Angiotensin II reduces the surface abundance of KV1.5 channels in arterial myocytes to stimulate vasoconstriction

Smooth muscle cells (myocytes) of resistance-size arteries express several different voltage-dependent K⁺ (K_V) channels, including K_V1.5 and K_V2.1, which regulate contractility. Myocyte K_V currents are inhibited by vasoconstrictors, including angiotensin II (Ang II), but mechanisms involved are unclear. Here, we tested the hypothesis that Ang II inhibits K_V currents by reducing the plasma membrane abundance of K_V channels in myocytes. Ang II (2 h) reduced surface and total K_V1.5 protein in rat mesenteric arteries. In contrast, Ang II did not alter total or surface K_V2.1, or K_V1.5 or K_V2.1 cellular distribution, measured as the percentage of total protein at the surface. Bisindolylmaleimide (BIM), a protein kinase C (PKC) blocker, a PKC inhibitory peptide, or bafilomycin A, a lysosomal degradation inhibitor, each blocked the Ang II-induced decrease in total and surface K_V1.5. Immunofluorescence also suggested that Ang II reduced surface K_V1.5 protein in isolated myocytes; an effect inhibited by BIM. Arteries were exposed to Ang II or Ang II plus BIM (2 h), after which these agents were removed and contractility measurements performed or myocytes isolated for patch-clamp electrophysiology. Ang II reduced both whole-cell K_V currents and currents inhibited by psora-4, a K_V1.5 channel blocker. Ang II also reduced vasoconstriction stimulated by psora-4 or 4-aminopyridine, another K_V channel inhibitor. These data indicate that Ang II activates PKC, which stimulates K_V1.5 channel degradation, leading to a decrease in surface K_V1.5, a reduction in whole-cell K_V1.5 currents and a loss of functional K_V1.5 channels in myocytes of pressurized arteries.

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