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(Circulation Research. 2005;97:354.)
© 2005 American Heart Association, Inc.

Cellular Biology

Mitochondria-Derived Reactive Oxygen Species Dilate Cerebral Arteries by Activating Ca²⁺ Sparks

Qi Xi, Sergei Y. Cheranov, Jonathan H. Jaggar

From the Department of Physiology, University of Tennessee Health Science Center, Memphis, Tenn.

Correspondence to Dr Jonathan H. Jaggar, Department of Physiology, University of Tennessee Health Science Center, 894 Union Ave, Nash Bldg, Memphis, TN 38163. E-mail jjaggar{at}physio1.utmem.edu

Mitochondria regulate intracellular calcium (Ca²⁺) signals in smooth muscle cells, but mechanisms mediating these effects, and the functional relevance, are poorly understood. Similarly, antihypertensive ATP-sensitive potassium (K_ATP) channel openers (KCOs) activate plasma membrane K_ATP channels and depolarize mitochondria in several cell types, but the contribution of each of these mechanisms to vasodilation is unclear. Here, we show that cerebral artery smooth muscle cell mitochondria are most effectively depolarized by diazoxide (–15%, tetramethylrhodamine [TMRM]), less so by levcromakalim, and not depolarized by pinacidil. KCO-induced mitochondrial depolarization increased the generation of mitochondria-derived reactive oxygen species (ROS) that stimulated Ca²⁺ sparks and large-conductance Ca²⁺-activated potassium (K_Ca) channels, leading to transient K_Ca current activation. KCO-induced mitochondrial depolarization and transient K_Ca current activation were attenuated by 5-HD and glibenclamide, K_ATP channel blockers. MnTMPyP, an antioxidant, and Ca²⁺ spark and K_Ca channel blockers reduced diazoxide-induced vasodilations by >60%, but did not alter dilations induced by pinacidil, which did not elevate ROS. Data suggest diazoxide drives ROS generation by inducing a small mitochondrial depolarization, because nanomolar CCCP, a protonophore, similarly depolarized mitochondria, elevated ROS, and activated transient K_Ca currents. In contrast, micromolar CCCP, or rotenone, an electron transport chain blocker, induced a large mitochondrial depolarization (–84%, TMRM), reduced ROS, and inhibited transient K_Ca currents. In summary, data demonstrate that mitochondria-derived ROS dilate cerebral arteries by activating Ca²⁺ sparks, that some antihypertensive KCOs dilate by stimulating this pathway, and that small and large mitochondrial depolarizations lead to differential regulation of ROS and Ca²⁺ sparks.

Key Words: vascular smooth muscle • ryanodine receptor • vasodilation • redox

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