Role of the AT2 receptor in modulating the angiotensin II contractile response of the uterine artery at mid-gestation

Introduction: During human pregnancy, circulating concentrations of components of the renin—angiotensin system increase, but pressor refractoriness to angiotensin II (Ang-II) is observed. Given the importance of the Ang-II pressor response in deciding susceptibility to preeclampsia and of the Ang-II system for controlling uterine vasoreactivity, we sought to address the effects of pregnancy on the reactivity of the isolated uterine artery (UA) in mice. Materials and methods : Blood pressure was measured throughout pregnancy in awake C57BL/6J mice. UA segments were isolated from three groups of animals (non-pregnant, mid [day 12—13] and late [day 18—19] gestation) and studied by wire myography. Results: UA diameters, KCl-mediated responses, and acetylcholine-dependent vasorelaxation were greater at mid and late gestation than in non-pregnant animals. Ang-II responses were also greater during pregnancy, with an increased contraction in response to AT2 receptor blockade at mid-gestation. AT1 receptor blockade abolished the Ang-II response in all groups. Conclusions: Study findings are consistent with the possibility that AT2 receptor-mediated vasodilatation plays a role in modulating Ang-II contractile responses in pregnancy

Role of the AT2 receptor in modulating the angiotensin II contractile response of the uterine artery at mid-gestation

Introduction: During human pregnancy, circulating concentrations of components of the renin—angiotensin system increase, but pressor refractoriness to angiotensin II (Ang-II) is observed. Given the importance of the Ang-II pressor response in deciding susceptibility to preeclampsia and of the Ang-II system for controlling uterine vasoreactivity, we sought to address the effects of pregnancy on the reactivity of the isolated uterine artery (UA) in mice. Materials and methods : Blood pressure was measured throughout pregnancy in awake C57BL/6J mice. UA segments were isolated from three groups of animals (non-pregnant, mid [day 12—13] and late [day 18—19] gestation) and studied by wire myography. Results: UA diameters, KCl-mediated responses, and acetylcholine-dependent vasorelaxation were greater at mid and late gestation than in non-pregnant animals. Ang-II responses were also greater during pregnancy, with an increased contraction in response to AT2 receptor blockade at mid-gestation. AT1 receptor blockade abolished the Ang-II response in all groups. Conclusions: Study findings are consistent with the possibility that AT2 receptor-mediated vasodilatation plays a role in modulating Ang-II contractile responses in pregnancy

Local uterine Ang-(1-7) infusion augments the expression of cannabinoid receptors and differentially alters endocannabinoid metabolizing enzymes in the decidualized uterus of pseudopregnant rats

Background Endocannabinoids (ECs) are important contributors to implantation and decidualization and are suppressed in early pregnancy. Elevated levels of anandamide (AEA), the endogenous ligand for the CB1 and CB2 receptors (R), interfere with receptivity of the blastocyst. Ang-(1–7) is down-regulated in the implantation site (IS) in normal pregnancy at day 7 of gestation. We determined the effects of intra-uterine angiotensin-(1–7) [Ang-(1–7)] (24 microg/kg/h) or vehicle given into the left uterine horn on the ECs in the decidualized uterus. Methods Ovariectomized rats were sensitized for the decidual cell reaction by steroid treatment and decidualization was induced by a bolus of oil injected into the left horn; the right horn served as a control. Results Decidualization increased endometrial permeability (3.1+/−0.2 vs. 7.1+/−0.5 uterus/muscle of cpm of (125)I-BSA, p \u3c 0.0001). VEGF mRNA was increased by the decidualization (1.4-fold, p \u3c 0.05) and by Ang-(1–7) (2.0-fold, p \u3c 0.001). CB1R mRNA was reduced by decidualization (2.7-fold, p \u3c 0.001), but increased by Ang-(1–7) (1.9-fold, p \u3c 0.05). CB2R mRNA was increased by decidualization (4-fold, p \u3c 0.05) and by Ang-(1–7) (2.4-fold, p \u3c 0.001). The enzyme metabolizing AEA, fatty acid amide hydrolase (FAAH), was reduced by decidualization (7.8 fold, p \u3c 0.001) and unchanged by Ang-(1–7) (p \u3e 0.05), whereas the enzyme metabolizing 2-arachidonoylglycerol, monoacyl glycerol lipase (MAGL), was unchanged by decidualization (p \u3e 0.05) and increased by Ang-(1–7) (1.7 fold, p \u3c 0.001). Conclusions These findings report for the first time that Ang-(1–7) augments the expression of CB1R, CB2R and MAGL in the decidualized uterus and thus may interfere with the early events of decidualization

Local intra-uterine Ang-(1-7) infusion attenuates PGE2 and 6-keto PGF1α in decidualized uterus of pseudopregnant rats

