Estrogen relaxation of coronary artery smooth muscle is mediated by nitric oxide and cGMP.
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.
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Department of Physiology and Biophysics, Wright State University School of Medicine, Dayton, Ohio 45435, USA.
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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
D004791:Enzyme Inhibitors; D004967:Estrogens; D015221:Potassium Channels; D019335:Nitroarginine; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D006152:Cyclic GMP; D002118:Calcium