Published online before print June 12, 2003, doi: 10.1161/01.RES.0000081980.63146.69
© 2003 American Heart Association, Inc.
Integrative Physiology |
Altered Expression of Small-Conductance Ca2+-Activated K+ (SK3) Channels Modulates Arterial Tone and Blood Pressure
From the Department of Pharmacology (M.S.T., A.D.B., T.P.G., D.M.E., J.E.B., M.T.N.), University of Vermont, Burlington, Vt, and Oregon Health Sciences University (C.T.B., J.P.A.), Portland, Ore.
Correspondence to Mark T. Nelson, Department of Pharmacology, University of Vermont, 89 Beaumont Ave, Burlington, VT 05405. E-mail mtnelson{at}zoo.uvm.edu
The endothelium is a critical regulator of vascular tone, and dysfunction of the endothelium contributes to numerous cardiovascular pathologies. Recent studies suggest that apamin-sensitive, small-conductance, Ca2+-activated K+ channels may play an important role in active endothelium-dependent vasodilations, and expression of these channels may be altered in disease states characterized by vascular dysfunction. Here, we used a transgenic mouse (SK3T/T) in which SK3 expression levels can be manipulated with dietary doxycycline (DOX) to test the hypothesis that the level of expression of the SK subunit, SK3, in endothelial cells alters arterial function and blood pressure. SK3 protein was elevated in small mesenteric arteries from SK3T/T mice compared with wild-type mice and was greatly suppressed by dietary DOX. SK3 was detected in the endothelium and not in the smooth muscle by immunohistochemistry. In whole-cell patch-clamp experiments, SK currents in endothelial cells from SK3T/T mice were almost completely suppressed by dietary DOX. In intact arteries, SK3 channels contributed to sustained hyperpolarization of the endothelial membrane potential, which was communicated to the arterial smooth muscle. Pressure- and phenylephrine-induced constrictions of SK3T/T arteries were substantially enhanced by treatment with apamin, suppression of SK3 expression with DOX, or removal of the endothelium. In addition, suppression of SK3 expression caused a pronounced and reversible elevation of blood pressure. These results indicate that endothelial SK3 channels exert a profound, tonic, hyperpolarizing influence in resistance arteries and suggest that the level of SK3 channel expression in endothelial cells is a fundamental determinant of vascular tone and blood pressure.
Key Words: endothelium • potassium channels • vascular tone • blood pressure
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