Circulation Research. 2003;93:965-971
Published online before print October 9, 2003, doi: 10.1161/01.RES.0000100068.43006.36
Published online before print October 9, 2003, doi: 10.1161/01.RES.0000100068.43006.36
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© 2003 American Heart Association, Inc.
Cellular Biology |
Downregulation of the BK Channel ß1 Subunit in Genetic Hypertension
From the Department of Physiology and Biophysics, University of Washington, Seattle, Wash.
Correspondence to L.F. Santana, Department of Physiology and Biophysics, University of Washington, Box 357290, Seattle, WA 98195. E-mail santana{at}u.washington.edu
The molecular mechanisms underlying increased arterial tone during hypertension are unclear. In vascular smooth muscle, localized Ca2+ release events through ryanodine-sensitive channels located in the sarcoplasmic reticulum (Ca2+ sparks) activate large-conductance, Ca2+-sensitive K+ (BK) channels. Ca2+ sparks and BK channels provide a negative feedback mechanism that hyperpolarizes smooth muscle and thereby opposes vasoconstriction. In this study, we examined Ca2+ sparks and BK channel function in Wistar-Kyoto (WKY) rats with borderline hypertension and in spontaneously hypertensive rats (SHR), a widely used genetic model of severe hypertension. We found that the amplitude of spontaneous BK currents in WKY and SHR cells were smaller than in normotensive cells even though Ca2+ sparks were of similar magnitude. BK channels in WKY and SHR cells were less sensitive to physiological changes in intracellular Ca2+ than normotensive cells. Our data indicate that decreased expression of the BK channel ß1 subunit underlies the lower Ca2+ sensitivity of BK channels in SHR and WKY myocytes. We conclude that the lower expression of the ß1 subunit during genetic borderline and severe hypertension reduced BK channel activity by decreasing the sensitivity of these channels to physiological changes in Ca2+. These results support the view that changes in the molecular composition of BK channels may be a fundamental event contributing to the development of vascular dysfunction during hypertension.
Key Words: Ca2+ sparks • ryanodine receptors • sarcoplasmic reticulum • iberiotoxin
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