Effect of Proteasome Pathway on Initiation of Mouse Labor Induced by Antiprogesterone

Kimura, Tadashi; Nakamura, Hitomi; Ogita, Kazuhide; Koyama, Shinsuke; Tomiie, Mari; Yoshida, Susumu; Tsutsui, Tateki; Shimoya, Koichiro; Koyama, Masayasu; Murata, Yuji

doi:10.1111/j.1600-0897.2004.00226.x

Cited by 5 publications

(3 citation statements)

References 26 publications

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“…Here, we specifically assessed the ability of CyPPA to delay preterm parturition in mice induced with the progesterone receptor antagonist RU486. This method reliably induced preterm birth because 100% of control (RU486 ϩ vehicle) animals delivered within 20 h of injection, concordant with previous studies utilizing this model (8,11,18,25,26). We employed DPC 16 mice since induction at earlier gestation times was associated with pup resorption in pilot studies.…”

Section: Discussionsupporting

confidence: 49%

CyPPA, a positive modulator of small-conductance Ca²⁺-activated K⁺ channels, inhibits phasic uterine contractions and delays preterm birth in mice

Skarra

Cornwell

Solodushko

et al. 2011

American Journal of Physiology-Cell Physiology

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Skarra DV, Cornwell T, Solodushko V, Brown A, Taylor MS. CyPPA, a positive modulator of small-conductance Ca 2ϩ -activated K ϩ channels, inhibits phasic uterine contractions and delays preterm birth in mice. Am J Physiol Cell Physiol 301: C1027-C1035, 2011. First published July 27, 2011; doi:10.1152/ajpcell.00082.2011.-Organized uterine contractions, including those necessary for parturition, are dependent on calcium entry through voltage-gated calcium channels in myometrial smooth muscle cells. Recent evidence suggests that small-conductance Ca 2ϩ -activated potassium channels (K Ca 2), specifically isoforms K Ca2.2 and 2.3, may control these contractions through negative feedback regulation of Ca 2ϩ entry. We tested whether selective pharmacologic activation of K Ca2.2/2.3 channels might depress uterine contractions, providing a new strategy for preterm labor intervention. Western blot analysis and immunofluorescence microscopy revealed expression of both KCa2.2 and KCa2.3 in the myometrium of nonpregnant (NP) and pregnant (gestation day 10 and 16; D10 and D16, respectively) mice. Spontaneous phasic contractions of isolated NP, D10, and D16 uterine strips were all suppressed by the KCa2.2/2.3-selective activator CyPPA in a concentration-dependent manner. This effect was antagonized by the selective KCa2 inhibitor apamin. Whereas CyPPA sensitivity was reduced in D10 and D16 versus NP strips (pIC50 5.33 Ϯ 0.09, 4.64 Ϯ 0.03, 4.72 Ϯ 0.10, respectively), all contractions were abolished between 30 and 60 M. Blunted contractions were associated with CyPPA depression of spontaneous Ca 2ϩ events in myometrial smooth muscle bundles. Augmentation of uterine contractions with oxytocin or prostaglandin F2␣ did not reduce CyPPA sensitivity or efficacy. Finally, in an RU486-induced preterm labor model, CyPPA significantly delayed time to delivery by 3.4 h and caused a 2.5-fold increase in pup retention. These data indicate that pharmacologic stimulation of myometrial KCa2.2/2.3 channels effectively suppresses Ca 2ϩ -mediated uterine contractions and delays preterm birth in mice, supporting the potential utility of this approach in tocolytic therapies.

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Section: Discussionsupporting

confidence: 49%

CyPPA, a positive modulator of small-conductance Ca²⁺-activated K⁺ channels, inhibits phasic uterine contractions and delays preterm birth in mice

Skarra

Cornwell

Solodushko

et al. 2011

American Journal of Physiology-Cell Physiology

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“…Proteolysis has been reported to occur during labor in rats, possibly changing amino acid concentrations in the umbilical arteries more than in the umbilical vein (32). However, this phenomenon would not be sufficient to explain the high amino acid concentration observed in the intervillous space of preterm placentas.…”

Section: Discussionmentioning

confidence: 98%

Plasma amino acids in pregnancy, placental intervillous space and preterm newborn infants

