title: Hypersensitivity of BKCa to Ca2+ sparks underlies hyporeactivity of arterial smooth muscle in shock.
abstract: Large conductance Ca(2+)-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 Ca(2+) sparks resulting from its altered beta1 subunit stoichiometry underlies vasoconstriction in animal models of hypertension. Here we demonstrate hypersensitivity of BK(Ca) to Ca(2+) 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 Ca(2+) 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 Ca(2+) 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 beta1 subunit of the channel, and single-channel recording substantiated BK(Ca) hypersensitivity at micromolar Ca(2+), which promotes the alpha and beta1 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)-Ca(2+) spark coupling and its therapeutic potential in hemorrhagic shock-associated vascular disorders.
authors.affiliation: Department of Pathophysiology, Southern Medical University, Guangzhou, China.
authors.forename: Guiling
authors.initials: G
authors.lastname: Zhao
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhao
authors.forename: Bingxing
authors.initials: B
authors.lastname: Pan
authors.forename: Jie
authors.initials: J
authors.lastname: Liu
authors.forename: Xuliang
authors.initials: X
authors.lastname: Huang
authors.forename: Xiuqin
authors.initials: X
authors.lastname: Zhang
authors.forename: Chunmei
authors.initials: C
authors.lastname: Cao
authors.forename: Ning
authors.initials: N
authors.lastname: Hou
authors.forename: Caihong
authors.initials: C
authors.lastname: Wu
authors.forename: Ke-Seng
authors.initials: KS
authors.lastname: Zhao
authors.forename: Heping
authors.initials: H
authors.lastname: Cheng
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000502:physiology; D002118:Calcium / Q000502:physiology*; D004195:Disease Models, Animal; D005260:Female; D007022:Hypotension / Q000209:etiology / Q000503:physiopathology; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits; D008297:Male; D008564:Membrane Potentials / Q000502:physiology; D008638:Mesenteric Arteries / Q000503:physiopathology; D009131:Muscle, Smooth, Vascular / Q000503:physiopathology*; D009638:Norepinephrine / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D012771:Shock, Hemorrhagic / Q000503:physiopathology*; D015854:Up-Regulation / Q000502:physiology; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology
chemical_list: C494842:Kcnma1 protein, rat; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits; D015221:Potassium Channels; D002118:Calcium; D009638:Norepinephrine