Fetal sex and the relative reactivity of human umbilical vein and arteries are key determinants in potential beneficial effects of phosphodiesterase inhibitors.

Intrauterine growth restriction (IUGR) is a common complication of pregnancy. We previously demonstrated that IUGR is associated with an impaired nitric oxide (NO)-induced relaxation in the human umbilical vein (HUV) of growth-restricted females compared to appropriate for gestational age (AGA) newborns. We found that phosphodiesterase (PDE) inhibition improved NO-induced relaxation in HUV, suggesting that PDEs could represent promising targets for therapeutic intervention. This study aimed to investigate the effects of PDE inhibition on human umbilical arteries (HUAs) compared to HUV. Umbilical vessels were collected in IUGR and AGA term newborns. NO-induced relaxation was studied using isolated vessel tension experiments in the presence or absence of the nonspecific PDE inhibitor 3-isobutyl-1-methylxanthine (IBMX). PDE1B, PDE1C, PDE3A, PDE4B, and PDE5A were investigated by Western blot. NO-induced vasodilation was similar between IUGR and AGA HUAs. In HUAs precontracted with serotonin, IBMX enhanced NO-induced relaxation only in IUGR females, whereas in HUV IBMX increased NO-induced relaxation in all groups except IUGR males. In umbilical vessels preconstricted with the thromboxane A2 analog U46619, IBMX improved NO-induced relaxation in all groups to a greater extent in HUV than HUAs. However, the PDE protein content was higher in HUAs than HUV in all study groups. Therefore, the effects of PDE inhibition depend on the presence of IUGR, fetal sex, vessel type, and vasoconstrictors implicated. Despite a higher PDE protein content, HUAs are less sensitive to IBMX than HUV, which could lead to adverse effects of PDE inhibition in vivo by impairment of the fetoplacental hemodynamics.NEW & NOTEWORTHY The effects of phosphodiesterase inhibition on the umbilical circulation depend on the presence of intrauterine growth restriction, the fetal sex, vessel type, and vasoconstrictors implicated. The human umbilical vascular tone regulation is complex and depends on the amount and activity of specific proteins but also probably on the subcellular organization mediating protein interactions. Therefore, therapeutic interventions using phosphodiesterase inhibitors to improve the placental-fetal circulation should consider fetal sex and both umbilical vein and artery reactivity.

Citral relaxes umbilical vessels of normotensive and preeclamptic parturients.

INTRODUCTION: Citral is a low-toxicity monoterpene that has a vasodilator effect on various smooth muscles, and The present study aimed to evaluate its vasorelaxant effect on umbilical vessels of normotensive parturients (NTP) and with preeclampsia parturients (PEP). METHOD: Segments of human umbilical artery (HUA) and vein (HUV) of NTP or PEP were mounted in a bath to record the force of contraction, under tension of 3.0 gf and contracted with the contracting agents: K+ (60 mM), 5 -HT (10 µM) and Ba2+ (1-30 mM). Next, the effect of citral (1-3000 µM) on these contractions and on basal tone was evaluated. RESULTS: In HUA and HUV, citral (1-1000 µM), in NTP condition, inhibited contractions evoked by K+ (IC50 of 413.5 and 271.3, respectively) and by 5-HT (IC50 of 164.8 and 574.3). In the PEP condition, in HUA and HUV, citral also inhibited the contractions evoked by K+ (IC50 of 363.3 and 218.3, respectively) and 5-HT (IC50 of 432.1 and 520.4). At a concentration of 1000 µM, citral completely or almost completely (>90 %) inhibited all contractions. At a concentration of 100-1000 µM, citral, in general, was already able to reduce the contraction induced by 1-3 mM Ba2+ in both AUH and VUH, under NTP and PEP conditions. DISCUSSION: Citral has been shown to be an effective HUA and HUV vasodilator in NTP and PEP. As its toxicity is low, it suggests that this substance can be considered a potential therapeutic agent.

Emotional temperaments in advanced pregnant goats and its relationship with the feto-maternal blood flow and placentome echotexture.

