Abstract
Angiotensin II (Ang II) type 1 receptor (AT(1)) 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 (GC-MS) [corrected] 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 F2alpha as determined by GC-MS [corrected]. Thus, antiinflammatory properties of LOS are mediated via its EXP3179 metabolite by abolishing COX-2 mRNA upregulation and COX-dependent TXA2 and PGF2alpha generation. Serum levels of EXP3179 are detectable in patients in concentrations that exhibit antiinflammatory and antiaggregatory properties in vitro.
Publication types
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Clinical Trial
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Research Support, Non-U.S. Gov't
MeSH terms
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Angiotensin II / pharmacology
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Angiotensin Receptor Antagonists*
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Arachidonic Acid / pharmacology
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Biotransformation
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Cells, Cultured
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Cyclooxygenase 2
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Dinoprost / antagonists & inhibitors
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Dinoprost / biosynthesis
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Drug Design
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Endothelium, Vascular / cytology
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Endothelium, Vascular / drug effects
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Endothelium, Vascular / metabolism
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Enzyme Activation / drug effects
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Female
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Humans
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Hypertension / drug therapy*
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Hypertension / metabolism
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Imidazoles / blood
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Inflammation / drug therapy*
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Inflammation / metabolism
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Intercellular Adhesion Molecule-1 / genetics
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Intercellular Adhesion Molecule-1 / metabolism
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Isoenzymes / antagonists & inhibitors
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Isoenzymes / genetics
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Isoenzymes / metabolism
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Lipopolysaccharides / pharmacology
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Losartan / analogs & derivatives
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Losartan / chemistry
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Losartan / metabolism*
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Losartan / pharmacology*
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Male
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Membrane Proteins
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Middle Aged
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Platelet Aggregation / drug effects*
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Prostaglandin-Endoperoxide Synthases / genetics
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Prostaglandin-Endoperoxide Synthases / metabolism
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RNA, Messenger / analysis
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RNA, Messenger / metabolism
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Receptor, Angiotensin, Type 1
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Receptors, Angiotensin / metabolism
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Tetrazoles / blood
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Thromboxane A2 / antagonists & inhibitors
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Thromboxane A2 / biosynthesis
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Up-Regulation / drug effects
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Vasoconstrictor Agents / pharmacology
Substances
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Angiotensin Receptor Antagonists
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Imidazoles
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Isoenzymes
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Lipopolysaccharides
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Membrane Proteins
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RNA, Messenger
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Receptor, Angiotensin, Type 1
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Receptors, Angiotensin
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Tetrazoles
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Vasoconstrictor Agents
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Angiotensin II
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Intercellular Adhesion Molecule-1
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Arachidonic Acid
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Thromboxane A2
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Dinoprost
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Cyclooxygenase 2
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PTGS2 protein, human
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Prostaglandin-Endoperoxide Synthases
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losartan carboxylic acid
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Losartan