The effect of docosahexaenoic acid treatment on intracellular Ca(2+) dynamics in rat vascular smooth muscle cells stimulated with 5-hydroxytryptamine (5-HT) has been investigated in order to elucidate one of the mechanisms for its beneficial effect on cardiovascular disorders. The treatment of cells with 30 microM docosahexaenoic acid for 2 days inhibited an increase in intracellular Ca(2+) concentration induced by 5-HT (10 microM) and a depolarizing concentration of KCl (80 mM). Docosahexaenoic acid treatment significantly inhibited divalent cation influx stimulated by 5-HT and KCl, as measured by Mn(2+) quenching method, whereas had no effect on 5-HT-induced Ca(2+) release from the internal stores. Docosahexaenoic acid treatment also significantly inhibited 5-HT receptor-mediated Ca(2+) influx through Ni(2+)-insensitive channels that were distinct from store-operated channels. These results suggest that the specific inhibition of intracellular Ca(2+) dynamics in vascular smooth muscle cells may contribute to the beneficial properties of docosahexaenoic acid on cardiovascular disorders.