ng drug/ml was determined for each individual as a normalized index of active renin release: It was calculated for each participant as the ratio of the AUC0 to 24 for absolute changes in plasma active renin concentration to the AUC0 to 24 for plasma aliskiren or valsartan concentrations when the drugs where given alone as described previously (14). This made it possible to take true drug exposure into account for comparisons of the intensity of the renin response to renin inhibition and AT1 receptor blockade.

Statistical Analyses
Data were analyzed by an ANOVA for a four-by-four crossover design. When the F test was significant (P < 0.05), paired comparisons were made between specific treatments, using the Holm procedure (15). Regression was estimated by the least-squares method. Stata Statistical Software (Release 7.0; Stata Corp., College Station, TX) was used for statistical analysis. Data are expressed as geometric means with 95% confidence intervals (CI) for non-normally distributed data and as means ± 1 SD for normally distributed data. P < 0.05 was considered to be significant.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 Conclusions
 Disclosures
 References
 
Pharmacokinetics
The plasma half-life of aliskiren (A150 26 ± 9 h; A300 22 ± 5 h) was longer than that of valsartan (V160 7.25 ± 2.35 h; V320 8.88 ± 4.08 h). Doubling the dosage of valsartan from 160 to 320 mg increased by approximately two-fold the AUC0 to {infty} (from 10963 ± 4164 to 20616 ± 10766 ng·h/ml). Doubling the dosage of aliskiren from 150 to 300 mg increased by approximately three-fold the AUC0 to {infty} (from 395 ± 203 to 1122 ± 655 ng·h/ml). Therefore, the exposure to 300 mg of aliskiren was more important than expected from a doubling of the 150-mg single oral dose.

Effects of A300, V320, and the A150+V160 Combination on Plasma Renin Variables
As expected, plasma immunoreactive active renin, as well as PRA, AngI, AngII, and aldosterone concentrations at baseline (Table 1), were on average two to three times lower in participants who were on a high-sodium diet than the values previously reported for sodium-depleted volunteers (2). Plasma active renin concentrations were higher after treatment with active drugs than placebo. Peak plasma active renin concentration was of similar magnitude for A300 alone and for the A150+V160 combination (Table 1). In both cases, it tended to be higher than that observed with V320 alone, although the difference between treatments did not achieve statistical significance in paired comparisons. The 24- and 48-h postdose plasma active renin concentrations and AUC of plasma active renin concentration for A300 and the A150+V160 combination were similar and significantly higher than that for V320, demonstrating that the duration of the increase in plasma active renin concentration was significantly longer (Table 1, Figure 1). To adjust for the nonproportionality of the plasma drug concentration increase with the dosage doubling, we calculated the RPI for each participant as the ratio of the AUC0 to 24 for absolute changes in plasma active renin concentration to the AUC0 to 24 for plasma aliskiren or valsartan concentrations. The RPI for A300 was 2.38 pg/ml per ng/ml (95% CI 2.02 to 2.80) and that for V320 was 0.05 pg/ml per ng/ml (95% CI 0.04 to 0.07).


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  		Table 1. Plasma active renin concentration, PRA, and AngI production ratea

 

Figure 1
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  		Figure 1. Effects on plasma immunoreactive active renin and plasma angiotensin II (AngII) of a single-dose administration of 300 mg of aliskiren (A300), 320 mg of valsartan (V320), 150 mg of aliskiren + 160 mg of valsartan (A150+V160), and placebo (P) administered to normotensive male volunteers who were on a high-sodium diet. Data are expressed as geometric means for area under curves up to 48 h after drug intake (95% confidence intervals are reported in Tables 1 and 2). *P < 0.05.

 
Baseline PRA values were low and highly and significantly correlated with baseline plasma active renin concentrations (r = 0.88, P < 0.001; data not shown). As expected and contrasting with plasma active renin results, A300 and V320 had opposite effects on PRA. Within 4 h of V320 intake, PRA increased in parallel with the increase in plasma active renin concentration (this increase being maintained for 48 h), and the AngI production rate (PRA/active renin ratio) remained constant. In contrast, A300 completely inhibited PRA and AngI production rate, and this inhibition persisted for 48 h after intake (Table 1). In the combination, A150 completely neutralized the expected increase in PRA and decreased the AngI production rate to a similar extent as A300 at peak (Table 1). This inhibition was maintained up to 48 h after drug intake but was significantly lower than that achieved with A300 (Table 1).

