Document Detail

New Renin Inhibitor VTP-27999 Alters Renin Immunoreactivity and Does Not Unfold Prorenin.
MedLine Citation:
PMID:  23460288     Owner:  NLM     Status:  Publisher    
Renin inhibitors like aliskiren not only block renin but also bind prorenin, thereby inducing a conformational change (like the change induced by acid) allowing its recognition in a renin-specific assay. Consequently, aliskiren can be used to measure prorenin. VTP-27999 is a new renin inhibitor with an aliskiren-like IC50 and t1/2, and a much higher bioavailability. This study addressed (pro)renin changes during treatment of volunteers with VTP-27999 or aliskiren. Both drugs increased renin immunoreactivity. Treatment of plasma samples from aliskiren-treated subjects with excess aliskiren yielded higher renin immunoreactivity levels, confirming the presence of prorenin. Unexpectedly, this approach did not work in VTP-27999-treated subjects, although an assay detecting the prosegment revealed that their blood still contained prorenin. Subsequent in vitro analysis showed that VTP-27999 increased renin immunoreactivity for a given amount of renin by ≥30% but did not unfold prorenin. Yet, it did bind to acid-activated, intact prorenin and then again increased immunoreactivity in a renin assay. However, no such increase in immunoreactivity was seen when measuring acid-activated prorenin bound to VTP-27999 with a prosegment-directed assay. The VTP-27999-induced rises in renin immunoreactivity could be competitively prevented by aliskiren, and antibody displacement studies revealed a higher affinity of the active site-directed antibodies in the presence of VTP-27999. In conclusion, VTP-27999 increases renin immunoreactivity in renin immunoassays because it affects the affinity of the active site-directed antibody. Combined with its lack of effect on prorenin, these data show that VTP-27999 differs from aliskiren. The clinical relevance of these results needs to be established.
Manne Krop; Xifeng Lu; Koen Verdonk; Maarten A D H Schalekamp; Jeanette M G van Gool; Brian M McKeever; Richard Gregg; A H Jan Danser
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2013-3-4
Journal Detail:
Title:  Hypertension     Volume:  -     ISSN:  1524-4563     ISO Abbreviation:  Hypertension     Publication Date:  2013 Mar 
Date Detail:
Created Date:  2013-3-5     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  7906255     Medline TA:  Hypertension     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Department of Internal Medicine, Division of Pharmacology and Vascular Medicine, Erasmus MC, Rotterdam, The Netherlands.
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