Aims: The aim of the presented study was to clarify the relationship between the pulsatility index of the uterine arteries and the maternal cubital artery and peripheral concentrations of the metabolites of nitric oxide (NO) and its second messenger cyclic guanosinmonophophate (cGMP) during the normal course of pregnancy and postpartum. Methods: 49 uncomplicated pregnancies were investigated every 46 weeks until delivery, 29 of them were additionally investigated postpartum. Paralleling each Doppler sonografic investigation maternal blood and urine samples were taken. The measurements of nitrite/ nitrate and cGMP were performed with a colorimetric and radio immuno assay. We demonstrate a significant decrease of the PI of the uterine arteries and of the cubital artery with inverse correlation to advancing gestational age. Results: The concentrations of nitrite/nitrate and cGMP remain stable during gestation and do not correlate to the PI of the uterine and cubital artery. Postpartum a reincrease in the uterine and peripheral resistance can be shown. The concentrations of urinary cGMP and nitrite/ nitrate as well as plasma cGMP remain unchanged, whereas plasma nitrite/nitrate decreases postpartum. Conclusions: The status of NO biosyntheses in normal pregnancy remains controversial. We hypothesize further systemically acting mediators which contribute to the decreasing vascular resistance

Bidlingmaier, M.

Kainer, Franz

Schiessl, B.

Spannagl, M.

Strasburger, C. J.

Ugele, B.

English

Open Access LMU ( Ludwig-Maximilians-Univ. München)

