Estrogen relaxes coronary arteries by opening BKCa channels through a cGMP-dependent mechanism.
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 demonstrate that 17 beta-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 17 beta-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 17 beta-estradiol on the gating of the large-conductance, Ca(2+)- and voltage-activated K+ (BKCa) channels, while 17 alpha-estradiol had no effect. Furthermore, blocking BKCa channels in intact arteries inhibited estrogen-induced relaxation. The effect of 17 beta-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 17 beta-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.
White
R E
RE
Department of Physiology and Biophysics, Wright State University School of Medicine, Dayton, OH 45435, USA.
Darkow
D J
DJ
Lang
J L
JL
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002469:Cell Separation; D003331:Coronary Vessels / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D006152:Cyclic GMP / Q000378:metabolism*; D003627:Data Interpretation, Statistical; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D004958:Estradiol / Q000494:pharmacology; D004967:Estrogens / Q000494:pharmacology*; D005260:Female; D066298:In Vitro Techniques; D008297:Male; D008954:Models, Biological; D009126:Muscle Relaxation; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000187:drug effects* / Q000378:metabolism*; D013552:Swine; D013997:Time Factors
D004967:Estrogens; D015221:Potassium Channels; D004958:Estradiol; D006152:Cyclic GMP; D002118:Calcium