© 1995 American Heart Association, Inc.
Articles |
Estrogen Relaxes Coronary Arteries by Opening BKCa Channels Through a cGMP-Dependent Mechanism
From the Department of Physiology & Biophysics, Wright State University School of Medicine, Dayton, Ohio.
Correspondence to Richard E. White, PhD, Department of Physiology and Biophysics, Room 158 Biological Science Bldg, Wright State University School of Medicine, Dayton, OH 45435. E-mail rwhite@sirius.bio.wright.edu
Abstract Women rarely suffer cardiovascular
dysfunction before menopause, but by the age of 65 a woman becomes as
vulnerable to cardiovascular mortality as a man. It has
been proposed that estrogens protect against
cardiovascular disease; however, the
physiological basis of estrogen protection is
unknown. In the present study the mechanism of estrogen-induced
relaxation of coronary arteries was investigated at the tissue,
cellular, and molecular levels. Tissue studies demonstrated that
17ß-estradiol relaxes porcine coronary arteries by an
endothelium-independent mechanism involving
K+ efflux, and subsequent studies employing the
patch-clamp technique confirmed that estrogen stimulates
K+ channel gating in coronary smooth muscle.
Perforated-patch recordings from metabolically
intact coronary myocytes revealed that 17ß-estradiol more
than doubles steady state outward currents in these cells at positive
voltages. Studies of on-cell patches demonstrated a potent
stimulatory effect of 17ß-estradiol on the gating of the
large-conductance, Ca2+- and
voltage-activated K+ (BKCa)
channels, while 17
-estradiol had no effect. Furthermore,
blocking BKCa channels in intact arteries inhibited
estrogen-induced relaxation. The effect of 17ß-estradiol on
BKCa channels was blocked by inhibiting cGMP-dependent
protein kinase (PKG) activity and was mimicked by exogenous cGMP or by
stimulating PKG activity. Therefore, we propose that
17ß-estradiol relaxes coronary arteries by opening
BKCa channels via cGMP-dependent
phosphorylation. This novel mechanism could account for
the hypotensive effect of estrogens and help explain, at least in part,
why postmenopausal estrogen therapy lowers the risk of
cardiovascular disease.
Key Words: estradiol • coronary artery • BKCa channel • cGMP • Ca2+-activated K+ channel
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|
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|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
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|
|
|
 |
|
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|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
 |
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
 |
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
 |
|
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|
|
|
|
|
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|
|
|
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|
|
|
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