1 IntroductionPhysiologic pregnancy is associated with an in-crease in cardiac output due to an increase in circu-lating intravascular volume and an increase inheart rate. Paralleling this phenomenon in nor-motensive women a steady decrease in systolic anddiastolic arterial blood pressure (BP) is describedas a result of decreased peripheral vascular resist-ance. Nitric oxide (NO) is a potent vasodilator andis thought to cause a majority of the vasodilationduring the course of normal pregnancy [1, 8, 14].NO is synthesized by the enzyme nitric oxide syn-thase (NOS) from the substrate L-arginin. The en-zyme is localized in the vascular endothelium, inplatelets and placental tissue and exists in a consti-tutive (calcium-dependent) and as an inducible(calcium-independent) form [11].According to classical embryology intervillous cir-culation is established early in the first trimesterstarting with the first trophoblast invasion. Thesegradual processes finish with the second tro-phoblast invasion with direct opening of the spiralarteries in the intervillous space [9]. The transfor-mation is characterized by a gradual loss of thenormal musculoelastic structure of the arterialwall [10]. This phenomenon is reflected in the dis-appearance of the early diastolic notch and in adecrease in resistance index and pulsatility indexof the uterine arteries until 24 weeks of gestation.Uterine artery Doppler examination can identifyimpaired trophoblast invasion in the secondtrimester of pregnancy when a high resistance andan early diastolic notch persists after 24 weeks ofgestation [7].NO is released from placental tissue into the mater-nal circulation. Several investigations have beenundertaken to describe the amount of NO-produc-tion and the level of NO-metabolites in the mater-nal circulation. Seligman reported that serumconcentrations of nitrite/nitrate were significantlyincreased in pregnant compared with non-preg-nant women [13]. Begum analyzed urinary ni-trate/nitrite levels which tended to be higher in thesecond and third trimester than in the firsttrimester of pregnancy. These levels as well as thelevel of cGMP tended to be lower in the puerperialperiod. No correlation could be found betweenNO-metabolites and maternal blood pressure.Uri-nary nitrite/nitrate was significantly lower in pa-tients with preeclampsia [2]. Davidge also reportson a decrease of urinary nitrite/nitrate levels in thepresence of unchanged plasma levels in preeclamp-tic women compared to normal pregnancies [5]. Incontrast to these reports Di Irio and colleaguescould not demonstrate a change in nitrite/nitrateplasma concentrations or urinary excretion in pa-tients with preeclampsia [6]. Curtis demonstratedno difference between the plasma Nitrate/Nitriteconcentrations of normal or preeclamptic preg-nant women and non-pregnant women [4].Schiessl et al, Decreasing arterial resistance is unrelated to NO-metabolites during pregnancy 281© 2003 by Walter de Gruyter GmbH & Co. KG Berlin · New YorkDecreasing resistance in the maternal uterine and peripheralarterial system is apparently unrelated to plasma and urinarylevels of nitrite/nitrate and cyclic-guanosinmonophosohateduring the course of normal pregnanciesBarbara Schiessl1, Christian J. Strasburger2, Martin Bidlingmaier2,Michael Spannagl3, Bernhard Ugele4, and Franz Kainer11Department of Obstetrics and Gynaecology, Prenatal Medicine Unit, 2Departmentof Internal Medicine, Neuroendocrine Unit, 3Department of Internal Medicine,Angiology, 4Department of Obstetrics and Gynecology, Clinical Chemistry, Ludwig-Maximilians-University, Munich, GermanyJ. Perinat. Med.31 (2003) 281–286Bereitgestellt von | Universitaetsbibliothek der LMU MuenchenAngemeldet | 129.187.254.47Heruntergeladen am | 18.11.13 12:36Few investigations have been undertaken to ex-amine the relation of Doppler sonografic parame-ters and NO-production. Beinder et al. found ele-vated blood flow resistance in the uterine arteriesin patients with preeclampsia and a reduced NOS-activity in the placental bed [3]. We have previous-ly demonstrated a significant decrease of the PImonitored at the maternal cubital artery with a sig-nificant correlation to the PI of the uterine arteriesduring the course of normal pregnancies [12]. Totest the hypothesis that changes in the maternalvascular peripheral and uterine arterial resistanceare mediated by the NO-system located in theuteroplacental tissue we conducted a prospectivelongitudinal trial: Plasma and urinary concentra-tions of nitrite/nitrate as the stable end-products ofNO and of its second messenger cGMP were de-termined and correlated to the PI of the maternalcubital,placental and non-placental uterine artery.2 Methods49 patients were investigated in a prospectivestudy for repeated Doppler sonografic evaluationand determination of serum and urinary levels ofnitrate/nitrite and cGMP. They were admitted tothe trial between 10 and 16 weeks of gestation. In-clusion criteria were: singleton pregnancy, normalmaternal blood pressure, and absence of maternalproteinuria.Fetal intrauterine growth retardation, maternalpregnancy induced hypertension or proteinuria,pathologic pregnancy outcome, maternal heartrate beyond 60 or above 100 beats per minute wereexclusion criteria. None of the women had evi-dence of any active or potential infective process,such as urinary tract infection or chorioamnionitis.Doppler sonografic examination, urine and serumsampling was repeated every four to six weeks un-til delivery and once within the first seven dayspostpartum. Ultrasound and Doppler sonograficexamination during pregnancy included evalua-tion of biometric data of the fetus, estimation ofthe amniotic fluid index, localization of the pla-centa and vitality of the fetus. Doppler sonograficinvestigations were performed on the left andright uterine artery – but were characterized bythe localization of the placenta (placental andnon-placental uterine artery). The maternal rightcubital artery was chosen as an easily accessibleperipheral arterial vessel. Doppler sonografic in-vestigation was performed on a Logic 400 ma-chine (GE, Kranzbühler, Solingen, Germany)with a 3,5 MHz device. From the analysis of theDoppler spectra the parameters maximum sys-tolic velocity (Vmax), maximum enddiastolic ve-locity (Vmin) and mean velocity (Vmean) werederived. From these parameters the pulsatility in-dex (PI) was calculated: PI = [Vmax – Vmin/Vmean]. All examinations were conducted by thesame experienced investigator.At each interval maternal blood and urine sam-ples were collected and, in addition, blood andurine samples were collected on admission to thedelivery room. The blood samples underwent cen-trifugation and both plasma and urinary probeswere stored at –21 °C in aliquots until determina-tion. Plasma NO-concentrations were determinedusing the Greiss reaction by