Genomic and Nongenomic Effects of Mifepristone at the Cardiovascular Level: A Review

Abstract

Mifepristone (RU 486) is a compound that is structurally related to steroid hormones, which is derived from the estrane progestins. This compound strongly binds the progesterone and glucocorticoid receptor and, to a lesser extent, the androgen receptor. This compound has its effects through different signaling pathways, related to genomic and nongenomic effects. The genomic effect involves the activation or blockage of nuclear or intracellular receptor, that in this case the progesterone, glucocorticoid, and androgen receptors. On the contrary, the nongenomic effect of mifepristone is independent of the activation of these receptors. Regarding the nongenomic, several authors observed that mifepristone induces higher uterine artery blood flow probably due to the decrease in serum nitric oxide level. Moreover, recently it has been demonstrated that mifepristone induces relaxation, and this effect is independent of the endothelium and due to the activation of the calcium channels. The main side effects associated with this pathway are hemorrhage and inhibition of platelet aggregation that can lead to hypovolemia or to hypotension. Concerning the genomic effect, this drug blocks progesterone, androgens, and glucocorticoids receptors and also activates the progesterone receptor and their respective effects. The most frequently reported adverse effects of mifepristone are nausea, vomiting, hypovolemia, hypotension, amenorrhea, and infertility. The main purpose of this review is to describe the genomic and nongenomic effects of mifepristone at vascular level and describe some pathologies in which mifepristone is used as a treatment.

Glucocorticoid receptor activation stimulates the sodium-chloride cotransporter and influences the diurnal rhythm of its phosphorylation

“…RU486 is a steroidal antagonist of GR with greater binding affinity than the endogenous glucocorticoid. It does not bind to MR but is an effective antagonist of both the progesterone receptor (6) and the androgen receptor (14). We do not consider that androgen receptor inhibition is an important factor in the current study, since previous work has shown that orchiectomy did not affect pNCC or total protein levels (16).…”

A Look Into the Promising World of Selective Progesterone Receptor Modulators

“…Selective progesterone receptor modulators have been reported to have many potential clinical applications in female reproduction and for the therapy of several gynecological disorders. [3][4][5][6][7] In the current issue of Reproductive Sciences, 2 independent groups report their findings regarding the use, effectiveness, and safety of specific SPRMS as either a contraceptive or a therapeutic agent for ovarian endometrioma. 8,9 Kannan and colleagues focused their research on the effects of ulipristal acetate (UPA), which has been used as an emergency contraceptive and demonstrated to be efficient as an ovulation blocker.…”

Non-reproductive system effects of progesterone and its non-selective antagonists mifepristone

“…Мифепристон имеет высокое сродство как к прогестероновым (Kd < 10M), так и к глюкокортикостероидным рецепторам (Kd < 10M), таким образом оказывая двойное воздействие на ткани, содержа-щие эти рецепторы [61]. В 2012 году препарат был одобрен Управлением по контролю за пищевыми продуктами и лекар-ственными средствами (Food and Drug Administration, FDA) США для лечения синдрома Иценко-Кушинга [23]. Ряд экспер-тов рассматривают его для лечения как медикаментозно об-условленного синдрома Иценко-Кушинга, так и связанного с аденомой надпочечников [15], что, безусловно, подтверждает способность препарата ингибировать продукцию или предот-вращать биологические эффекты гормонов надпочечников.…”

“…Точный механизм негеномного влияния прогестерона на организм не установлен, хотя наличие быстрого негеномного эффекта не вызывает сомнения. Именно с негеномными эффектами прогестерона in vitro связывают усиление сократимости кар-диомиоцитов, гладкомышечных клеток и влияние на возбуди-мость нейроцитов [23].…”