A proposed mechanism for the cardioprotective effect of oestrogen in women: enhanced endothelial nitric oxide release decreases coronary artery reactivity

Abstract

1. During their reproductive years women have a much lower incidence of coronary heart disease than men of similar age. A cardioprotective effect of circulating oestrogen appears to be responsible for this decrease in cardiovascular mortality in women. 2. Oestrogen can enhance nitric oxide (NO) production by the vascular endothelium, possibly through enhanced production of the enzyme NO synthase. 3. Pressure-induced constrictions in isolated coronary arteries from rats with physiological circulating levels of oestrogen are reduced compared to oestrogen-deficient animals. This difference is abolished by endothelial removal or inhibition of NO synthase. 4. NO through stimulation of guanylyl cyclase increases levels of the cytosolic second messenger cyclic GMP (cGMP) which activates a cGMP-dependent protein kinase in vascular smooth muscle cells. 5. Potassium currents through calcium-activated channels in vascular smooth muscle cells are increased in response to NO or upon exposure to cGMP-dependent protein kinase. 6. In rat coronary arteries dilations to NO are reduced by agents which inhibit calcium-activated potassium channels. NO can also hyperpolarize this tissue, suggesting membrane potential changes are involved in the response to NO. 7. We propose that oestrogen increases NO production leading to more negative membrane potentials and decreased calcium entry in coronary vascular smooth muscle cells.