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Endothelin is thought to be related to cardiovascular disease. The purpose of this study was to determine whether endothelin levels could be reduced by a calcium antagonist and a 'natural factor'.Since calcium ionophores can induce endothelin-1 messenger RNA synthesis in cultured endothelial cells, the calcium antagonist nisoldipine was used in this study to determine whether it could reduce endothelin levels. It has been reported that coculture of endothelial cells and smooth muscle cells from different species and different parts of the body can reduce endothelin levels. This study was also designed to determine whether coculture of the two cell types from the same species and the same section of an artery could reduce endothelin levels.Cultured endothelial cells from human umbilical artery (HUAEC) and umbilical vein (HUVEC) were treated with increasing concentrations of nisoldipine. HUAEC were cocultured with human umbilical artery smooth muscle cells (HUASMC). Endothelin levels were measured by a radioimmunoassay.Incubation of the HUAEC with nisoldipine for either 7 or 24 h resulted in a dose-dependent (10-810-5mol/l) reduction in endothelin levels in the conditioned media. Endothelin levels in cell lysates were not detectable in either the absence or the presence of nisoldipine. This suggests that the reduction of endothelin levels in the media could be due to inhibition of endothelin synthesis. Under the same conditions, incubation of HUVEC with the same concentrations of nisoldipine produced a similar concentration-dependent reduction in endothelin levels. Endothelin levels were undetectable in the conditioned media from HUASMC. Coculture of HUAEC with HUASMC significantly reduced endothelin levels (P<0.01) compared with HUAEC cultured alone.Endothelin levels can be reduced by the calcium antagonist nisoldipine and a 'natural factor' associated with smooth muscle cells.