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Aliskiren penetrates adipose and skeletal muscle tissue and reduces renin-angiotensin system activity in obese hypertensive patients.

Abstract

OBJECTIVE
In animals, the direct renin inhibitor aliskiren showed extensive tissue binding in the kidney and long-lasting renal effects. Aliskiren provides prolonged blood pressure-lowering effects following treatment discontinuation in patients. Therefore, we investigated whether aliskiren attains tissue concentrations sufficient to inhibit local renin-angiotensin system (RAS) activity in patients.
METHODS
We included 10 hypertensive patients with abdominal adiposity in an open-label study. Following 1-2 weeks washout, patients received 2 weeks placebo, then 4 weeks aliskiren 300 mg once daily, followed by 4 weeks washout, and then 4 weeks amlodipine 5 mg once daily. Drug concentrations and RAS biomarkers were measured in interstitial fluid using microdialysis and in biopsies from abdominal subcutaneous adipose and skeletal muscle.
RESULTS
We detected aliskiren in all compartments. After 4 weeks of treatment, microdialysate aliskiren concentrations (ng/ml) were 2.4 ± 2.1 (adipose) and 7.1 ± 4.2 (skeletal muscle), similar to plasma concentrations (8.4 ± 4.4); tissue concentrations (ng/g) were 29.0 ± 16.7 (adipose) and 107.3 ± 68.6 (skeletal muscle). Eight weeks after discontinuation, aliskiren was measurable in tissue biopsies but not in plasma or in interstitial fluid. Pooled microdialysate samples from two sets of four patients suggested reduction in tissue angiotensin II with aliskiren but not with amlodipine.
CONCLUSION
In obese hypertensive patients, aliskiren penetrates adipose and skeletal muscle tissue at levels that are apparently sufficient to reduce tissue RAS activity. Furthermore, tissue binding may contribute to aliskiren's prolonged blood pressure-lowering effect following discontinuation.

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  • Publisher Full Text

    • Authors

    Boschmann M, Nussberger J, Engeli S, Danser AH, Yeh CM, Prescott MF, Dahlke M, Jordan J

    Institution

    Franz Volhard Clinical Research Center, Charité, Berlin, Germany.

    Source

    Journal of hypertension 30:3 2012 Mar pg 561-6

    MeSH

    Adipose Tissue
    Adult
    Amides
    Amlodipine
    Antihypertensive Agents
    Calcium Channel Blockers
    Extracellular Fluid
    Female
    Fumarates
    Humans
    Hypertension
    Male
    Middle Aged
    Muscle, Skeletal
    Obesity
    Pilot Projects
    Renin-Angiotensin System

    Pub Type(s)

    Clinical Trial
    Journal Article
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    22278138