This Article Full Text Full Text (PDF) All Versions of this Article: 54/4/707    most recent HYPERTENSIONAHA.109.136218v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Wenzel, P. Articles by Münzel, T. PubMed PubMed Citation Articles by Wenzel, P. Articles by Münzel, T. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Medline Plus Health Information High Blood Pressure Hazardous Substances DB LOSARTAN POTASSIUM Related Collections Cardiovascular Pharmacology ACE/Angiotension receptors Oxidant stress Other Vascular biology Related Article

(Hypertension. 2009;54:707.)
© 2009 American Heart Association, Inc.

Editorial Commentaries

Protein Kinase C-Inhibiting Properties of the Losartan Metabolite EXP3179 Make the Difference

Philip Wenzel; Eberhard Schulz; Thomas Münzel

From the II. Medizinische Klinik, Universitätsmedizin der Johannes-Gutenberg-Universität Mainz, Mainz, Germany.

Correspondence to Thomas Münzel, II. Medizinische Klinik, Universitätsmedizin der Johannes Gutenberg-Universität Mainz, Langenbeckstr 1, 55131 Mainz, Germany. E-mail tmuenzel@uni-mainz.de

An extract of the first 250 words of the full text is provided, because this article has no abstract.

The inhibition of the renin-angiotensin axis with the angiotensin II (ATII) receptor blockers, such as losartan, candesartan, and valsartan, has been demonstrated, similar to angiotensin-converting enzyme inhibitors, to reduce mortality in patients with arterial hypertension, chronic congestive heart failure, and acute myocardial infarction.¹

Initially, the ATII receptor antagonist losartan helped to demonstrate new classes of ATII receptors and substantially expanded our knowledge about the cardiovascular effects of the renin-angiotensin-aldosterone system and its effector peptide ATII. Researchers dealing with this compound soon revealed that, beyond its antihypertensive effects attributed to blockade of the ATII receptor type 1 (AT1R), losartan has antiaggregatory and anti-inflammatory actions that are potentially independent of the hypotensive actions. In this regard, it is important to note that losartan is a prodrug. In vivo cytochrome P450-mediated oxidation leads to the formation of the metabolite EXP3174 with an 40-fold higher capacity to bind the AT1R. Another metabolite, EXP3179, has a striking structural homology to the cyclooxygenase inhibitor indomethacin and abolishes cyclooxygenase-2-mediated formation of thromboxane₂ and prostaglandin-F₂. Additional beneficial effects include stimulation of endothelial NO synthase, suppression of tumor necrosis factor--induced apoptosis, and agonistic action on peroxisome proliferator-activated receptor-.

Vascular function, especially in the setting of arterial hypertension, is influenced by the balance between NO and superoxide. One of the most important vascular superoxide sources is NADPH oxidase, an enzyme that was initially characterized in inflammatory cells and later demonstrated to also exist in vascular cells. The important question, whether superoxide produced by the vascular NADPH oxidase . . . [Full Text of this Article]

Related Article:

Losartan Metabolite EXP3179 Blocks NADPH Oxidase-Mediated Superoxide Production by Inhibiting Protein Kinase C: Potential Clinical Implications in Hypertension

Ana Fortuño, Julen Bidegain, Pablo A. Robador, José Hermida, Jacinto López-Sagaseta, Oscar Beloqui, Javier Díez, and Guillermo Zalba
Hypertension 2009 54: 744-750. [Abstract] [Full Text] [PDF]