The current study aimed to investigate the effect of xylazine sedation (non-sedated versus sedated conditions) and animal temperament on the fetal and maternal hemodynamics during the late stage of gestation in goats. In addition, it aimed to study the concentrations of cortisol and the echotexture of the placentome. Fourteen goats were assigned into two equal groups (n = 7, each) based on the animal's emotional temperament (calm versus nervous groups). All goats were examined for assessment of the blood flow within the fetal aorta (FA), umbilical artery (UMA), and middle uterine artery (MUA) using color-pulsed Doppler ultrasonography. Goats were exposed to light sedation using the recommended dose of xylazine (0.05 mg/Kg Bw) intramuscularly. Goats in each group were reassessed for the studied parameters after sedation. Blood samples were drawn to determine the concentrations of cortisol. Placentome echotexture pixel intensity (PXI) was evaluated using computer image analysis software. Results revealed the significant impact of the xylazine sedation on the Doppler indices of the blood flow within the measured arteries (FA, UMA, and MUA), the PXI of placentome echotexture, and cortisol concentrations. The emotional temperament of goats had significant effects on the blood flow parameters of the MUA and UMA, concentrations of cortisol, and the PXI of the placentome. The interaction effect (sedation x temperament) was noticed in the measured parameters of the UMA blood flow, fetal heart rate, and cortisol concentrations. In conclusion, xylazine sedation and emotional temperaments induced alterations in the echotexture of the placentomes as well as the hemodynamic parameters of late-stage pregnant goats without affecting the pregnancy outcomes.

Human umbilical artery smooth muscle exhibits a 2-APB-sensitive capacitative contractile response evoked by vasoactive substances and expresses mRNAs for STIM, Orai and TRPC channels

After depletion of intracellular Ca2+ stores the capacitative response triggers an extracellular Ca2+ influx through store-operated channels (SOCs) which refills these stores. Our objective was to explore if human umbilical artery smooth muscle presented this response and if it was involved in the mechanism of serotonin- and histamine-induced contractions. Intracellular Ca2+ depletion by a Ca2+-free extracellular solution followed by Ca2+ readdition produced a contraction in artery rings which was inhibited by the blocker of Orai and TRPC channels 2-aminoethoxydiphenyl borate (2-APB), suggesting a capacitative response. In presence of 2-APB the magnitude of a second paired contraction by serotonin or histamine was significantly less than a first one, likely because 2-APB inhibited store refilling by capacitative Ca2+ entry. 2-APB inhibition of sarcoplasmic reticulum Ca2+ release was excluded because this blocker did not affect serotonin force development in a Ca2+-free solution. The PCR technique showed the presence of mRNAs for STIM proteins (1 and 2), for Orai proteins (1, 2 and 3) and for TRPC channels (subtypes 1, 3, 4 and 6) in the smooth muscle of the human umbilical artery. Hence, this artery presents a capacitative contractile response triggered by stimulation with physiological vasoconstrictors and expresses mRNAs for proteins and channels previously identified as SOCs.

Human umbilical artery smooth muscle exhibits a 2-APB-sensitive capacitative contractile response evoked by vasoactive substances and expresses mRNAs for STIM, Orai and TRPC channels

After depletion of intracellular Ca2+ stores the capacitative response triggers an extracellular Ca2+ influx through store-operated channels (SOCs) which refills these stores. Our objective was to explore if human umbilical artery smooth muscle presented this response and if it was involved in the mechanism of serotonin- and histamine-induced contractions. Intracellular Ca2+ depletion by a Ca2+-free extracellular solution followed by Ca2+ readdition produced a contraction in artery rings which was inhibited by the blocker of Orai and TRPC channels 2-aminoethoxydiphenyl borate (2-APB), suggesting a capacitative response. In presence of 2-APB the magnitude of a second paired contraction by serotonin or histamine was significantly less than a first one, likely because 2-APB inhibited store refilling by capacitative Ca2+ entry. 2-APB inhibition of sarcoplasmic reticulum Ca2+ release was excluded because this blocker did not affect serotonin force development in a Ca2+-free solution. The PCR technique showed the presence of mRNAs for STIM proteins (1 and 2), for Orai proteins (1, 2 and 3) and for TRPC channels (subtypes 1, 3, 4 and 6) in the smooth muscle of the human umbilical artery. Hence, this artery presents a capacitative contractile response triggered by stimulation with physiological vasoconstrictors and expresses mRNAs for proteins and channels previously identified as SOCs.(AU)

Efeito do sulfato de magnésio sobre o índice de pulsatilidade das artérias uterinas, umbilical e cerebral média fetal de acordo com a persistência da incisura protodiastólica da artéria uterina na pré-eclâmpsia grave / Effect of magnesium sulfate on pulsatility index of uterine, umbilical and fetal middle cerebral arteries according to the persistence of bilateral diastolic notch of uterine arteries in patients with severe preeclampsia

