Uterus-relaxing effect of ß2-agonists in combination with phosphodiesterase inhibitors: studies on pregnant rat in vivo and on pregnant human myometrium in vitro.

AIMS: Our aims were to examine the effects of a simultaneous stimulation of ß(2) -adrenergic receptors and inhibition of uterine phosphodiesterases (PDE), in the pregnant rat uterus in vivo and on human uterine tissue in vitro. We also set out to measure cAMP levels and detect the expressions of the isoenzymes PDE4B and PDE4D in human uterine tissue samples. MATERIAL AND METHODS: Preterm birth was induced in Sprague-Dawley rats with bacterial lipopolysaccharide. The uterine effects of terbutaline alone or in combination with rolipram were tested in vivo. Human myometrial strips from cesarean sections at full-term pregnancy and at preterm labor were stimulated with oxytocin, and the inhibitory effects of theophylline, rolipram and terbutaline were studied. The myometrial accumulation of cAMP in the presence of rolipram and terbutaline was determined by enzyme immunoassay. The expressions of PDE4B and PDE4D proteins were detected by Western blotting. RESULTS: The selective PDE4 inhibitor rolipram was more effective than the non-selective PDE inhibitor theophylline in inhibiting the oxytocin-induced contractions in the human uterus. The uterus-relaxing effects of low doses of terbutaline were markedly potentiated by rolipram, both in rats and in human tissues. The changes in uterine cAMP levels correlated with these results. At preterm labor, PDE4B was the predominant form of PDE4 expressed; at full term, PDE4D was expressed more strongly. CONCLUSIONS: A combination of selective PDE4 inhibitors and ß(2) -agonists should be considered for the treatment of preterm contractions.

Transcriptome analysis indicates an enhanced activation of adaptive and innate immunity by chlamydia-infected murine epithelial cells treated with interferon γ.

BACKGROUND: Interferon γ (IFN­Î³) is the major cytokine involved in the elimination of Chlamydia infection. Despite its importance, the combined effect of Chlamydia infection and IFN­Î³ on the gene expression of murine epithelial cells has only partially been described. METHODS: The DNA chip method was used to evaluate the impact of IFN­Î³ and both the human strain Chlamydia trachomatis L2 infection and the murine strain Chlamydia muridarum infection on the transcriptome of murine epithelial cells. RESULTS: The gene expression analysis revealed that IFN­Î³ had an enhancing effect on both the up­regulation and down­regulation of the epithelial gene expression. The influenced gene functional classes included cytokine and chemokine expression, antigen presentation, apoptosis, and genes involved in basic metabolic processes such as fatty acid oxidation. We also detected the up­regulation of various genes that could be directly antichlamydial, such as members of the p47 GTPase family, inducible nitric oxide synthase, and monokine induced by IFN­Î³ (MIG). As a functional validation of DNA chip data, we measured the antichlamydial effect of MIG on the extracellular form of Chlamydia. CONCLUSIONS: Our results show that IFN­Î³ is a key cytokine that primes epithelial cells to activate adaptive and innate immunity and to express antichlamydial effector genes both intracellularly and extracellularly.

Potentiation of the uterus-relaxing effects of ß-adrenergic agonists with nifedipine: studies on rats and the human myometrium.

OBJECTIVE: We investigated how progesterone and salmeterol modify the effect of nifedipine in an in vivo preterm birth model in rats, and how terbutaline and nifedipine modify the contractions of the isolated human myometrium. DESIGN: Experimental animal and human myometrial studies. SAMPLE: Twenty-four female Sprague-Dawley rats and 13 human uterine tissues sampled from cesarean section. METHODS: Preterm birth was induced in Sprague-Dawley rats with a combination of mifepristone and prostaglandin-E(2). The animals were treated with nifedipine or its combination with salmeterol and progesterone. Additionally, isolated human myometrial strips from cesarean sections were stimulated with oxytocin, and the inhibitory effects of nifedipine and terbutaline were studied. RESULTS: Nifedipine delayed the preterm delivery in the rats, but its effect was tripled by the addition of ß(2)-mimetics, or abolished after progesterone pretreatment. Synergism was observed in the relaxing effects of nifedipine and terbutaline on the isolated human myometrium. CONCLUSION: The action of nifedipine in delaying labor is impeded by progesterone. A combination of nifedipine and ß(2)-agonists should be considered for the treatment or prevention of preterm birth.

[Investigation of uterus-relaxing effects of nifedipine in the presence of terbutaline and K(+)-channel blockers]. / Nifedipin miometrium relaxáló hatásának vizsgálata terbutalin és K(+)-csatorna gátlók jelenlétében in vitro.

UNLABELLED: Tocolysis is one of the greatest challenges in obstetrical practice. It is known that the calcium channel antagonists abolish the intracellular calcium ion transients and myometrial contraction. However there is a growing interest in experimental studies to use different tocolytic combination. The aims of the study were to investigate the effects of nifedipine on potassium chloride (KCl)-evoked rat uterine contractions on the last day of pregnancy (22) in vitro, and the alterations in the effects of nifedipine on combination with BK(Ca-channel blockers paxillin and tetraethyl ammonium chloride in late pregnancy in vitro. An other aim was to investigate the modification of the effect of nifedipine by terbutaline on the contraction of isolated rat and human myometrium. For human myometrial rings rhythmic contractions were evoked with oxytocin in an isolated organ bath. KCl-stimulated uterine contractions were inhibited concentration-dependently by nifedipine. In the presence of the potassium channel blockers, the action of nifedipine was not modified. Synergism was observed in the uterus-relaxing effect of nifedipine and terbutaline, though the extent of potentiation depended on the sequence of the administration of the two compounds. When terbutaline was added first in a single dose, the maximal inhibitory effect of nifedipine was lower. This decrease in the inhibition was suspended by a Ca(2+)-poor buffer, indicating the role of Ca2+ channel activating effect of terbutaline. However, in the isolated organ bath studies the BK(Ca) channel had no effect on the uterus relaxing effect of nifedipine in spite of literature. CONCLUSION: It is concluded that the combination of nifedipine and beta2-agonists should be considered for clinical use. However, the administration of terbutaline can not precede the administration of nifedipine.

