title: Estrogen relaxation of coronary artery smooth muscle is mediated by nitric oxide and cGMP.
abstract: Estrogens are proposed to exert protection against cardiovascular disease, and evidence now suggests that this protection involves a direct vasodilatory effect. We have shown previously that estrogen relaxes endothelium-denuded porcine coronary arteries by opening the large-conductance calcium- and voltage-activated potassium (BKCa) channel of myocytes through guanosine 3',5'-cyclic monophosphate (cGMP)-dependent phosphorylation (35). The present study confirms these results and now demonstrates that this mechanism involves production of nitric oxide (NO). S-nitroso-N-acetylpenicillamine (SNAP), an NO donor, or 8-bromo-cGMP mimicked the effect of estrogen on BKCa channels. Furthermore, inhibition of NO synthase (NOS) attenuated estrogen- or tamoxifen-induced BKCa-channel activity, and this effect was disinhibited by L-arginine. Inhibition of guanylyl cyclase activity blocked the stimulatory effect of estrogen, SNAP, or L-arginine on BKCa channels. Furthermore, 17 beta-estradiol stimulated accumulation of nitrite and cGMP in coronary myocytes. Therefore, we propose that the vasodilatory effect of estrogen on the coronary circulation is mediated by NO. A portion of the beneficial cardiovascular effects of estrogen may be attributed to relaxation of vascular smooth muscle by a process that involves NO- and cGMP-dependent stimulation of BKCa channels.
authors.affiliation: Department of Physiology and Biophysics, Wright State University School of Medicine, Dayton, Ohio 45435, USA.
authors.forename: D J
authors.initials: DJ
authors.lastname: Darkow
authors.forename: L
authors.initials: L
authors.lastname: Lu
authors.forename: R E
authors.initials: RE
authors.lastname: White
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002118:Calcium / Q000502:physiology; D003331:Coronary Vessels / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D006152:Cyclic GMP / Q000502:physiology*; D004553:Electric Conductivity; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004967:Estrogens / Q000494:pharmacology*; D005260:Female; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D019335:Nitroarginine / Q000494:pharmacology; D015221:Potassium Channels / Q000502:physiology; D013552:Swine; D014664:Vasodilation
chemical_list: D004791:Enzyme Inhibitors; D004967:Estrogens; D015221:Potassium Channels; D019335:Nitroarginine; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D006152:Cyclic GMP; D002118:Calcium