ESTROGEN RELAXATION OF CORONARY-ARTERY SMOOTH-MUSCLE IS MEDIATED BY NITRIC-OXIDE AND CGMP

Estrogens are proposed to exert protection against cardiovascular dise ase, and evidence now suggests that this protection involves a direct vasodilatory effect. We have shown previously that estrogen relaxes en dothelium-denuded porcine coronary arteries by opening the large-condu ctance calcium- and voltage-activated potassium (BKCa) channel of myoc ytes through guanosine 3',5'-cyclic monophosphate (cGMP)-dependent pho sphorylation (35). The present study confirms these results and now de monstrates that this mechanism involves production of nitric oxide (NO ). S-nitroso-N-acetylpenicillamine (SNAP), an NO donor, or 8-bromo-cGM P mimicked the effect of estrogen on BKCa channels. Furthermore, inhib ition of NO synthase (NOS) attenuated estrogen- or tamoxifen-induced B KCa-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 BKc, channels. Furthermore, 17 be ta-estradiol stimulated accumulation of nitrite and cGMP in coronary m yocytes. Therefore, we propose that the vasodilatory effect of estroge n on the coronary circulation is mediated by NO. A portion of the bene ficial cardiovascular effects of estrogen may be attributed to relaxat ion of vascular smooth muscle by a process that involves NO- and cGMP- dependent stimulation of BKCa channels.