Background: Cyclooxygenase (COX)-derived prostanoids (PGE2, PGI2) are important contributors to the process of decidualization. Previous studies showed the presence of Ang-(1-7) in the primary and secondary decidualized zones of the implantation site at early pregnancy. Decreased concentrations of Ang-(1-7) were found in the decidualized uterus compared to the non-decidualized uterus of pseudopregnant rats, suggesting that low levels of Ang-(1-7) are required for successful decidualization at early pregnancy. Methods: To understand the role of Ang-(1-7) in prostaglandin production in a decidualized uterus, induced by a bolus injection of sesame oil, Ang-(1-7) (24 μg/kg/h) or vehicle was then infused directly into the decidualized uterine horn using an osmotic minipump. The right horns were not injected or infused and served as nondecidualized uterine horns in both groups of animals. Results: Decidualization increased PGE2 concentration in the uterus (0.53±0.05 vs. 12.0±3.2 pmol/mg protein, p\u3c0.001, non-decidualized vs. decidualized horns); Ang-(1-7) infusion attenuated the increase of PGE2 (12.0± 3.2 vs. 5.1±1.3 pmol/mg protein, p\u3c0.01 control vs. Ang-(1-7) treated decidualized horns). The stable metabolite of PGI2 (6-keto PGF1α) was increased with decidualization (0.79±0.17 vs. 3.5±0.82 pmol/mg protein, p\u3c0.001, non-decidualized vs. decidualized horns). Ang-(1-7) infusion attenuated the increase in 6keto PGF1α in the decidualized horn (3.5±0.82 vs 1.8±0.37 pmol/mg protein, p\u3c0.05 control vs. Ang-(1-7) treated decidualized horns). The circulating levels of 6-keto-PGF1a and TXB2 were decreased by Ang-(1-7) infusion, while no difference was observed in circulating PGE2. Although the global assessment of cleaved caspase 3 immunostaining, a marker of apoptosis, was unchanged within the Ang-(1-7) decidualized horn, there were localized decreases in cleaved caspase 3 staining in the luminal region in the decidualized uterus of Ang-(1-7)-treated rats. Conclusions: These studies show that increased local uterine Ang-(1-7) alters the uterine prostaglandin environment, possibly leading to disruptions of early events of decidualization

Acclimatization to chronic intermittent hypoxia in mine workers: a challenge to mountain medicine in Chile

In the past two decades, Chile has developed intense mining activity in the Andes mountain range, whose altitude is over 4,000 meters above sea level. It is estimated that a workforce population of over 55,000 is exposed to high altitude hypobaric hypoxia. The miners work under shift systems which vary from 4 to 20 days at the worksite followed by rest days at sea level, in a cycle repeated for several years. This Chronic Intermittent Hypoxia (CIH) constitutes an unusual condition for workers involving a series of changes at the physiological, cellular and molecular levels attempting to compensate for the decrease in the environmental partial pressure of oxygen (PO2). The mine worker must become acclimatized to CIH, and consequently undergoes an acute acclimatization process when he reaches the worksite and an acute reverse process when he reaches sea level. We have observed that after a period of 3 to 8 years of CIH exposure workers acclimatize well, and evidence from our studies and those of others indicates that CIH induces acute and chronic multisystem adjustments which are effective in offsetting the reduced availability of oxygen at high altitudes. The aims of this review are to summarize findings of the physiological responses to CIH exposure, highlighting outstanding issues in the field

The estrogenicity of bisphenol A-related diphenylalkanes with various substituents at the central carbon and the hydroxy groups

This work was reported in part at the meeting Estrogens in the Environment IV: Linking Fundamental Knowledge, Risk Assessment, and Public Policy held in Washington, DC, 19-21 July 1997.The chemical structure of hydroxylated diphenylalkanes or bisphenols consists of two phenolic rings joined together through a bridging carbon. This class of endocrine disruptors that mimic estrogens is widely used in industry, particularly in plastics. Bisphenol F, bisphenol A, fluorine-containing bisphenol A (bisphenol AF), and other diphenylalkanes were found to be estrogenic in a bioassay with MCF7 human breast cancer cells in culture (E-SCREEN assay). Bisphenols promoted cell proliferation and increased the synthesis and secretion of cell type-specific proteins. When ranked by proliferative potency, the longer the alkyl substituent at the bridging carbon, the lower the concentration needed for maximal cell yield; the most active compound contained two propyl chains at the bridging carbon. Bisphenols with two hydroxyl groups in the para position and an angular configuration are suitable for appropriate hydrogen bonding to the acceptor site of the estrogen receptor. Our data suggest that estrogenicity is influenced not only by the length of the substituents at the bridging carbon but also by their nature. Because diphenylalkane derivatives are widespread and their production and use are increasing, potential exposure of humans to estrogenic bisphenols is becoming a significant issue. The hazardous effects of inadvertent exposure to bisphenol-releasing chemicals in professional workers and the general populations therefore deserve investigation.This research was supported by grants from the Spanish Ministry of Health (FIS, 95/1959) and the Andalusian Regional Government Department of Health (Consejerla de Salud, 96/159)