Angiotensin II Receptor–Independent Antiinflammatory and Antiaggregatory Properties of Losartan

Abstract

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 (LC-MS) from serum samples revealed a maximum of 10 Ϫ7 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 (Ϫ35Ϯ4%, PϽ0.001 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

Hemodynamic effects of vasorelaxant compounds in mice lacking one, two or all three angiotensin II receptors

“…It is well accepted that some AT 1 blockers also function as agonizts of the peroxisome proliferatoractivated receptor-g 43,44 or as cyclooxygenase inhibitors. 45 The most widely used AT 2 blocker, PD123319, was described originally as an AT 2 agonist. 46 In view of these Ang II receptor-independent effects of the receptor blockers, we consider our KO model to be superior and more accurate than the previously described pharmacological approaches.…”

<b>Downregulation of Peroxisme Proliferator Activated Receptor Gamma Co-Activator 1&alpha; in Diabetic Rats</b>

“…13) However, little is known as to whether DM causes dilated cardiomyopathy 12) and if left ventricular (LV) dysfunction is associated with downregulation of PGC-1α gene expression. Additionally, although the pleiotropic effects of statins and losartan have recently been recognized, 18,19) little is known regarding the impacts of these pharmacological agents on the regulation of PGC-1α gene expression in DM. Thus, this study tested the hypothesis that mRNA expression of PGC-1α and LV contractility are suppressed by DM, and that simvastatin and losartan therapy reverses the affects of DM on mRNA expression of PGC-1α and LV function.…”

LIFE and SCOPE: what guidance do they offer alongside ALLHAT and ANBP2?

“…This in turn may have led to a lower central arterial systolic pressure (and pulse pressure) at any given level of peripheral pressure by diminishing the reflected pressure wave. [24][25][26] Molecule-specific effects of losartan could also, in theory, have contributed to its stroke-protective ability, for example via a platelet inhibitory action, 27 an antiinflammatory effect of the metabolite EXP3179, 28 and its uricosuric action. [29][30][31][32][33] Although some of these specific effects attributed to losartan are of considerable interest, the available experimental and epidemiological data are of uncertain importance in regard to clinical therapeutics.…”