title: Reduced vascular smooth muscle BK channel current underlies heart failure-induced vasoconstriction in mice.
abstract: Excessively increased peripheral vasoconstriction is a hallmark of heart failure (HF). Here, we show that in mice with systolic HF post-myocardial infarction, the myogenic tone of third-order mesenteric resistance vessels is increased, the vascular smooth muscle (VSM) membrane potential is depolarized by ~20 mV, and vessel wall intracellular [Ca(2+)] is elevated relative to that in sham-operated control mice. Despite the increased [Ca(2+)], the frequency and amplitude of spontaneous transient outward currents (STOCs), mediated by large conductance, Ca(2+)-activated BK channels, were reduced by nearly 80% (P<0.01) and 25% (P<0.05), respectively, in HF. The expression of the BK α and β1 subunits was reduced in HF mice compared to controls (65 and 82% lower, respectively, P<0.01). Consistent with the importance of a reduction in BK channel expression and function in mediating the HF-induced increase in myogenic tone are two further findings: a blunting of paxilline-induced increase in myogenic tone in HF mice compared to controls (0.9 vs. 10.9%, respectively), and that HF does not alter the increased myogenic tone of BK β1-null mice. These findings identify electrical dysregulation within VSM, specifically the reduction of BK currents, as a key molecular mechanism sensitizing resistance vessels to pressure-induced vasoconstriction in systolic HF.
authors: Division of Cardiology, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA. sm460@columbia.edu
authors: Elaine
authors: E
authors: Wan
authors: Jared S
authors: JS
authors: Kushner
authors: Sergey
authors: S
authors: Zakharov
authors: Xiao-Wei
authors: XW
authors: Nui
authors: Neelesh
authors: N
authors: Chudasama
authors: Christopher
authors: C
authors: Kelly
authors: Marc
authors: M
authors: Waase
authors: Darshan
authors: D
authors: Doshi
authors: Guoxia
authors: G
authors: Liu
authors: Shinichi
authors: S
authors: Iwata
authors: Takayuki
authors: T
authors: Shiomi
authors: Alexander
authors: A
authors: Katchman
authors: Jeanine
authors: J
authors: D'Armiento
authors: Shunichi
authors: S
authors: Homma
authors: Steven O
authors: SO
authors: Marx
mesh_terms: D000818:Animals; D020013:Calcium Signaling; D006333:Heart Failure / Q000503:physiopathology*; D051036:Large-Conductance Calcium-Activated Potassium Channels / Q000378:metabolism*; D008297:Male; D008564:Membrane Potentials; D008638:Mesenteric Arteries / Q000502:physiology; D051379:Mice; D009131:Muscle, Smooth, Vascular / Q000502:physiology; D014655:Vascular Resistance / Q000502:physiology; D014661:Vasoconstriction / Q000502:physiology*
chemical_list: D051036:Large-Conductance Calcium-Activated Potassium Channels