Mechanism of mifepristone-induced spasmolytic effect on isolated rat uterus

Parra, Joaquín Zamarro; Cantabrana, Begoña; Hidalgo, Agustı́n

doi:10.1016/s0024-3205(00)00590-7

Cited by 7 publications

(8 citation statements)

References 37 publications

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“…The effect of RU-486 is unlikely to be a direct action on contractile proteins, because RU-486 is a progesterone nuclear receptor antagonist (19). In contrast to contraction, RU-486 actually relaxed KCl-induced contraction of rat nonpregnant uterine smooth muscle in vitro (38). In the present study, the in vitro persistent increase in contractility caused by in vivo administration of RU-486 could be a consequence of progesterone-related signal transduction or an indirect consequence resulting from labor commencing.…”

Section: Discussionmentioning

confidence: 93%

Role of ERK1/2 in uterine contractility and preterm labor in rats

Li¹,

Je²,

Malek³

et al. 2004

American Journal of Physiology-Regulatory, Integrative and Comp

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The present study tested the hypothesis that ERK activation is an essential step in the onset of labor in a rat model of preterm labor. The administration of RU-486, an antiprogesterone agent, to rats induced preterm delivery 22.2 +/- 0.24 h after treatment. Changes in basal signaling events were studied in myometrial tissue from CO(2)-euthanized rats. Rats treated with RU-486 displayed a dramatically increased in vitro uterine contractility compared with gestational stage-matched, sham-treated rats. In vitro contractility was not significantly different from that during spontaneous labor. During RU-486-induced preterm labor, as previously described for spontaneous labor, ERK phosphorylation levels increased, as did phosphorylation of caldesmon at Ser(789), an ERK phosphorylation site. Also, a small but significant increase in 20-kDa myosin light chain phosphorylation was seen at a constant intracellular pCa of 7. When rats were chronically treated with an agent that prevents ERK activation, U-0126, the onset of RU-486-induced preterm labor was delayed in a statistically significant manner. Chronic in vivo treatment with U-0126 also significantly inhibited the RU-486-induced increase in in vitro contractility and ERK and caldesmon phosphorylation but did not alter the RU-486-induced increase in 20-kDa myosin light chain phosphorylation. These data indicate that ERK activation is a component of the multiple events leading to the development of labor in this rat model. We suggest that the ERK pathway could possibly be used to identify targets for the development of a novel class of tocolytic agents.

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Section: Discussionmentioning

confidence: 93%

Role of ERK1/2 in uterine contractility and preterm labor in rats

Li¹,

Je²,

Malek³

et al. 2004

American Journal of Physiology-Regulatory, Integrative and Comp

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“…The nongenomic effects are rapid in onset and not modified by inhibitors of protein synthesis. 13,[39][40][41] Several studies (Table 1) in a variety of species, including human, have demonstrated the nongenomic effects of steroids in vitro including the modification of myocardial contractility, [52][53][54] smooth muscle contractility, 14,37,40,50,[55][56][57][58][59][60][61][62] and membrane excitability of nerve cells. 39,41,63 Concerning mifepristone, some studies have demonstrated that it decreased uterine contractility.…”

Section: Nongenomic Pathways Of Mifepristonementioning

confidence: 99%

“…9,11 Besides this action, mifepristone also can induce rapid (seconds to minutes) nongenomic effects, which are not due to changes in gene expression or protein synthesis. [12][13][14] The nongenomic effects of mifepristone are independent of the activation of classical PR. A membrane receptor can be involved and different mechanisms have been pointed to explain this effect.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2017

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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.

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“…Compounds 1 -13 were tested for the contraction of uterus rings using the following protocol: The uterus rings were contracted with depolarizing solution, and the test substances were added upon tonic contraction 20 min after stimulus; this time corresponds approximately to a plateau phase of methods previously used (Parra et al, 2000;Revuelta et al, 2000;Shimizu et al, 2000). The tested concentrations for all the compounds were 30, 10, and 3 μg/mL and were dissolved in an ethanol/DMSO (2:1) mixture in such a way that the fi nal vehicle content in the organ bath was 0.15%, demonstrating the innocuity.…”

Section: Methodsmentioning

confidence: 99%

Structure-Activity Relationships of Aromadendranes in Uterus- Relaxant Activity

Pérez‐Hernández

Ponce‐Monter

Ortiz

et al. 2009

Zeitschrift Für Naturforschung C

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Aromadendranes belong to a class of sesquiterpenes present in higher plant essential oils and marine animals. Although the biological activities include antifungal, antibacterial, antiviral, plant growth regulatory, antifeedant, repellent and cytotoxic, there is only one precedent for spasmolytic effects. In a previous report we have shown that the aromadendrene molecule known as spathulenol, isolated from Lepechinia caulescens, effi ciently relaxes rat uterus rings and therefore in the present work we describe structure-activity relationships of thirteen aromadendranes, most of them having the trans-fused perhydroazulene skeleton, with spasmolytic activity.

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Mechanism of mifepristone-induced spasmolytic effect on isolated rat uterus

Cited by 7 publications

References 37 publications

Role of ERK1/2 in uterine contractility and preterm labor in rats

Role of ERK1/2 in uterine contractility and preterm labor in rats

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

Structure-Activity Relationships of Aromadendranes in Uterus- Relaxant Activity

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