Homocysteinemia is a major and independent risk factor for vascular disease. Oxidative stress is a possible mechanism for homocysteine (HCY)-induced vascular disease. Herein, we evaluated the antioxidant property of melatonin (MLT) in relation to the vasoconstrictive effect of HCY on the human umbilical artery. Helical umbilical arterial strips without endothelium were obtained at elective Cesarean delivery near term. Changes in potassium chloride (KCl)-induced vasoconstriction were measured. Arterial strips were treated with HCY (10 or 100 muM) plus FeSO4 (10 muM) alone or pretreated with a hydroxyl radical ((OH)-O-.) scavenger, mannitol (20 mM), or MLT (1 or 10 muM). The effect of HCY on the response of arterial strips to external calcium (Ca2+) in the presence of KCI (20 mM) was determined. HCY plus FeSO4 potentiated KCl-induced vasoconstriction in a concentration-dependent manner; pretreatment with mannitol sig nificantly reduced this vasospastic effect. HCY (100 muM) significantly augmented the contractile response to external Ca2+. MLT (10 muM) significantly suppressed the contractile response to external Ca2+. These results suggest that HCY potentiates KCl-induced umbilical artery vasoconstriction, in part by increasing Ca2+ influx in vascular smooth muscle cells via activation of Ca2+ channels. MLT significantly suppressed the vasoconstrictive effect of HCY, probably by scavenging (OH)-O-. arising from HCY autooxidation.