Effects of A300, V320, and the A150+V160 Combination on Plasma AngI and AngII
Baseline plasma AngI and AngII concentrations were low and strongly correlated with plasma active renin concentrations (r = 0.84 and r = 0.76, respectively, P < 0.001 for both; data not shown). Plasma AngI and AngII profiles after treatment with A300, V320, or the A150+V160 combination followed the same pattern as the PRA profile (Table 2, Figure 1). V320 increased plasma AngI and AngII levels, but A300 decreased them for 48 h. In combination, A150 neutralized the V160-induced expected increase in plasma AngI and AngII concentrations, both of which remained similar to the values obtained after placebo administration (Table 2, Figure 1).


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  		Table 2. Plasma AngI and AngII concentrationsa

 
Effects of A300, V320, and the A150+V160 Combination on Plasma and Urinary Aldosterone Concentrations
Relative to placebo, plasma aldosterone concentrations and urinary aldosterone excretion decreased significantly during the 4 to 8 h after active drug intake, with no significant difference among the three active treatments (Table 3). However, A300 and the A150+V160 combination significantly decreased urine aldosterone excretion up to 48 h after drug intake compared with placebo, whereas the effect of V320 on urinary aldosterone concentration persisted for no more than 18 h. The effects of the three active treatments on the cumulative excretion of aldosterone for 48 h are shown in Figure 2.


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  		Table 3. Plasma and urinary aldosterone concentrationsa

 

Figure 2
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  		Figure 2. Effects on mean arterial pressure (MAP) and urinary aldosterone of a single-dose administration of A300, V320, A150+V160, and P administered to normotensive male volunteers who were on a high-sodium diet. Data are expressed as means for area under curves up to 48 h of MAP (SD are reported in Table 4) and as geometric means for cumulative aldosterone excretion (95% confidence intervals are reported in Table 3). *P < 0.05.

 
Effects of A300, V320, and the A150+V160 Combination on MAP Decrease
MAP was significantly lower 4 h after intake of A300, V320, and the A150+V160 combination than that of placebo. There was a nonsignificant trend toward the combination being more effective than the two drugs given individually. The A150+V160 combination was the only treatment to show a significant difference from placebo in paired comparisons of the AUC0 to 24 for MAP (Table 4). The AUC0 to 48 for MAP are shown in Figure 2.


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  		Table 4. MAPa

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
Conclusions
 Disclosures
 References
 
In this single oral dose study performed in sodium-replete normotensive individuals, we used a pharmacologic test of potency based on active renin release to test the plausibility of a pharmacologic additivity of two RAS inhibitors acting on different steps of the pathway. Our findings demonstrate a synergistic effect on renin release of 150 mg of aliskiren combined with 160 mg of valsartan in the presence of a high-salt intake. Although the circulating RAS is less reactive during a high-salt diet, studies of its blockade in this condition are needed, because daily sodium intake is large in most industrialized countries (9). Moreover, an increased intrarenal generation of AngII has been demonstrated in subgroups of hypertensive patients on a high-sodium diet (16–18). A high-salt diet also resulted in optimal conditions for evaluating the effect on renin release of high dosages of RAS blockers alone and in combination, by avoiding the renin secretion plateau that may occur in some sodium-depleted individuals after a strong stimulation of renin release by the interruption of the AngII-renin feedback (14).

