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

Abstract

Background and Objectives: An AT 1 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 AT 1 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.Clin J Am Soc Nephrol 2: 947-955, 2007.

Angiotensin Receptor Neprilysin Inhibition in Heart Failure: Mechanistic Action and Clinical Impact

“…63 Healthy human volunteers receiving escalating doses of LCZ696 were noted to have significant acute increases in plasma cGMP levels that returned to baseline by 24 hours as well as dosedependent increases in plasma renin concentration, renin activity, and Ang II that were sustained after 12 days. 63 The effects on RAAS-mediated neurohormonal levels were similar to those seen previously with valsartan 66 and likely mediated through loss of the normal feedback inhibition via the Ang II type 1 receptor. 13 These early data with LCZ696 in the context of previously demonstrated beneficial effects of neprilysin inhibition by means of other agents provided the rationale to proceed with larger phase III studies of LCZ696 without additional phase II work.…”

Effects of aliskiren, a renin inhibitor, on biomarkers of platelet activity, coagulation and fibrinolysis in subjects with multiple risk factors for vascular disease

“…Other possibilities linking aliskiren and modulation of hemostasis may be due to compliment inhibition, 44 and/or hormonal disturbances. 45 Despite the fact, that in the in vitro setting aliskiren exhibited no pronounced changes in the hemostatic indices, it is possible that in the clinical ex vivo setting, chronic RAAS modulation will be associated with the mild inhibition of platelet activity, 46 coagulation 47 and enhanced fibrinolysis by blocking t-PA and PAI-1. 48 …”

Effect of Contrasted Sodium Diets on the Pharmacokinetics and Pharmacodynamic Effects of Renin–Angiotensin System Blockers

“…11,12 After informed written consent had been obtained, 64 (n=16 per panel) healthy white normotensive male volunteers (aged 18-35 years) were randomly assigned to SR or SD. In each of these 2 sodium loading conditions, they received a single oral dose of 8 mg candesartan cilexetil (n=16), 160 mg valsartan (n=16), 10 mg ramipril (n=16), or 50 mg atenolol (n=16).…”

“…11,12 To induce SR, subjects were given slow release sodium tablets (6 g/d) for 9 days (from day −5 to day 3) and were instructed to eat high-sodium foods preferentially to reach an intake of ≈250 mmol NaCl per day. 11,12 Fluid intake (≈1500 mL/d) was unrestricted throughout the study. A 2-week washout period on unrestricted sodium diet was allowed between each hospitalization.…”