A PROPOSED MECHANISM FOR THE CARDIOPROTECTIVE EFFECT OF ESTROGEN IN WOMEN - ENHANCED ENDOTHELIAL NITRIC-OXIDE RELEASE DECREASES CORONARY-ARTERY REACTIVITY

1. During their reproductive years women have a much lower incidence o f coronary heart disease than men of similar age. A cardioprotective e ffect of circulating oestrogen appears to be responsible for this decr ease in cardiovascular mortality in women. 2. Oestrogen can enhance ni tric oxide (NO) production by the vacular endothelium, possibly throug h enhanced production of the enzyme NO synthase. 3. Pressure-induced c onstrictions in isolated coronary arteries from rats with physiologica l circulating levels of oestrogen are reduced compared to oestrogen-de ficient animals. This difference is abolished by endothelial removal o r inhibition of NO synthase. 4. NO through stimulation of guanylyl cyc lase increases levels of the cytosolic second messenger cyclic GMP (cG MP) which activates a cGMP-dependent protein kinase in vascular smooth muscle cells. 5. Potassium currents through calcium-activated channel s in vascular smooth muscle cells are increased in response to NO or u pon exposure to cCMP-dependent protein kinase. 6. In rat coronary arte ries dilations to NO are reduced by agents which inhibit calcium-activ ated potassium channels. NO can also hyperpolarize this tissue, sugges ting membrane potential changes are involved in the response to NO. 7. We propose that oestrogen increases NO production leading to more neg ative membrane potentials and decreased calcium entry in coronary vasc ular smooth muscle cells.