Molecular and cellular effects of azilsartan: a new generation angiotensin II receptor blocker

Background Azilsartan medoxomil is a newly approved angiotensin receptor blocker (ARB) reported to lower 24-h blood pressure more effectively than maximally recommended doses of older ARBs. Although azilsartan is considered to be an unusually potent angiotensin II type 1 (AT(1)) receptor antagonist, little is known about the potential pleiotropic effects of this molecule. Methods and results We investigated pleiotropic features of azilsartan in cell-based assay systems independent of its effects on blood pressure. In cultured 3T3-L1 preadipocytes, azilsartan enhanced adipogenesis and exerted greater effects than valsartan on expression of genes encoding peroxisome proliferator-activated receptor-alpha (PPAR alpha), PPAR delta, leptin, adipsin, and adiponectin. The effects of azilsartan on adipocyte differentiation and gene expression were observed at concentrations of azilsartan that did not classically stimulate PPAR activity in cell-based transactivation assays. Azilsartan also potently inhibited vascular cell proliferation in the absence of exogenously supplemented angiotensin II. In aortic endothelial cells, azilsartan inhibited cell proliferation at concentrations as low as 1 mu mol/l, whereas valsartan showed little or no antiproliferative effects at concentrations below 10 mu mol/l. Antiproliferative effects of azilsartan were also observed in cells lacking AT(1) receptors. In addition, azilsartan, but not valsartan, blocked angiotensin II-induced activation of mitogen-activated protein kinase in vascular smooth muscle cells 4-8 h after washout of drug from the incubation media. Conclusion These findings suggest that azilsartan can function as a pleiotropic ARB with potentially beneficial effects on cellular mechanisms of cardiometabolic disease through actions that could involve more than just blockade of AT(1) receptors and/or reduction in blood pressure. J Hypertens 29: 2476-2483 (C) 2011 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.