Published online before print July 19, 2007, doi: 10.1161/CIRCRESAHA.107.157271
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Submitted on September 14, 2004
Revised on June 19, 2007
Accepted on July 9, 2007
Hypersensitivity of BKCa to Ca2+ Sparks Underlies Hyporeactivity of Arterial Smooth Muscle in Shock
Guiling Zhao ;
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 Department of Molecular Medicine (X.Z., C.C., N.H., C.W., H.C.), Peking University, Beijing, China.
* To whom correspondence should be addressed. E-mail: zhaoks1937{at}yahoo.com.
Large conductance Ca2+-activated K+ channels (BKCa) play a critical role in blood pressure regulation by tuning the vascular smooth muscle tone, and hyposensitivity of BKCa to Ca2+ sparks resulting from its altered 
1 subunit stoichiometry underlies vasoconstriction in animal models of hypertension. Here we demonstrate hypersensitivity of BKCa 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 BKCa 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 BKCa 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 1 subunit of the channel, and single-channel recording substantiated BKCa hypersensitivity at micromolar Ca2+, which promotes the 
and 1 subunit interaction. Treatment of shock animals with the BKCa 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 BKCa-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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