Comparison of the Hormonal and BP Effects of the Renin Inhibitor and the AT1 Receptor Antagonist
In conditions in which oral bioavailability was not affected by food intake for either drug, we found that a single oral dose of the orally active renin inhibitor A300 (1) decreased plasma AngI and AngII concentrations, whereas a single oral dose of V320 increased them, and (2) decreased aldosterone excretion in fractionated urine samples for longer than V320 and decreased MAP to a similar extent as V320. The drug-induced increase in plasma immunoreactive renin needs particular consideration. Indeed, this is the only method available to quantify and compare the magnitude and duration of RAS blockade achieved with blockers acting at different sites. This phenomenon is common to ACE inhibition and AngII antagonism and their combination and renin inhibition. It is due to the neutralization of the effects of AngII on kidney juxtaglomerular cells, even though all of these RAS blockers differ by their effects on circulating angiotensin peptides. Immunoreactive plasma active renin was stimulated more strongly and for longer by A300 than by V320. The longer duration of the AngII-renin feedback interruption and decrease in aldosterone excretion induced by A300 than by V320 is mainly explained by a combination of its long plasma half-life of this drug and its high affinity for human renin in the low nanomolar range (3). Although stimulation of AT2 receptors as a result of the administration of V320 might theoretically have attenuated the rise in plasma active renin by inhibiting renin synthesis (19) and/or inhibiting prorenin processing in juxtaglomerular cells (20), these phenomena initially described in animal and cellular models cannot be explored in these clinical investigations. Another factor that might have influenced the findings for renin is a conformational change of plasma prorenin in the presence of aliskiren, resulting an overestimation of active renin measurements in some immunoradiometric assays (21,22); however, we have verified that this phenomenon is not significant in the assay used for these experiments (22).

The potency of aliskiren by comparison with valsartan was assessed according to the plasma levels achieved by each drug, by the calculation of the RPI, which is a pharmacokinetic/pharmacodynamic index that takes into account actual drug exposure rather than the oral dosage of the drug administered (14). This correction is especially important in studies in which drug pharmacokinetics is nonlinear, as was the case for aliskiren. The RPI for A300 was 2.38 pg/ml per ng/ml (95% CI 2.02 to 2.80) and for V320 was 0.05 pg/ml per ng/ml (95% CI 0.04 to 0.07). Even after adjustment for the differences in molecular weight between the two drugs, this renin inhibitor is more potent on renin release than this AT1 receptor antagonist.

Combined Blockade of the RAS by Aliskiren and Valsartan
The combination of aliskiren and valsartan, administered at half dosage, to inhibit the initial and final RAS steps, renin and the AT1 receptor, minimizes or even overcomes the rise in AngII as a result of the AT1 receptor blockade. Reinforcement of the RAS blockade has already been demonstrated for different dual RAS blockades that combine an ACE inhibitor with an AT1 receptor antagonist (1). The single oral dose of 150 mg of aliskiren in the combination neutralized for 48 h the increase in PRA and plasma AngI and AngII concentrations that would have been induced by 160 mg of valsartan in its absence (see Figure 1). The effects of the combination on plasma AngI and AngII in vivo confirm its effects on the AngI production rate measured in vitro. This effect on plasma AngII explains the more complete blockade observed with the combination therapy, as assessed by the increase in immunoreactive renin release. The AUC0 to 48 of plasma active renin concentration achieved with the A150+V160 combination was significantly higher than that achieved by doubling the dosage of valsartan. It was apparently similar to that achieved by doubling the dosage of aliskiren (300 mg alone), but the absence of dosage proportionality in aliskiren pharmacokinetics must be taken into account when interpreting the results. The plasma concentrations of aliskiren increased by a factor of 3 (95% CI 2 to 4.4) rather than two when the dosage was doubled from 150 to 300 mg, and this presumably explains the larger increase in renin release than expected from doubling the aliskiren dosage. We can therefore conclude that there is a synergistic effect between a 150-mg dose of aliskiren and a 160-mg dose of valsartan on immunoreactive active renin release.

The A150+V160 combination decreased urinary aldosterone excretion to a greater extent than V320 and to the same extent as A300 at 24 and 48 h after drug intake. The values observed may be the maximal decrease that can be obtained for aldosterone, whose secretion is regulated by several other stimuli (23). Part of the effects of the combination of aliskiren and valsartan on urinary aldosterone excretion may be due to the difference in plasma half-life of each drug. Because of its prolonged pharmacokinetic/pharmacodynamic half-life, aliskiren makes less AngII available at the end of the dosing interval, when plasma valsartan concentrations are declining.

