Reduced vascular smooth muscle BK channel current underlies heart failure-induced vasoconstriction in mice.

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.

Citation

Elaine Wan, Jared S Kushner, Sergey Zakharov, Xiao-Wei Nui, Neelesh Chudasama, Christopher Kelly, Marc Waase, Darshan Doshi, Guoxia Liu, Shinichi Iwata, Takayuki Shiomi, Alexander Katchman, Jeanine D'Armiento, Shunichi Homma, Steven O Marx. Reduced vascular smooth muscle BK channel current underlies heart failure-induced vasoconstriction in mice. FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 2013 May;27(5):1859-67

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PMID: 23325318

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