Hormonal and hemodynamic effects of aliskiren and valsartan and their combination in sodium-replete normotensive individuals.

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.

Conformational changes in prorenin during renin inhibition in vitro and in vivo.

BACKGROUND: Some renin inhibitors induce changes in the conformation of prorenin in vitro and influence the quantification of active renin by immunoradiometric assays. Whether such changes in renin recognition by monoclonal antibodies exist after oral administration of aliskiren, the first orally available renin inhibitor, is not known. METHODS: Two commercially available immunoradiometric assays (Cisbio and Nichols) were compared to determine immunoreactive active renin concentrations in plasma samples collected in a single oral dose crossover study comparing the renin inhibitor, aliskiren (300 mg), with the angiotensin II antagonist, valsartan (160 mg), in healthy male subjects. RESULTS: The addition of aliskiren to plasma samples in vitro, at concentrations of 1-100 micromol/l, increased active renin immunoreactivity in both the Cisbio and Nichols assays. In the crossover study, the two assays gave similar values for the plasma immunoreactive active renin concentration before treatment and following valsartan administration (intraclass coefficient for agreement between the two assays = 0.92). However, a Bland-Altman plot showed a systematic bias towards higher values (1.75-fold higher; 95% confidence interval = 1.02-3.01) in the Nichols than in the Cisbio assay following aliskiren administration. The difference between the results obtained with the two assays depended on incubation time. CONCLUSIONS: Depending on incubation conditions, circulating renin inhibitors interfere with the recognition of active renin molecules by the monoclonal antibodies used in commercially available assays. Careful consideration must therefore be given to the methodology used for quantifying immunoreactive plasma active renin when patients are treated with renin inhibitors, to avoid an overestimation of the magnitude of active renin release attributable to conformational changes in plasma prorenin.

Pharmacokinetics and pharmacodynamics of the vasopeptidase inhibitor AVE7688 in humans.

OBJECTIVE: Our objective was to define the pharmacodynamic profile of the new dual neutral endopeptidase (NEP)/angiotensin-converting enzyme (ACE) inhibitor AVE7688. METHODS: We compared the effects of single oral doses of AVE7688 (5 and 25 mg) with those of 10 mg ramipril (R10), a selective ACE inhibitor, in a placebo-controlled crossover study in sodium-depleted normotensive subjects. We also compared the effects of 25 mg AVE7688 with those of a renin-angiotensin system (RAS) blockade induced by a high dose of an angiotensin II receptor antagonist (300 mg irbesartan) and a dual blockade of the RAS (150 mg irbesartan plus 10 mg ramipril) in sodium-replete normotensive subjects by use of the same study design. The in vivo inhibition of ACE and NEP was monitored by measuring the urinary excretion of N-acetyl-Ser-Asp-Lys-Pro (AcSDKP) and atrial natriuretic peptide (ANP), respectively. The intensity of RAS blockade was assessed by the increase in plasma active renin concentration. RESULTS: The 24-hour urine AcSDKP cumulative excretion increased significantly more after 25 mg AVE7688 (919 nmol [95% confidence interval (CI), 803-1052 nmol], P < .05) than after 5 mg AVE7688 (706 nmol [95% CI, 612-813 nmol]) or 10 mg ramipril (511 nmol [95% CI, 440-593 nmol]). The 25-mg dose of AVE7866 significantly and transiently (4 to 8 hours after drug intake) increased urinary ANP (2.02 +/- 1.05 ng/h, P < .05), whereas 5 mg AVE7688 (1.14 +/- 0.77 ng/h) and 10 mg ramipril (0.93 +/- 0.65 ng/h) had no effect compared with placebo (0.80 +/- 0.37 ng/h). In the low-salt panel the rise in plasma active renin concentration achieved 24 hours after dosing by 25 mg AVE7688 (247 pg/mL [95% CI, 157-389 pg/mL], P < .05) was significantly higher than that achieved by 5 mg AVE7688 (129 pg/mL [95% CI, 75-221 pg/mL]) or 10 mg ramipril (113 pg/mL [95% CI, 67-193 pg/mL]), which did not differ. In the high-salt panel group the effects of 25 mg AVE7688 on renin release did not significantly differ from those after administration of the combination of 150 mg irbesartan plus 10 mg ramipril or 300 mg irbesartan alone. All of these active drugs similarly decreased blood pressure compared with placebo. CONCLUSION: AVE7688 at a dose of 25 mg has a favorable pharmacodynamic profile compared with other RAS blockers. These results support further clinical studies of its long-term effects in essential or resistant hypertension, chronic proteinuric nephropathy, and chronic heart failure.

Physiologic consequences of vasopeptidase inhibition in humans: effect of sodium intake.

The in vivo inhibition of angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP) were monitored simultaneously by sequentially measuring the urinary excretion of N-Acetyl-Ser-Asp-Lys-Pro and of the atrial natriuretic factor to compare the magnitude and the duration of action of a vasopeptidase inhibitor, omapatrilat, and an ACE inhibitor, fosinopril. Single oral doses of 40 or 80 mg of omapatrilat or 20 mg of fosinopril were administered to 24 normotensive, sodium-depleted or -replete volunteers in a placebo-controlled crossover study. ACE inhibition persisted longer after treatment with omapatrilat than with fosinopril, and there was no major difference between the effects of 40 and 80 mg of omapatrilat. The duration of NEP inhibition by omapatrilat was shorter than that of ACE inhibition. Although omapatrilat effectively inhibited NEP, it had a mild and transient natriuretic effect and did not increase natriuresis more than fosinopril. Omapatrilat induced a decrease in BP and an increase in plasma renin more rapidly and more effectively than fosinopril. The BP and renin effects of omapatrilat persisted despite high sodium intake, which neutralized the effects of fosinopril. The simultaneous inhibition of ACE and NEP may be more effective in reducing BP than the inhibition of ACE alone and less dependent on sodium balance.