The combination tended to be slightly, although not significantly, more effective than either A300 or V320 at decreasing MAP, especially 24 h after drug intake, when the plasma concentrations of both aliskiren and valsartan were low. In terms of AUC0 to 24 for MAP, the combination is the only active treatment that differs from the placebo. The interpretation of the BP results should be done with caution in our study, which included normotensive individuals who were on a high-sodium diet, which blunts the BP-lowering effects of RAS blockers. Indeed, even in our controlled conditions, BP remains highly variable from one individual to another, and its range of variation in condition of high-salt diet is small. It is consequently difficult to detect BP differences between drugs, combination of drugs, or dosages. The BP-lowering effect of a combination treatment associating various dosages of aliskiren and valsartan has been tested in hypertensive patients and has shown the additivity of low-dosage combinations in terms of BP lowering (5). Other trials to explore the therapeutic benefits of such combination on different end points are ongoing.

The potential therapeutic interest of aliskiren alone or in combination on renal and cardiac function has previously been discussed (2) and is now expanded toward conditions of low-renin status. The combination may offer an alternative strategy for treating patients with various renin levels and various sodium intake to obtain the cardio- and nephroprotective benefits expected from a more complete RAS blockade (24). Many explanations have been proposed for why the combination of an ACE inhibitor and an AT1 receptor antagonist have in most but not all (25) experimental and clinical experiments an additive or synergistic effect on BP levels and/or target organ damage (26,27). Our results indicate the importance of the self-limitation of a single-drug RAS blockade, and this has major consequences for selecting both the timing of drug administration (28) and the daily dosage (7). Besides this physiologic interpretation, intraindividual variations in drug pharmacokinetics may contribute in hypertensive (29) and renal (30) patients to the recruitment of nonresponders by a second blocker acting at another site, within the limits imposed by the variable participation of the RAS in individual BP control (31).

The largest study so far planned with a combined blockade of the RAS the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET), is ongoing (32). It is exploring the risk–benefit ratio of a more intense RAS blockade obtained by combining 10 mg of ramipril with 80 mg of telmisartan, by comparison with 10 mg of ramipril once daily, a treatment that prevented cardiovascular events in the patients with high cardiovascular risk in the Heart Outcomes Prevention Evaluation (HOPE) Study (33).


   Conclusions
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusions
Disclosures
 References
 
In this context, our two studies of a combination of a renin inhibitor and an AT1 receptor antagonist, performed in normal volunteers during sodium depletion and sodium repletion, demonstrate the mutual pharmacologic reinforcement of RAS blockade, as assessed by the release of immunoreactive active renin by the juxtaglomerular cells. This could be another therapeutic alternative to optimize RAS blockade. The clinical results so far obtained on BP with the combination of aliskiren and valsartan (5) and aliskiren and ramipril (34) are in agreement with this pharmacologic concept, which attributes to the reactive rise in renin release and synthesis associated with all RAS inhibitors a self-limiting role to their efficacy, as a result of the reappearance of AngI and/or AngII, in addition to AngII-producing enzymes other that ACE, such as chymase (35,36).


   Disclosures
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusions
 Disclosures
References
 
None.


   Acknowledgments
 
This study was supported by Novartis-Pharma (Basel, Switzerland).

We thank the nursing staff of the Clinical Investigation Center who ran the protocol. We thank Christiane Dollin for performing the hormone assays and Dr. Sujata Vaidyanathan at Novartis Pharmaceuticals Corp. (East Hanover, NJ) for performing the drug measurements.

M.A. and J.M. designed the study, which was accepted by Novartis. They analyzed the data and wrote the manuscript. A.B.-R. recruited the healthy volunteers. A.B. generated the database and performed the statistical analysis. T.T.G. supervised or performed the hormone assays. All co-authors participated to the redaction of the manuscript. Novartis had full access to the data and reimbursed the hospital costs, the dosages, and the payments to the healthy volunteers and monitored the study performance.


   Footnotes
 
Published online ahead of print. Publication date available at www.cjasn.org.

Received January 19, 2007. Accepted May 7, 2007.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusions
 Disclosures
 References
 

  1. Azizi M, Chatellier G, Guyene TT, Murieta-Geoffroy D, Menard J: Additive effects of combined angiotensin-converting enzyme inhibition and angiotensin II antagonism on blood pressure and renin release in sodium-depleted normotensives. Circulation92 :825 –834,1995[Abstract/Free Full Text]
  2. 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 Nephrol15 :3126 –3133,2004[Abstract/Free Full Text]
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