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Based on the genetic relationship, single-channel conductance, and gating mechanisms, calcium-activated potassium (KCa) channels identified in vasculature can be divided into 3 groups including large-conductance KCa, small, and intermediate conductance KCa. KCa channels in smooth muscle and endothelial cells are essential for the regulation of vascular tone. Vascular dysfunction under ischemia-reperfusion (I-R) or hypoxia-reoxygenation (H-R) conditions is associated with modulations of KCa channels that are attributable to multiple mechanisms. Most studies in this regard relied on the change of relaxation components sensitive to certain channel blockers to indicate the alteration of KCa channels under I-R conditions, which however provided conflicting results for the effect of I-R. The possible mechanisms involved in KCa channel modulation under I-R/H-R include overproduction of reactive oxygen species such as superoxide anion, hydrogen peroxide, and peroxynitrite, increase of intracellular H+ ion, and lactate accumulation, etc. However, more studies are necessary to further understand the discrepancies in the sensitivity of KCa channels to I-R injury in different vascular beds.