TNF- dilates cerebral arteries via NAD(P)H oxidase-dependent Ca2 spark activation

sion of TNF-, a pleiotropic cytokine, is elevated during stroke and cerebral ischemia. TNF- regulates arterial diameter, although mech-anisms mediating this effect are unclear. In the present study, we tested the hypothesis that TNF- regulates the diameter of resistance-sized (150-m diameter) cerebral arteries by modulating local and global intracellular Ca2 signals in smooth muscle cells. Laser-scanning confocal imaging revealed that TNF- increased Ca2 spark and Ca2 wave frequency but reduced global intracellular Ca2 concentration ([Ca2]i) in smooth muscle cells of intact arteries. TNF- elevated reactive oxygen species (ROS) in smooth muscle cells of intact arteries, and this increase was prevented by apocynin or diphenyleneiodonium (DPI), both of which are NAD(P)H oxidase blockers, but was unaffected by inhibitors of other ROS-generating enzymes. In voltage-clamped (40 mV) cells, TNF- increased the frequency and amplitude of Ca2 spark-induced, large-conductance