Modulation of tumor necrosis factor-alpha production with anti-hypertensive drugs.
It is well known that some anti-hypertensive drugs affect insulin sensitivity and that tumor necrosis factor-alpha (TNF-alpha) is a mediator of obesity-associated insulin resistance. In this study, we have investigated the effect of anti-hypertensive drugs, calcium (Ca) channel blockers (amlodipine, manidipine and nicardipine), an alpha(1)-blocker (doxazosin), a beta(1)-blocker (metoprolol), and a thiazide diuretic (hydrochlorothiazide), on lipopolysaccharide (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 blood mononuclear cell culture, respectively. Nicardipine, or amlodipine, manidipine and doxazosin significantly inhibited TNF-alpha production in mice at doses more than one or ten times higher than those used clinically, respectively. On the other hand, metoprolol increased TNF-alpha production at doses of more than 10 times those used clinically, whereas hydrochlorothiazide did not alter production of the cytokine. The in vivo effects of these drugs were not necessary parallel to the in vitro effects. Because high doses of these drugs in mice correspond to clinical doses and effects in human, these actions may be related to beneficial and/or harmful effects of these drugs on TNF-alpha mediated diseases, including insulin resistance.
Fukuzawa
M
M
Third Department of Internal Medicine, Tohoku University School of Medicine, 1-1 Seiryo-machi, Aoba-ku, 980-8574, Sendai, Japan.
Satoh
J
J
Ohta
S
S
Takahashi
K
K
Miyaguchi
S
S
Qiang
X
X
Sakata
Y
Y
Nakazawa
T
T
Takizawa
Y
Y
Toyota
T
T
D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D017311:Amlodipine / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002478:Cells, Cultured; D004095:Dihydropyridines / Q000494:pharmacology; D004232:Diuretics; D017292:Doxazosin / Q000494:pharmacology; D006801:Humans; D006852:Hydrochlorothiazide / Q000494:pharmacology; D007375:Interleukin-1 / Q000096:biosynthesis; D015850:Interleukin-6 / Q000096:biosynthesis; D008070:Lipopolysaccharides; D008297:Male; D008790:Metoprolol / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D009000:Monocytes / Q000187:drug effects* / Q000276:immunology; D009529:Nicardipine / Q000494:pharmacology; D009578:Nitrobenzenes; D010879:Piperazines; D049993:Sodium Chloride Symporter Inhibitors / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
D000317:Adrenergic alpha-Antagonists; D000319:Adrenergic beta-Antagonists; D000959:Antihypertensive Agents; D002121:Calcium Channel Blockers; D004095:Dihydropyridines; D004232:Diuretics; D007375:Interleukin-1; D015850:Interleukin-6; D008070:Lipopolysaccharides; D009578:Nitrobenzenes; D010879:Piperazines; D049993:Sodium Chloride Symporter Inhibitors; D014409:Tumor Necrosis Factor-alpha; D006852:Hydrochlorothiazide; D017311:Amlodipine; C054218:manidipine; D009529:Nicardipine; D008790:Metoprolol; D017292:Doxazosin