OBJETIVO: avaliar o efeito do sulfato de magnésio sobre o índice de pulsatilidade (IP) das artérias uterinas, umbilicais e cerebral média fetal, de acordo com a persistência ou não da incisura protodiastólica bilateral das artérias uterinas na pré-eclâmpsia grave. MÉTODOS: foi desenvolvido um estudo do tipo coorte, incluindo 40 gestantes com pré-eclâmpsia grave, das quais 23 apresentavam incisura protodiastólica bilateral e 17, incisura ausente/unilateral. As pacientes foram submetidas a doplervelocimetria antes e depois de 20 minutos da administração intravenosa de 6 g do sulfato de magnésio. O exame foi realizado com a paciente em posição semi-Fowler, obtendo-se os sonogramas durante a inatividade fetal, em períodos de apneia e ausência de contrações uterinas. Todos os exames foram realizados por dois pesquisadores, considerando a média como resultado final. A comparação dos IP antes e depois do sulfato de magnésio em cada grupo foi realizada pelo teste de Wilcoxon. A diferença das duas medidas (antes e depois do sulfato de magnésio) foi comparada entre os grupos (incisura bilateral e incisura ausente/unilateral) utilizando-se o teste de Mann-Whitney. RESULTADOS: houve um aumento significativo da frequência cardíaca materna e uma diminuição da pressão arterial materna e da mediana dos IP das duas artérias uterinas e da artéria cerebral média fetal depois da utilização do sulfato de magnésio em ambos os grupos. Houve redução significativa do IP da artéria uterina esquerda e da artéria umbilical apenas no grupo com incisura protodiastólica unilateral/ausente. No entanto, não foram encontradas diferenças significativas em relação ao IP da artéria uterina direita e relação umbilical/cerebral antes e depois do sulfato de magnésio em cada grupo. Não se encontrou diferença entre os grupos, antes e depois do sulfato de magnésio, para nenhum dos desfechos estudados. CONCLUSÕES: após a administração intravenosa de 6 g do sulfato de magnésio nas...

PURPOSE: to evaluate the effect of magnesium sulphate on the pulsatility index (PI) of the uterine, umbilical and fetal middle cerebral arteries, according to the persistency or not of the bilateral protodiastolic notch of the uterine arteries in severe pre-eclampsia. METHODS: a cohort study including 40 pregnant women with severe pre-eclampsia, 23 of them presenting bilateral protodiastolic notch, and 17, unilateral/absent notch. The patients were submitted to Doppler velocimetry before and 20 minutes after the intravenous administration of 6 g of magnesium sulphate. The examination was carried out with the patient in semi-Fowler position, the sonograms being obtained during fetal inactivity, in apnea and absent uterine contraction periods. All the exams were performed by two researchers, the average being considered as the final result. Wilcoxon's test was used to compare the PI, before and after magnesium sulphate in both groups. The difference between the two measurements (before and after magnesium sulphate) was compared between the groups (bilateral incision and unilateral/absent incision) using the Mann-Whitney test. RESULTS: there was a significant increase in the maternal heart rate (MHR) and decrease in the maternal blood pressure, and in the PI medians of the two uterine arteries and in the fetal middle cerebral artery, after magnesium sulphate in both groups. There was a significant decrease in the PI of the left uterine artery and in the umbilical artery, only in the protodiastolic unilateral/absent notch group. Nevertheless, it was not found any significant difference regarding the PI of the right uterine artery, or the cerebral/umbilical relationship, before and after magnesium sulphate in each group. No difference between the groups was found, before and after magnesium sulphate, for any of the studied outcomes. CONCLUSIONS: after the intravenous administration of 6 g of magnesium sulphate to patients with severe pre-eclampsia...

Evaluación de la circulación materno-fetal en la anestesia peridural medida por el efecto Doppler / Evaluation of the materno-fetal circulation in the anesthesia epidural measure by Doppler effect

El siguiente trabajo tuvo por objetivo valorar las modificaciones producidas por la anestesia peridural, mediante el efecto Doppler, sobre la circulación de ambas arterias uterinas y arteria umbilical. Fue realizado en la Maternidad del Hospital D. F. Santojanni en el período comprendido entre octubre de 1993 y agosto de 1994. Se seleccionaron 33 pacientes con embarazos de término y 2 cesáreas anteriores, sin complicaciones médicas y/o quirúrgicas durante la gestación. Se efectuó la Velocimetría Doppler de arteria uterina derecha e izquierda y arteria umbilical con Doppler pulsado previa a la anestesia, 5 y 15 minutos después. Se calculó el cociente S/D. Los resultados mostraron a pesar de no encontrarse modificaciones significativas de la tensión arterial materna, un aumento del índice S/D a los 5 minutos en las arterias estudiadas sugiriendo una disminución del flujo útero-placentario y del flujo umbilical. Estos valores vuelven a estados preanestésicos excepto en arteria uterina izquierda. Pensamos que los 5 primeros minutos son críticos para los mecanismos de regulación hemodinámica maternos, motivo por el cual consideramos que aumentan los valores del índice S/D (AU)

Evaluación de la circulación materno-fetal en la anestesia peridural medida por el efecto Doppler / Evaluation of the materno-fetal circulation in the anesthesia epidural measure by Doppler effect

