Drospirenone increases endothelial nitric oxide synthesis via a combined action on progesterone and mineralocorticoid receptors.

BACKGROUND Progestins have actions on the cardiovascular system, which depend on the structure as well as on receptor binding characteristics. Drospirenone (DRSP) is a progestin that uniquely interferes with the signaling of the mineralocorticoid receptor (MR). Hormone therapy containing DRSP results in blood pressure reduction in hypertensive post-menopausal women. METHODS We describe the effects of DRSP on endothelial nitric oxide (NO) synthesis and compare them with those of progesterone (P) and of medroxyprogesterone acetate (MPA). In addition, we herein tested the relevance of the anti-mineralocorticoid activity of DRSP for NO synthesis. RESULTS DRSP results in rapid activation of the endothelial NO synthase (eNOS) through mitogen-activated protein kinases and phosphatidylinositol 3-kinase as well as in enhanced eNOS expression. These actions depend on P receptor. When the cells are exposed to aldosterone, a reduction of eNOS expression is found that is antagonized by DRSP. This action is not shared by P or MPA. In addition, DRSP does not interfere with the induction or activation of eNOS induced by estradiol, as opposed to MPA. CONCLUSIONS DRSP acts on endothelial cells via a combined action through the P and MRs. These results help to interpret the anti-hypertensive effects of hormonal therapies containing DRSP.