Transient receptor potential vanilloid 1 (TRPV1) is a Ca(2+)-permeable cation channel activated by a variety of physicochemical stimuli. The effect of hypoxia (P(O(2)), 3%) on rat TRPV1 overexpressed in HEK293T has been studied. The basal TRPV1 current (I (TRPV1)) was partly activated by hypoxia, whereas capsaicin-induced TRPV1 (I (TRPV1,Cap)) was attenuated. Such changes were also suggested from hypoxia- and capsaicin-induced Ca(2+) signals in TRPV1-expressing cells. Regarding plausible changes of reactive oxygen species (ROS) under hypoxia, the effects of antioxidants, vitamin C and tiron, as membrane-impermeable and -permeable, respectively, were tested. Both I (TRPV1) and I (TRPV1,Cap) were increased by vitamin C, while only I (TRPV1) was slightly increased by tiron. The hypoxic inhibition of I (TRPV1,Cap) was still persistent under hypoxia/vitamin C. Interestingly, hypoxia/tiron strongly inhibited both I (TRPV1) and I (TRPV1,Cap). Also, with vitamin C applied through a pipette solution, hypoxia inhibited I (TRPV1) and I (TRPV1,Cap). In contrast, hypoxia and hypoxia/tiron had no effect on the I (TRPV1) induced by acid (pH 6.2, I (TRPV1,Acid)). Taken together, hypoxia partly activated TRPV1 while it decreased their sensitivity to capsaicin. Putative changes of ROS under hypoxia might underlie the side-specific effects of ROS on TRPV1: inhibitory at the extracellular and stimulatory at the intracellular side, respectively. The differential effects of hypoxia on I (TRPV1,Cap) and I (TRPV1,Acid) suggested that the intracellular ROS increase might attenuate the pharmacological potency of capsaicin.