Abstract 2468: Chronic Treatment Of Hypertensive Patients With The At1 Receptor Blocker Losartan Results In Sufficient Serum Levels Of The Metabolite Exp3179 Exhibiting Pparγ-stimulating Properties

Abstract

The losartan metabolite EXP3174 exhibits angiotensin II receptor 1 (AT1R)-blocking properties, whereas the metabolite EXP3179 potently induces the activity of the insulin-sensititzing peroxisome proliferator-activated receptor γ (PPARγ) as a partial agonist in vitro.. We investigated, whether hypertensive patients chronically treated with losartan exhibit sufficient plasma levels of EXP3179 to activate PPARγ in monocytes derived from losartan-treated patients. Hypertensive patients (n=9) treated with losartan (100mg/daily during at least the past two months), and control patients (n=7) with no chronic AT1R-blocking therapy were included. Blood was taken from all individuals and serum was prepared. Monocytes were extracted by negative isolation using a Dynal Monocyte Kit, followed by RNA-isolation and measurement of PPARγ target gene expression (CD36, ABC transporter G1 (ABCG1)) by quantitative real-time RT-PCR. Losartan-treated patients received 100mg orally, and serum was prepared 2, 4, and 6h after drug ingestion for HPLC-based determination of losartan and losartan metabolites (EXP3174/ EXP3179) in serum. Serum levels were standardized to measurements of purified compounds. Chronic treatment with losartan resulted in basal levels (24h after drug intake) of losartan, EXP3174 and EXP3179 of 382,5ng/ml, 97,0ng/ml and 164,2ng/ml, respectively. Levels of both, EXP3174 and EXP3179 were time-dependently enhanced in serum with a maximum 2h after drug intake (2619,6ng/ml, 980,9ng/ml, respectively). In order to evaluate the possible agonistic property of chronic EXP3179 serum levels on PPARγ, we determined the transcript levels of CD36 and ABCG1 as known PPARγ target genes. Gene expression was significantly upregulated in patients chronically treated with losartan by 5.26±1.55- and 188.54±56.92-fold for CD36 and ABCG1 (p=0.039, p=0.023 vs. control patients, respectively). This is the first clinical description of monocytic PPARγ-target gene regulation by chronic treatment with losartan, which likely is mediated by its metabolite EXP3179. Our data show that sufficient serum levels of EXP3179 are present under losartan treatment. PPARγ activation by AT1R-blockers may translate into synergistic beneficial actions in monocytes.