Camelo

Martinez

Gonçalves

et al. 2007

Braz J Med Biol Res

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Plasma amino acid levels have never been studied in the placental intervillous space of preterm gestations. Our objective was to determine the possible relationship between plasma amino acids of maternal venous blood (M), of the placental intervillous space (PIVS) and of the umbilical vein (UV) of preterm newborn infants. Plasma amino acid levels were analyzed by ion-exchange chromatography in M from 14 parturients and in the PIVS and UV of their preterm newborn infants. Mean gestational age was 34 ± 2 weeks, weight = 1827 ± 510 g, and all newborns were considered adequate for gestational age. The mean Apgar score was 8 and 9 at the first and fifth minutes. Plasma amino acid values were significantly lower in M than in PIVS (166%), except for aminobutyric acid. On average, plasma amino acid levels were significantly higher in UV than in M (107%) and were closer to PIVS than to M values, except for cystine and aminobutyric acid (P < 0.05). Comparison of the mean plasma amino acid concentrations in the UV of preterm to those of term newborn infants previously studied by our group showed no significant difference, except for proline (P < 0.05), preterm > term. These data suggest that the mechanisms of active amino acid transport are centralized in the syncytiotrophoblast, with their passage to the fetus being an active bidirectional process with asymmetric efflux. PIVS could be a reserve amino acid space for the protection of the fetal compartment from inadequate maternal amino acid variations. Correspondence

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“…Bilateral ovariectomy or administration of a progesterone antagonist (RU-486) induces uterine oxytocin receptor and connexin-43 and leads to pup delivery within 16–24 hours in the Cox-1, cPLA 2 and PGF2α receptor KO mice. Administration of PGF2α also induces delivery in the Cox-1 and cPLA 2 KO mice [10,11,16,19,21-23]. Since some parturition-related genes have low levels in these murine models that deliver their pups late but are increased to normal after labor is induced, we hypothesized that the Cox-1 KO mouse model of delayed parturition will be useful in identifying other genes important in the parturition pathway.…”

Section: Introductionmentioning

confidence: 99%

Identification of 9 uterine genes that are regulated during mouse pregnancy and exhibit abnormal levels in the cyclooxygenase-1 knockout mouse

Zhao

Koon

Curtis

et al. 2007

Reprod Biol Endocrinol

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Background: Preterm birth is the leading cause of all infant mortality. In 2004, 12.5% of all births were preterm. In order to understand preterm labor, we must first understand normal labor. Since many of the myometrial changes that occur during pregnancy are similar in mice and humans and mouse gestation is short, we have studied the uterine genes that change in the mouse during pregnancy. Here, we used microarray analysis to identify uterine genes in the gravid mouse that are differentially regulated in the cyclooxygenase-1 knockout mouse model of delayed parturition.

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Effect of Proteasome Pathway on Initiation of Mouse Labor Induced by Antiprogesterone

Abstract: Proteolysis by proteasomes in the uterus regulates the initiation of labor, at least in part, via control of contraction-associated molecules such as FP.

Cited by 5 publications

References 26 publications

CyPPA, a positive modulator of small-conductance Ca²⁺-activated K⁺ channels, inhibits phasic uterine contractions and delays preterm birth in mice

CyPPA, a positive modulator of small-conductance Ca²⁺-activated K⁺ channels, inhibits phasic uterine contractions and delays preterm birth in mice

Plasma amino acids in pregnancy, placental intervillous space and preterm newborn infants

Identification of 9 uterine genes that are regulated during mouse pregnancy and exhibit abnormal levels in the cyclooxygenase-1 knockout mouse

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Effect of Proteasome Pathway on Initiation of Mouse Labor Induced by Antiprogesterone

Abstract: Proteolysis by proteasomes in the uterus regulates the initiation of labor, at least in part, via control of contraction-associated molecules such as FP.

Cited by 5 publications

References 26 publications

CyPPA, a positive modulator of small-conductance Ca2+-activated K+ channels, inhibits phasic uterine contractions and delays preterm birth in mice

CyPPA, a positive modulator of small-conductance Ca2+-activated K+ channels, inhibits phasic uterine contractions and delays preterm birth in mice

Plasma amino acids in pregnancy, placental intervillous space and preterm newborn infants

Identification of 9 uterine genes that are regulated during mouse pregnancy and exhibit abnormal levels in the cyclooxygenase-1 knockout mouse

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Product

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CyPPA, a positive modulator of small-conductance Ca²⁺-activated K⁺ channels, inhibits phasic uterine contractions and delays preterm birth in mice

CyPPA, a positive modulator of small-conductance Ca²⁺-activated K⁺ channels, inhibits phasic uterine contractions and delays preterm birth in mice