We examined the effect of troglitazone on immunoreactive endothelin-1 (ET-1) secretion from cultured bovine vascular endothelial cells (bVECs). Insulin (10⁻⁹–10⁻⁷M) stimulated ET-1 secretion in a dose-dependent fashion without any kinetic change. Troglitazone (1–20 μM) dose-dependently inhibited both spontaneous and insulin-stimulated ET-1 secretion. This inhibitory effect of troglitazone was associated with reduced ET-1 mRNA levels. Addition of indomethacin (100 μM) orNw-nitro-l -arginine methyl ester (1 mM) and downregulation of protein kinase C by prolonged pretreatment of the cells with a phorbol ester, 12-O-tetradecanoylphorbol 13-acetate, did not affect the inhibitory effect of troglitazone at concentrations up to 10 μM. Troglitazone did not change the intracellular Ca²⁺concentration stimulated by angiotensin II (10 μM). Other PPARγ ligands, pioglitazone (1–10 μM) and 15-deoxy-delta 12, 14-prostaglandin J₂(1–10 μM), but not a PPARα ligand, bezafibrate (1–10 μM), dose-dependently suppressed spontaneous ET-1 secretion from bVECs. These results, taken together, suggest that troglitazone inhibits ET-1 mRNA expression and secretion in bVECs possibly through activation of PPARγ. This inhibition may contribute to the hypotensive effect of troglitazone in insulin-resistant subjects.