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(Hypertension. 2006;47:586.)
© 2006 American Heart Association, Inc.

Part 2 Original Articles

Regulation of Peroxisome Proliferator–Activated Receptor Activity by Losartan Metabolites

Michael Schupp; Lucas D. Lee; Nikolaj Frost; Sumaira Umbreen; Boris Schmidt; Thomas Unger; Ulrich Kintscher

From the Center for Cardiovascular Research (M.S., L.D.L., N.F., T.U., U.K.), Institute of Pharmacology and Toxicology, Charité-Universitätsmedizin Berlin, Berlin, Germany; Division of Endocrinology, Diabetes, and Metabolism (M.S.), Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pa; and Technical University (S.U., B.S.), Institute for Organic Chemistry and Biochemistry, Darmstadt, Germany.

Correspondence to Ulrich Kintscher, Center for Cardiovascular Research, Institute of Pharmacology and Toxicology, Charité Campus Mitte, Universitätsmedizin Berlin, Hessische Str 3/4, 10115 Berlin, Germany. E-mail ulrich.kintscher{at}charite.de

Two active metabolites of the angiotensin type 1 (AT₁) receptor blocker losartan have been described previously, EXP3174 and EXP3179. Whereas EXP3174 is the main antihypertensive AT₁ receptor–blocking metabolite, the role of EXP3179 is widely unknown. Recently, a subgroup of AT₁ receptor blockers has been identified as ligands for the peroxisome proliferator–activated receptor (PPAR-). Here we characterize the PPAR-–activating properties of the 2 active losartan metabolites. PPAR- activity was measured with a chimeric Gal4-DNA–binding domain–hPPAR-ligand–binding domain (LBD) fusion protein on a Gal4-dependent luciferase reporter system. EXP3179 prominently induced the activation of the PPAR-–LBD reaching a maximum at 100 µmol/L with a 7.1±1-fold induction (P<0.05 versus vehicle-treated cells). Maximum PPAR-–LBD activation by EXP3179 reached 51% of the maximum response induced by the full PPAR- agonist pioglitazone, identifying EXP3179 as a partial PPAR- agonist. EXP3174 did not induce PPAR-–LBD activation. EC₅₀ values were calculated for PPAR-–LBD activity (pioglitazone EC₅₀: 0.88 µmol/L; EXP3179 EC₅₀: 17.1 µmol/L; losartan EC₅₀: >50 µmol/L). Consistent with the activation of PPAR-, EXP3179 potently induced 3T3-L1 adipocyte differentiation, a typical PPAR-–dependent cell function, and markedly stimulated PPAR- target gene expression. EXP3174 failed to regulate differentiation or PPAR- target gene expression. The present study characterizes the active losartan metabolite EXP3179 as a partial PPAR- agonist. PPAR- activation by EXP3179 may help us to understand the beneficial metabolic effects of losartan observed in clinical trials.

Key Words: diabetes mellitus • insulin resistance • angiotensin antagonists

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