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(Circulation Research. 2007;101:493.)
© 2007 American Heart Association, Inc.

Cellular Biology

Hypersensitivity of BK_Ca to Ca²⁺ Sparks Underlies Hyporeactivity of Arterial Smooth Muscle in Shock

Guiling Zhao, Yan Zhao^*, Bingxing Pan^*, Jie Liu, Xuliang Huang, Xiuqin Zhang, Chunmei Cao, Ning Hou, Caihong Wu, Ke-seng Zhao, Heping Cheng

From the Departments of Pathophysiology (G.Z., B.P., J.L., X.H., K.-s.Z) and Physiology (G.Z., Y.Z.), Southern Medical University, Guangzhou, China; and Institute of Molecular Medicine (X.Z., C.C., N.H., C.W., H.C.), Peking University, Beijing, China.

Correspondence to Dr Ke-seng Zhao, Southern Medical University, Department of Pathophysiology, Guangzhou 510515, China. E-mail zhaoks1937{at}jhyahoo.com

Large conductance Ca²⁺-activated K⁺ channels (BK_Ca) play a critical role in blood pressure regulation by tuning the vascular smooth muscle tone, and hyposensitivity of BK_Ca to Ca²⁺ sparks resulting from its altered ß1 subunit stoichiometry underlies vasoconstriction in animal models of hypertension. Here we demonstrate hypersensitivity of BK_Ca to Ca²⁺ sparks that contributes to hypotension and blunted vasoreactivity in acute hemorrhagic shock. In arterial smooth muscle cells under voltage-clamp conditions (0 mV), the amplitude and duration, but not the frequency, of spontaneous transient outward currents of BK_Ca origin were markedly enhanced in hemorrhagic shock, resulting in a 265% greater hyperpolarizing current. Concomitantly, subsurface Ca²⁺ spark frequency was either unaltered (at 0 mV) or decreased in hyperpolarized resting cells. Examining the relationship between spark and spontaneous transient outward current amplitudes revealed a hypersensitive BK_Ca activity to Ca²⁺ spark in hemorrhagic shock, whereas the spark–spontaneous transient outward current coupling fidelity was near unity in both groups. Importantly, we found an acute upregulation of the ß1 subunit of the channel, and single-channel recording substantiated BK_Ca hypersensitivity at micromolar Ca²⁺, which promotes the and ß1 subunit interaction. Treatment of shock animals with the BK_Ca inhibitors iberiotoxin and charybdotoxin partially restored vascular membrane potential and vasoreactivity to norepinephrine and blood reinfusion. Thus, the results underscore a dynamic regulation of the BK_Ca–Ca²⁺ spark coupling and its therapeutic potential in hemorrhagic shock–associated vascular disorders.

Key Words: Ca²⁺ sparks • Ca²⁺-activated K⁺ channels • vascular reactivity • hemorrhagic shock

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Stoking Up BK_Ca Channels in Hemorrhagic Shock: Which Channel Subunit Is Really Fueling the Fire?

Lucie H. Clapp and Nelson N. Orie
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