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.
Simoncini
T
T
Molecular and Cellular Gynecological Endocrinology Laboratory (MCGEL), Department of Reproductive Medicine and Child Development, Division of Obstetrics and Gynecology, University of Pisa, Via Roma 57, Pisa 56100, Italy. t.simoncini@obgyn.med.unipi.it
Fu
X-D
XD
Caruso
A
A
Garibaldi
S
S
Baldacci
C
C
Giretti
M S
MS
Mannella
P
P
Flamini
M I
MI
Sanchez
A M
AM
Genazzani
A R
AR
D000450:Aldosterone / Q000494:pharmacology; D000730:Androstadienes / Q000494:pharmacology; D000736:Androstenes / Q000494:pharmacology*; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology; D004789:Enzyme Activation; D004958:Estradiol / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D017258:Medroxyprogesterone Acetate / Q000494:pharmacology; D015735:Mifepristone / Q000494:pharmacology; D009569:Nitric Oxide / Q000096:biosynthesis; D052250:Nitric Oxide Synthase Type III / Q000187:drug effects / Q000378:metabolism*; D011374:Progesterone / Q000494:pharmacology; D018161:Receptors, Mineralocorticoid / Q000187:drug effects*; D011980:Receptors, Progesterone / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D000077191:Wortmannin
D000730:Androstadienes; D000736:Androstenes; D005419:Flavonoids; D018161:Receptors, Mineralocorticoid; D011980:Receptors, Progesterone; D009569:Nitric Oxide; D015735:Mifepristone; D000450:Aldosterone; D011374:Progesterone; D004958:Estradiol; D017258:Medroxyprogesterone Acetate; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; C035144:drospirenone; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; D000077191:Wortmannin