Manidipine reduces pro-inflammatory cytokines secretion in human endothelial cells and macrophages

The dihydropyridine calcium antagonists (DHP-CA), commonly used for the treatment of hypertension, may exert antiatherosclerotic activity independent of the blood-pressure lowering properties. The aim of this study was to evaluate the effect in cell culture of the third generation DHP-CA Manidipine on the release of interleukin-6 (IL-6) and interleukin-8 (IL-8) from human endothelial cells and human macrophages, in response to different pro-inflammatory signals. In endothelial cells, incubation with acetylated LDL (acLDL), oxidized LDL (oxLDL) or tumor necrosis factor-alpha (TNF-alpha), increased the release of IL-6 from 50% to 100%. Manidipine 1-5 mu M was able to completely inhibit IL-6 production induced by either of these factors. In these cells TNF-alpha increased by about 4 times the secretion of IL-8 and Manidipine 5 mu M reduced the amount of IL-8 in the culture media by about 40%. In human macrophages THP-1, treatment with different cytokines was able to stimulate by about 3-folds the release of IL-6 and Manidipine 1 mu M showed a 25% inhibition on TNF-alpha-induced IL-6 secretion. In these cells, a combined treatment with multiple cytokines, induced IL-6 production of about 6-folds and Manidipine was able to reduce such inflammatory response by 30%. Our experiments highlighted the anti-inflammatory properties of Manidipine in either human endothelial cells or macrophages. The mechanism by which Manidipine exert this effect is not related to its blocking activity on calcium channels and it involves an inhibition of NF-kappa B activation, that, in analogy with what is observed for other DHP-CA, may be related to the high lipophilicity and the antioxidant activity of this compound.