6533b837fe1ef96bd12a31ec

RESEARCH PRODUCT

Protein kinase C-inhibiting properties of the losartan metabolite EXP3179 make the difference.

subject

description

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-F2α. Additional beneficial effects include stimulation of endothelial NO synthase, suppression of tumor necrosis factor-α-induced apoptosis, and agonistic action on peroxisome proliferator-activated receptor-γ. 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 …