Modulation of tumor necrosis factor-alpha production with anti-hypertensive drugs

It is well known that some anti-hypertensive drugs affect insulin sensitivi ty and that turner necrosis factor-alpha (TNF-alpha) is a mediator of obesi ty-associated insulin resistance. In this study, rye have investigated the effect of anti-hypertensive drugs, calcium (Ca) channel blockers (amlodipin e, manidipine and nicardipine), an alpha(1)-blocker (doxazosin), a beta(1)- blocker (metoprolol), and a thiazide diuretic (hydrochlorothiazide), on lip opolysaccharide (LPS)-induced TNF-alpha, production. TNF-alpha production, measured with a bioassay and an immunoassay, was evaluated both in vivo and in vitro, by utilizing mice and a human peripheral blued mononuclear cell culture, respectively, Nicardipine, or amlodipine, manidipine and doxazosin significantly inhibited TNF-alpha production in mice at doses more than on e or ten times higher than those used clinically, respectively. On the othe r hand, metoprolol increased TNF-alpha production at doses of more than 10 times those used clinically, whereas hydrochlorothiazide did not alter prod uction of the cytokine, The in vivo effects of these drugs were not necessa ry parallel to the in vitro effects. Because high doses of these drugs in m ice correspond to clinical doses and effects in human, these actions may he related to beneficial and/or harmful effects of these drugs on TNF-alpha m ediated diseases, including insulin resistance. (C) 2000 Elsevier Science B .V, All rights reserved.