El siguiente trabajo tuvo por objetivo valorar las modificaciones producidas por la anestesia peridural, mediante el efecto Doppler, sobre la circulación de ambas arterias uterinas y arteria umbilical. Fue realizado en la Maternidad del Hospital D. F. Santojanni en el período comprendido entre octubre de 1993 y agosto de 1994. Se seleccionaron 33 pacientes con embarazos de término y 2 cesáreas anteriores, sin complicaciones médicas y/o quirúrgicas durante la gestación. Se efectuó la Velocimetría Doppler de arteria uterina derecha e izquierda y arteria umbilical con Doppler pulsado previa a la anestesia, 5 y 15 minutos después. Se calculó el cociente S/D. Los resultados mostraron a pesar de no encontrarse modificaciones significativas de la tensión arterial materna, un aumento del índice S/D a los 5 minutos en las arterias estudiadas sugiriendo una disminución del flujo útero-placentario y del flujo umbilical. Estos valores vuelven a estados preanestésicos excepto en arteria uterina izquierda. Pensamos que los 5 primeros minutos son críticos para los mecanismos de regulación hemodinámica maternos, motivo por el cual consideramos que aumentan los valores del índice S/D

Amplicación de la respuesta contráctil a noradrenalina por serotonina en la arteria umbilical humana / Amplification of contractile response by serotonin on noradrenaline in the human umbilical artery

Durante el transcurso del embarazo, se ha observado el incremento progresivo de los niveles plasmáticos de serotonina (5-HT). Además, se ha descripto el aumento de la concentración de noradrenalina (NA) durante el parto. Por otro lado, en diferentes arterias se ha observado que concentraciones efectivas mínimas de 5-HT pueden producir un aumento o "amplificación" de la respuesta contráctil a un segundo agonista. A partir de estos trabajos, se consideró relevante determinar la existencia de una interacción sinérgica entre la 5-HT y la NA en la arteria umbilical humana (AUH), y los posibles mecanismos involucrados en este fenómeno. Para ello, se emplearon tiras de esta arteria incubadas en solución de Krebs a 37 grados Celsius, burbujeadas con carbógeno en las que se evaluó la respuesta contráctil isométrica. La máxima respuesta contráctil a NA fue del 21 por ciento con respecto a la respuesta máxima de vasoconstricción, obtenida con 5-HT. Por otro lado, cuando se administró previamente una dosis efectiva mínima de 5-HT, la respuesta a la NA resultó significativamente mayor que la control (0,53 ñ 0,06 g y 0,24 ñ 0,06, respectivamente, p < 0,01). Esta respuesta "amplificada" a NA se correlacionó inversamente con el grado de contracción previa con 5-HT, cuando ésta tenía valores entre el 3 y 30% del máximo. Además, precontracciones superiores al 40 por ciento abolieron las respuestas a la NA. En otra serie de experimentos, la incubación previa con diltiazem, bioqueante de los canales de calcio, produjo una disminución de la respuesta tanto control como amplificada a NA. En este trabajo se demuestra la existencia de un efecto amplificador de la 5-HT sobre las respuestas a NA en la AUH y se discute la posible relevancia clínica en la preeclampsia y los mecanismos involucrados en este fenómeno.(AU)

Contractilidad "in vitro" de los vasos coriales de la placenta humana: efecto del peróxido de hidrógeno / "In vitro" contractility of chorionic vase of human placenta: hydrogen peroxide effect

Según metodología descripta en trabajos anteriores, se estudia la contractilidad "in vitro" de los vasos coriales de 30 placentas humanas normales, y el efecto provocado por el aumento del PO**2 en el medio perfusor a expensas de concentraciones de H**2 O**2 de 1.25, 2.5 y 5.0 mM. El H**2 O**2 provoca una respuesta contráctil monofásica; la intensidad de la contraccíon aumenta proporcionalmente a la concentración de H**2 O**2 (F = 8.9 p > 0,01). La indometacina y la aspirina a concentraciones de 2.5 micronM y 0.25 mM respectivamente, inhiben aquella respuesta (AU)

Contractilidad "in vitro" de los vasos coriales de la placenta humana: efecto del peróxido de hidrógeno / \"In vitro\" contractility of chorionic vase of human placenta: hydrogen peroxide effect

Según metodología descripta en trabajos anteriores, se estudia la contractilidad "in vitro" de los vasos coriales de 30 placentas humanas normales, y el efecto provocado por el aumento del PO**2 en el medio perfusor a expensas de concentraciones de H**2 O**2 de 1.25, 2.5 y 5.0 mM. El H**2 O**2 provoca una respuesta contráctil monofásica; la intensidad de la contraccíon aumenta proporcionalmente a la concentración de H**2 O**2 (F = 8.9 p > 0,01). La indometacina y la aspirina a concentraciones de 2.5 micronM y 0.25 mM respectivamente, inhiben aquella respuesta