Catechol-O-Methyltransferase Expression and 2-Methoxyestradiol Affect Microtubule Dynamics and Modify Steroid Receptor Signaling in Leiomyoma Cells

CONTEXT: Development of optimal medicinal treatments of uterine leiomyomas represents a significant challenge. 2-Methoxyestradiol (2ME) is an endogenous estrogen metabolite formed by sequential action of CYP450s and catechol-O-methyltransferase (COMT). Our previous study demonstrated that 2ME is a potent antiproliferative, proapoptotic, antiangiogenic, and collagen synthesis inhibitor in human leiomyomas cells (huLM). OBJECTIVES: Our objectives were to investigate whether COMT expression, by the virtue of 2ME formation, affects the growth of huLM, and to explore the cellular and molecular mechanisms whereby COMT expression or treatment with 2ME affect these cells. RESULTS: Our data demonstrated that E(2)-induced proliferation was less pronounced in cells over-expressing COMT or treated with 2ME (500 nM). This effect on cell proliferation was associated with microtubules stabilization and diminution of estrogen receptor alpha (ERalpha) and progesterone receptor (PR) transcriptional activities, due to shifts in their subcellular localization and sequestration in the cytoplasm. In addition, COMT over expression or treatment with 2ME reduced the expression of hypoxia-inducible factor -1alpha (HIF-1 alpha) and the basal level as well as TNF-alpha-induced aromatase (CYP19) expression. CONCLUSIONS: COMT over expression or treatment with 2ME stabilize microtubules, ameliorates E(2)-induced proliferation, inhibits ERalpha and PR signaling, and reduces HIF-1 alpha and CYP19 expression in human uterine leiomyoma cells. Thus, microtubules are a candidate target for treatment of uterine leiomyomas. In addition, the naturally occurring microtubule-targeting agent 2ME represents a potential new therapeutic for uterine leiomyomas

The effect of glyceryl trinitrate on hypertension in women with severe preeclampsia, HELLP syndrome, and eclampsia

Objective: The goal of this study is to evaluate the effect of glyceryl trinitrate (GTN) in the management of hypertension in women with preeclampsia, eclampsia, and HELLP syndrome. Study Design: Fifty five women with preeclampsia, eclampsia, and HELLP syndrome administered GTN infusion for the management of hypertension were studied. Demographic, clinical, and perinatal outcome findings were collected for analyses. We recorded initial and maintenance doses of GTN, and duration of its use in prepartum and postpartum periods. We collected systolic and diastolic blood pressures (BPs) at admission and before the administration of GTN infusion. During the GTN infusion, we calculated average diastolic and systolic blood pressures 6 hours apart on the first day, 12 hours apart on the second day, and 24 hours apart on the third day. Results: Of 55 women, 24 with severe preeclampsia, 16 with HELLP syndrome, and 15 with eclampsia were included in this study. In severe preeclampsia group, GTN infusion significantly reduced systolic and diastolic BPs beginning from the second quarter and third quarter, respectively, of first day (p < 0.05). In the HELLP syndrome group, GTN infusion significantly decreased systolic and diastolic blood pressures beginning from the third quarter and second quarter, respectively, of the first day (p < 0.05). In the eclampsia group, GTN infusion significantly reduced systolic and diastolic blood pressures beginning from the third quarter and first quarter, respectively, of the first day (p < 0.05). Conclusion: In women with severe preeclampsia, eclampsia, and HELLP syndrome, infusion of GTN can be used as an alternative agent to well-known drugs and causes no significant adverse effect to the mother and fetus

Comparison of effects of formoterol and BRL 37344 on isolated term-pregnant rat myometrial strips in vitro

This study was designed to compare the effects of beta-adrenoccptoy agonists formoterol and BRL 37344 on spontaneous contractions and the levels of cAMP and cGMP of myometrial strips isolated from timed-pregnant rats. Myometrial strips were obtained from term-pregnant Wistar albino rats (n = 12), mounted in organ baths and tested for changes in isometric tension in response to formoterol and BRL 37344. We evaluated the effect of increasing concentrations of formoterol and BRL 37344 on oxytocin-induced myometrial contractions and on contractions of myometrial smooth muscle pretreated with metoprolol, ICI 118.551 and SR 59230A (beta(1), beta(2), beta(3)-adrenoceptor antagonist, respectively, 10-6 M). Effects of formoterol and BRL 37344 on cAMP and cGMP levels in isolated myornetrial strips (n=6) were evaluated by radio immunoassay kits. Formoterol (10(-12) - 10(-8) M) and BRL 37344 (10(-11)-10(-5) M) concentration-dependently decreased the amplitude of oxytocin-induced contractions. E-max value (100%) of formoterol was increased significantly more than E-max value (70.6%) of BRL 37344 (P 0.05). Fon-noterol and BRL 37344 decreased amplitude of myometrial contractions with similar potency, but efficacy of forinoterol was better than BRL 37344. (c) 2005 Elsevier B.V. All rights reserved