Long-term efficacy of transcervical endometrial resection with no preoperative hormonal preparation.

OBJECTIVE: To assess the level of patient satisfaction after transcervical endometrial resection (TCRE) with no preoperative hormonal preparation. STUDY DESIGN: A retrospective audit of a continuous case series was accomplished on 131 consecutive patients who underwent TCRE for dysfunctional uterine bleeding. Data of postal questionnaires were analysed and subjected to survival analysis. RESULTS: Thirty-three cases were lost to follow-up; thus, the data on 98 of the 131 (74.8%) patients were analysed. The average follow-up period was 94.8 months (60-132). Twenty (20.4%) women required D&C and 15 (15.3%) had hysterectomy. In eight of the 15 cases, the indication for hysterectomy was not related with the primary operation. The chance of avoiding hysterectomy reached a plateau after 72 months, at 78.3% (SE: 5.05%). The chance of avoiding D&C at up to 36 months was 98.6% (SE: 1.4%), and reached a plateau after 107 months at 67.11% (SE: 6.1%); 55.8% of the patients became amenorrhoeic, the remaining cases reporting good improvements in the amount and duration of bleeding, and dysmenorrhoea. Eighty-six of the 98 patients (88%) were satisfied or very satisfied with the result. CONCLUSIONS: TCRE affords reasonable long-term effectiveness in the treatment of dysfunctional uterine bleeding, even without any preoperative hormonal endometrial preparation.

Correlation between the alterations in the mRNA expressions of the alpha1-adrenoceptor and estrogen receptor subtypes in the pregnant human uterus and cervix.

Our present aim was to determine the association between the mRNA expressions of the estrogen and adrenoceptor subtypes in the pregnant human uterus and cervix. The presence of the mRNA expressions of all the alpha1-adrenoceptor and estrogen receptor subtypes in the uterus and cervix was proved by means of a reverse transcription polymerase chain reaction method, with a predominance of the mRNAs of the alpha1B-adrenoceptor and estrogen alpha receptors, respectively. The change in the mRNA expression of the estrogen receptor alpha correlated strongly with the change in mRNA level of the alpha1B-adrenoceptors. We presume that the expression of the alpha1B-adrenoceptors at 33-34 weeks in the pregnant human uterus is regulated by estrogen through the estrogen receptor alpha subtypes.

The roles of the alpha1-adrenergic receptor subtypes in rat embryonic implantation.

OBJECTIVE: To focus on the possible roles of alpha(1)-adrenergic receptors (alpha(1)-ARs) in rat embryonic implantation. DESIGN: Laboratory study. SETTING: Animal and pharmacology laboratory at Department of Pharmacodynamics and Biopharmacy, University of Szeged, Hungary. ANIMAL(S): Pregnant and nonpregnant Sprague-Dawley rats. INTERVENTION(S): Uterus tissues were collected during the peri-implantation period. MAIN OUTCOME MEASURE(S): We used a reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting to demonstrate the expressions of mRNAs and the protein expressions of the alpha(1)-AR subtypes in the early-pregnant uterus. Electric field stimulation was applied to test the pharmacologic reactivity of the alpha(1A)-AR, and the physiologic role of this receptor was tested in a knock-down transformed animal model using an antisense oligonucleotide that elicits sequence-selective inhibition of the alpha(1A)-AR gene expression. RESULT(S): The presence of all alpha(1)-AR subtypes (alpha(1A), alpha(1B), and alpha(1D)) was proved, with a predominance of alpha(1A)-AR. The maximal expression of the alpha(1A)-AR was attained on the day of implantation. The selective alpha(1A) antagonist 5-methylurapidil inhibited the contraction in a dose-dependent manner. The number of implantation sites was decreased ( approximately 75%) in the alpha(1A)-AR knock-down transformed rats. CONCLUSION(S): We assume that the alpha(1A)-AR predominance plays a crucial role in embryonic implantation in the rat.

Removal of a residual portion of a uterine septum in women of advanced reproductive age: obstetric outcome.

BACKGROUND: To learn more about the obstetric outcome after initial septum resection and remnant septum (< or =1 cm) resection. METHODS: In 94 patients with septate uteri who underwent uterine septum resection, the reproductive efficiency was analysed in a prospective observational study. The reproductive outcome was analysed after initial resection and (if required) consecutive procedures. RESULTS: A total of 94 women were enrolled in the study; all had had two or more miscarriages. The septum was completely removed during the first hysteroscopy in 58 (62%) cases. A residual septum was observed in 36 (38%) patients. Subsequent operative hysteroscopy was performed in the cases (29/36; 80.5%) involving repeated miscarriage and unsuccessful conception. The minimum observation time was 24 months. The difference in delivery rate after the first hysteroscopy between those with a normalized uterine cavity (26/58; 44.8%) and those with remnants (7/36; 19.4%) was statistically significant (P < 0.05). In fact, following the normalization of the uterine cavity, 62.1% (18/29) of the patients delivered, as compared with 19.4% of those (7/36) with a residue and Kaplan-Meyer curves revealed a statistically significant difference (P < 0.05). CONCLUSIONS: Women with a remnant uterine septum have an increased chance of successful pregnancy with an improved obstetric outcome after normalization of the uterine cavity.