Structure-activity relationship of resveratrol and its analogue, 4,4'-dihydroxy-trans-stilbene, toward the endothelin axis in human endothelial cells.

Abstract Resveratrol inhibits endothelin-1, a vascular tension regulator. We synthesized the resveratrol analogue 4,4′-dihydroxy-trans-stilbene with 2 hydroxyl groups in the 4 and 4′ position to obtain a molecule more active than resveratrol (3,4′,5-trihydroxy-trans-stilbene). The results demonstrate that 4,4′-dihydroxy-trans-stilbene led to a significant decrease in total endothelin-1 secretion and in endothelin-1 messenger RNA (mRNA) levels in human endothelial cells. In addition, resveratrol and its analogue decreased endothelin-converting enzyme-1 mRNA levels and further reduced the activity of the enzyme. 4,4′-dihydroxy-trans-stilbene was more active than resveratrol because the new molecule exerted greater activity at the level of endothelin synthesis and conversion, even at a lower concentration. Although 4,4′-dihydroxy-trans-stilbene and resveratrol inhibited formation of reactive oxygen species and lipid peroxidation, the treatment of cells with different oxidant agents did not modify the endothe...