title: Aliskiren accumulates in Renin secretory granules and binds plasma prorenin.
abstract: The vascular effects of aliskiren last longer than expected based on its half life, and this renin inhibitor has been reported to cause a greater renin rise than other renin-angiotensin system blockers. To investigate whether aliskiren accumulation in secretory granules contributes to these phenomena, renin-synthesizing mast cells were incubated with aliskiren, washed, and exposed to forskolin in medium without aliskiren (0.1 to 1000 nmol/L). (Pro)renin concentrations were measured by renin- and prorenin-specific immunoradiometric assays, and renin activity was measured by enzyme-kinetic assay. Without aliskiren, the culture medium predominantly contained prorenin, the cells exclusively stored renin, and forskolin doubled renin release. Aliskiren dose-dependently bound to (pro)renin in the medium and cell lysates and did not alter the effect of forskolin. The aliskiren concentrations required to bind prorenin were 1 to 2 orders of magnitude higher than those needed to bind renin. Blockade of cell lysate renin activity ranged from 27+/-15% to 79+/-5%, and these percentages were identical for the renin that was released by forskolin, indicating that they represented the same renin pool, ie, the renin storage granules. Comparison of renin and prorenin measurements in blood samples obtained from human volunteers treated with aliskiren, both before and after prorenin activation, revealed that <or=30% of prorenin was detected in renin-specific assays. In conclusion, aliskiren accumulates in renin granules, thus allowing long-lasting renin-angiotensin system blockade beyond the half-life of this drug. Aliskiren also binds to prorenin. This allows its detection as renin, and might explain, in part, the renin rise during renin inhibition.
authors.affiliation: Department of Internal Medicine, Division of Pharmacology, Erasmus MC, Rotterdam, the Netherlands.
authors.forename: Manne
authors.initials: M
authors.lastname: Krop
authors.forename: Ingrid M
authors.initials: IM
authors.lastname: Garrelds
authors.forename: René J A
authors.initials: RJ
authors.lastname: de Bruin
authors.forename: Jeanette M G
authors.initials: JM
authors.lastname: van Gool
authors.forename: Naomi D L
authors.initials: ND
authors.lastname: Fisher
authors.forename: Norman K
authors.initials: NK
authors.lastname: Hollenberg
authors.forename: A H
authors.initials: AH
authors.lastname: Jan Danser
mesh_terms: D000577:Amides / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000803:Angiotensin I / Q000378:metabolism; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D045744:Cell Line, Tumor; D005576:Colforsin / Q000494:pharmacology; D003470:Culture Media / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005650:Fumarates / Q000008:administration & dosage / Q000493:pharmacokinetics*; D006801:Humans; D007946:Leukemia, Mast-Cell; D008407:Mast Cells / Q000187:drug effects* / Q000378:metabolism*; D012083:Renin / Q000097:blood* / Q000378:metabolism; D022142:Secretory Vesicles / Q000187:drug effects / Q000378:metabolism*
chemical_list: D000577:Amides; D000959:Antihypertensive Agents; D003470:Culture Media; D005650:Fumarates; D005576:Colforsin; C446481:aliskiren; D000803:Angiotensin I; D012083:Renin