REDUCTION OF ENDOTHELIN LEVELS BY THE DIHYDROPYRIDINE CALCIUM-ANTAGONIST NISOLDIPINE AND A NATURAL FACTOR IN CULTURED HUMAN ENDOTHELIAL-CELLS

Objective: Endothelin is thought to be related to cardiovascular disea se. The purpose of this study was to determine whether endothelin leve ls could be reduced by a calcium antagonist and a 'natural factor'. De sign: Since calcium ionophores can induce endothelin-1 messenger RNA s ynthesis in cultured endothelial cells, the calcium antagonist nisoldi pine was used in this study to determine whether it could reduce endot helin 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 t o determine whether coculture of the two cell types from the same spec ies and the same section of an artery could reduce endothelin levels. Methods: Cultured endothelial cells from human umbilical artery (HUAEC ) and umbilical vein (HUVEC) were treated with increasing concentratio ns of nisoldipine. HUAEC were cocultured with human umbilical artery s mooth muscle cells (HUASMC). Endothelin levels were measured by a radi oimmunoassay. Results: Incubation of the HUAEC with nisoldipine for ei ther 7 or 24 h resulted in a dose-dependent (10(-8)-10(-5) mol/l) redu ction in endothelin levels in the conditioned media. Endothelin levels in cell lysates were not detectable in either the absence or the pres ence of nisoldipine. This suggests that the reduction of endothelin le vels in the media could be due to inhibition of endothelin synthesis. Under the same conditions, incubation of HUVEC with the same concentra tions of nisoldipine produced a similar concentration-dependent reduct ion in endothelin levels. Endothelin levels were undetectable in the c onditioned media from HUASMC. Coculture of HUAEC with HUASMC significa ntly reduced endothelin levels (P < 0.01) compared with HUAEC cultured alone. Conclusions: Endothelin levels can be reduced by the calcium a ntagonist nisoldipine and a 'natural factor' associated with smooth mu scle cells.