Estrogen relaxes coronary arteries by opening BKCa channels through a cGMP-dependent mechanism
White, R.E.; Darkow, D.J.; Lang, J.L.
Circulation Research 77(5): 936-942
1995
ISSN/ISBN: 0009-7330 PMID: 7554147 Document Number: 439761
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 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+ (BK-Ca) channels, while 17-alpha-estradiol had no effect. Furthermore, blocking BK-Ca channels in intact arteries inhibited estrogen-induced relaxation. The effect of 17-beta-estradiol on BK-Ca 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 BK-Ca 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.