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Hypertension, Vol 18, 304-315, Copyright © 1991 by American Heart Association

ARTICLES

Endothelin-3 regulates endothelin-1 production in cultured human endothelial cells

K Yokokawa, M Kohno, K Yasunari, K Murakawa and T Takeda
1st Department of Internal Medicine, Osaka City University Medical School, Japan.

Effects of endothelin-3 on the secretion of endothelin-1 and other endothelium-derived substances were investigated in cultured human umbilical vein endothelial cells. The present binding study showed two distinct subpopulations of binding sites for endothelin-3 with higher and lower affinities in cultured human endothelial cells. Endothelin-3 caused an increase in intracellular Ca2+ and inositol 1,4,5- trisphosphate levels and activated protein kinase C in a dose-dependent manner. Endothelin-3 also caused an increase in [3H]thymidine incorporation into cellular DNA and stimulated the production of cyclic guanosine 3',5'-monophosphate, 6-ketoprostaglandin F1 alpha, and immunoreactive endothelin-1 in cultured human endothelial cells. NG- Monomethyl L-arginine (3 x 10(-4) mol/l) and indomethacin (10(-5) mol/l) enhanced endothelin-3-induced endothelin-1 production. These results suggest that endothelin-3 bound to its specific receptors and then caused phosphoinositide breakdown, subsequently mobilizing intracellular Ca2+ and leading to protein kinase C activation and the initiation of DNA synthesis, resulting in the stimulation of endothelin- 1 production by human endothelial cells. Furthermore, this endothelin-1 production may be suppressed by endothelium-derived relaxing factor and prostacyclin produced in response to endothelin-3 in cultured human endothelial cells.

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