Estrogen Relaxes Coronary Arteries by Opening BK Ca Channels Through a cGMP-Dependent Mechanism

Abstract

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 17β-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 17β-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 17β-estradiol on the gating of the large-conductance, Ca 2+ - and voltage-activated K + (BK Ca ) channels, while 17α-estradiol had no effect. Furthermore, blocking BK Ca channels in intact arteries inhibited estrogen-induced relaxation. The effect of 17β-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 17β-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.