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Modulation of the molecular composition of large conductance, Ca2+ activated K+ channels in vascular smooth muscle during hypertension
Gregory C. Amberg, … , Mark T. Nelson, Luis F. Santana
Gregory C. Amberg, … , Mark T. Nelson, Luis F. Santana
Published September 1, 2003
Citation Information: J Clin Invest. 2003;112(5):717-724. https://doi.org/10.1172/JCI18684.
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Article Cardiology

Modulation of the molecular composition of large conductance, Ca2+ activated K+ channels in vascular smooth muscle during hypertension

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Abstract

Hypertension is a clinical syndrome characterized by increased vascular tone. However, the molecular mechanisms underlying vascular dysfunction during acquired hypertension remain unresolved. Localized intracellular Ca2+ release events through ryanodine receptors (Ca2+ sparks) in the sarcoplasmic reticulum are tightly coupled to the activation of large-conductance, Ca2+-activated K+ (BK) channels to provide a hyperpolarizing influence that opposes vasoconstriction. In this study we tested the hypothesis that a reduction in Ca2+ spark–BK channel coupling underlies vascular smooth muscle dysfunction during acquired hypertension. We found that in hypertension, expression of the β1 subunit was decreased relative to the pore-forming α subunit of the BK channel. Consequently, the BK channels were functionally uncoupled from Ca2+ sparks. Consistent with this, the contribution of BK channels to vascular tone was reduced during hypertension. We conclude that downregulation of the β1 subunit of the BK channel contributes to vascular dysfunction in hypertension. These results support the novel concept that changes in BK channel subunit composition regulate arterial smooth muscle function.

Authors

Gregory C. Amberg, Adrian D. Bonev, Charles F. Rossow, Mark T. Nelson, Luis F. Santana

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Figure 3

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Functional and pharmacologic properties of single BK channels indicate d...
Functional and pharmacologic properties of single BK channels indicate decreased β1 subunit function in HT myocytes. (a) Ca2+sensitivity of BK channels in inside-out patches (HP = –40 mV) from NT and HT myocytes. Shown to the left are representative single BK channel records taken from NT and HT patches in the presence of 1 or 10 μM Ca2+. The bar plot to the right shows the mean ± SEM Po of BK channels in NT and HT patches at three Ca2+ concentrations. (b) Open-time analysis of BK channels in inside-out patches from NT and HT myocytes. Shown to the left are representative single BK channel records taken from NT and HT patches at +40 mV in the presence of 1 μM Ca2+. The open-time histograms of these BK channels from NT and HT myocytes are shown in the center. Histograms were fitted with a single exponential function. The bar plot to the right shows the mean ± SEM τopen of BK channels in NT and HT cells. (c) Tam (1 μM) sensitivity of BK channels in inside-out patches (HP = +40 mV; 100 nM free Ca2+) from NT and HT myocytes. Shown to the left are representative single BK channel records taken from NT and NT before and after the application of Tam. The bar plot to the right shows the mean ± SEM fold change in the Po of BK channels in NT and HT cells after the application of Tam. (d) Number of BK channels per patch. Dashed lines indicate open channels. o, open channel; c, closed channel. *P < 0.05.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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