Published online before print March 7, 2002, doi: 10.1161/01.RES.0000014434.48463.35
© 2002 American Heart Association, Inc.
Molecular Medicine |
Angiotensin II Receptor–Independent Antiinflammatory and Antiaggregatory Properties of Losartan
Role of the Active Metabolite EXP3179
From the Department of Cardiology and Angiology (C.K., J.S., J.W., M.L., H.D., B. Schieffer), Medizinische Hochschule Hannover; the Department of Chemistry (B. Schmidt), University Hannover; Lower-Saxony Institute of Peptide Research (M.W., W.-G.F.), Hannover, Germany; and the Clinical Pharmacology Unit (R.H.B.), Department of Pharmacology, University Hospital Hamburg, Germany.
Correspondence to Bernhard Schieffer, MD, Carl-Neuberg-Str. 1, 30625 Hannover, Germany. E-mail Schieffer.Bernhard{at}MH-Hannover.de
Angiotensin II (Ang II) type 1 receptor (AT1) antagonists such as losartan (LOS) are widely used for the treatment of hypertension and elicit antiinflammatory and antiaggregatory in vitro and in patients, although the underlying mechanism are unclear. Following computer-based molecule similarity, we proposed that on cytochrome-P450 degradation, the LOS metabolite EXP3179 is generated, which shows molecule homology to indomethacin, a cyclooxygenase inhibitor with antiinflammatory and antiaggregatory properties. Subsequently, serum-levels of EXP3179 were determined for 8 hours in patients receiving a single oral dose of 100 mg LOS. High-performance liquid chromatography followed by liquid chromatography–mass spectrometry (LC-MS) from serum samples revealed a maximum of 10-7 mol/L for EXP3179 peaking between 3 to 4 hours. The increase in serum-EXP3179 levels was associated with a significant reduction in platelet aggregation in vivo (-35±4%, P<0.001 versus control). EXP3179 generation was investigated in a chemical reaction mimicking the liver cytochrome-P450–dependent LOS-degradation and human endothelial cells were exposed to Ang II or lipopolysaccharides (LPS) in the presence of EXP3179 (10-7 mol/L). LPS- and Ang II–induced COX-2 transcription was abolished by EXP3179. Moreover, EXP3179 significantly reduced Ang II– and LPS-induced formation of prostaglandin F2
as determined by LC-MS. Thus, antiinflammatory properties of LOS are mediated via its EXP3179 metabolite by abolishing COX-2 mRNA upregulation and COX-dependent TXA2 and PGF2 generation. Serum levels of EXP3179 are detectable in patients in concentrations that exhibit antiinflammatory and antiaggregatory properties in vitro.
Key Words: cyclooxygenase • platelet aggregation • thromboxane A2 • prostaglandin F2 • atherosclerosis
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