Although the natural polyphenol resveratrol posses a direct vasorelaxant effect, its effects on cytoplasmic Ca 2+ concentration ([Ca 2+] i) in vascular cells remain still unclear. Here, we have investigated the effects of the isomers trans- and cis-resveratrol on agonist- and high-K +-induced [Ca 2+] i increases and on voltage-activated transmembrane Ca 2+ fluxes using imaging and patch-clamp techniques in vascular A7r5 myocytes. Arginine vasopressin (AVP) or angiotensin II caused a biphasic increase in [Ca 2+] i that was reduced by preincubation with trans-resveratrol and cis-resveratrol. Both isomers also reduced the agonist-induced increase in [Ca 2+] i in absence of extracellular Ca 2+. In high-K + Ca 2+-free solution, reintroduction of Ca 2+ caused a sustained rise in [Ca 2+] i that was reduced by preincubation with trans-resveratrol or cis-resveratrol. When the isomers were applied during the plateau phase of the agonist- or the high-K +-induced response, a biphasic change in [Ca 2+] i was observed: a transient reduction of the plateau (< 5 min) followed by an increase (> 10 min). Finally, trans-resveratrol and cis-resveratrol inhibited voltage-dependent L-type Ca 2+ currents ( I Ca(L)). In conclusion, resveratrol isomers exert a dual effect on [Ca 2+] i handling in A7r5 myocytes: 1) a blockade of I Ca(L) and 2) an increase in [Ca 2+] i by depletion of intracellular Ca 2+ stores (which interferes with the agonist-induced release of intracellular Ca 2+) and influx of Ca 2+, mainly due to activation of capacitative Ca 2+ entry, although other Ca 2+-permeable channels are also involved. Taken together, these effects may explain, in part, the endothelium-independent vasorelaxant effects of resveratrol in rat aorta.