measuring combinedoxidation products of NO, plasma nitrite [NO2–]and nitrate [NO3–] after reduction with nitrate re-ductase in a Colorimetric Assay (Cayman Inc.,USA). Concentrations of the second messengercGMP serum and urinary samples were deter-mined with a J125-Radio-Immuno-Assay (ibl Inc.,Germany).The Stat View Program (Abacus Concepts, Inc.,Berkeley, CA, 1992–98) was used for statisticalanalysis (Descriptive statistics, Correlation ma-trix, Fisher’s r to z transformation, Spearman rankcorrelation coefficient, Kruskal-Wallis-test, un-paired t-test, Wilcoxon signed rank test, MannWhitney U-test). A p-value beyond 0.05 was con-sidered to be significant.The study had the approval of the local universi-ty’s ethical committee (No.158/00) and was fund-ed by the Ludwig-Maximilians-University Projectfor FöFoLe (No. 151). Each patient gave writteninformed consent.The follow up during the protocol was in accor-dance with the procedures in our department andif any pathological findings occurred further diag-nostic approach and treatment was offered to thepatient.3 ResultsThe mean age of the pregnant patients was31,1 years (yrs) (SD 4,49), the mean week of deliv-282 Schiessl et al, Decreasing arterial resistance is unrelated to NO-metabolites during pregnancy J. Perinat. Med. 31 (2003)Bereitgestellt von | Universitaetsbibliothek der LMU MuenchenAngemeldet | 129.187.254.47Heruntergeladen am | 18.11.13 12:36ery was 40,4 (SD 1,06) and the mean birth weightof the newborns was 3353 grams (SD 363). Themean pH-value measured at the umbilical arterywas 7,316 (SD 0,09), the median APGAR scorewas 9 at five minutes (range 8–10) and 10 (range8–10) at ten minutes.During the course of pregnancy the PI of the pla-cental and non-placental uterine artery, as well ofthe cubital right artery, decreases continuouslywith a significant inverse correlation to the weekof gestation (p < 0,001 Cubital artery; p < 0,0001Uterine arteries). The PI of both the placentaluterine artery and the non-placental uterine ar-tery is significantly correlated with the PI of thecubital artery (p < 0,0001 each). The placental andnon-placental uterine artery also show a signifi-cant correlation (p < 0,0001). Postpartum meas-Schiessl et al, Decreasing arterial resistance is unrelated to NO-metabolites during pregnancy 283J. Perinat. Med. 31 (2003)Figure 1. Plasma nitrite/nitrate con-centration during pregnancy intervals,on admission to delivery and post par-tum.Figure 2. Urinary nitrite/nitrate con-centration during pregnancy intervals,on admission to delivery and post par-tum (Kruskal-Walis test p < 0,01;Wilcoxon signed rank test).Bereitgestellt von | Universitaetsbibliothek der LMU MuenchenAngemeldet | 129.187.254.47Heruntergeladen am | 18.11.13 12:36urements of the PI in the cubital artery (p < 0,005)as well as the PI of the uterine arteries show a sig-nificant re-increase within the first seven daysafter delivery (p < 0,001). (Correlation matrix,Fisher’s r to z transformation, Spearman rank cor-relation coefficient).The concentrations of plasma nitrite/nitrate(p = 0,08),plasma cGMP (p = 0,80),urinary nitrite/nitrate (p = 0,15) and urinary cGMP (p = 0,92) donot correlate with advancing gestational age.(Correlation matrix,Fisher’s r to z transformation,Spearman rank correlation coefficient).For the following intervals of pregnancy the meanvalue was calculated: 10 to 21, 22 to 31, and 32 to42 weeks of gestation, admission to delivery andpostpartum.By analyzing these intervals no significance can be calculated for the plasma nitrite/nitrate(p = 0,301), plasma cGMP (p = 0,793) and urinarycGMP (p = 0,897) (Kruskal-Wallis-test) (figure 1,3, 4).Postpartum measured concentrations of urinaryNitrite/Nitrate are significantly lower than the cal-culated intervals of pregnancy and admission tothe delivery room.(Kruskal-Walis-test p = 0,0075,Wilcoxon signed rank test) (figure 2).No correlation can be shown between the PI ofthe cubital and uterine arteries and the plasmaand urinary concentrations of nitrite/nitrate andcGMP during the course of pregnancy. (Correla-tion matrix, Fisher’s r to z transformation, Spear-man rank correlation coefficient) (table 1).284 Schiessl et al, Decreasing arterial resistance is unrelated to NO-metabolites during pregnancy J. Perinat. Med. 31 (2003)Figure 3. Plasma cGMP concentra-tion during pregnancy intervals, onadmission to delivery and post par-tum.Figure 4. Urinary cGMP concentra-tion during pregnancy intervals, onadmission to delivery and post par-tum.Bereitgestellt von | Universitaetsbibliothek der LMU MuenchenAngemeldet | 129.187.254.47Heruntergeladen am | 18.11.13 12:364 DiscussionIn the present study we analyzed the maternal cu-bital artery as an easily accessible and representa-tive peripheral maternal arterial vessel and theuterine arteries by Doppler sonografic evaluation.Paralleling each Doppler sonografic investigationblood and urine samples were taken. We focusedon the change in uterine and peripheral resistancein comparison to the concentrations of metabo-lites of NO (nitrite/nitrate) and its second messen-ger cGMP during the normal course of pregnancyand postpartum.In contrast to the decreasing local uterine anddecreasing peripheral arterial resistance, we can-not demonstrate an increase in the circulatingand renal excreted metabolites and the secondmessenger (cGMP) of NO. Several investigatorspostulate an increased production of NO duringpregnancy. Conrad reports on an increasing ex-cretion of cGMP with advancing gestational agein rats [14]. Our tests do not affirm these findingsin human pregnancy. If there is an increased NOproduction that is released into the maternal andfeto-placental circulation, there are stable pe-ripheral concentrations of nitrite/nitrate andcGMP.In contrast to these stable concentrations wemeasured a decreasing peripheral arterial resist-ance in the uterine and peripheral maternal arteri-al system with significant inversed correlation toadvancing gestational age.We found a significant difference in the concen-trations of urinary nitrite/nitrate comparing thepostpartum samples to those taken during thecourse of pregnancy. This may be a false positiveresult because of the low case number. On the oth-er hand this may be linked to a decreasingturnover of NO in maternal circulation postpar-tum. The plasma nitrite/nitrate does not show asignificant change nor do the concentrations ofplasma and urinary cGMP.Our findings support the reports of Lyall andRobson that the cytotrophoblast derived NO isunlikely to contribute to the spiral artery dilation[10]. That NO-production is increased only in cer-tain compartments [e.g. placenta, uterus or mater-nal platelets] cannot be excluded, and helps to ex-plain the confusing data in the literature. Eventhough we cannot measure peripheral plasma andurinary rising concentrations of nitrite/nitrate andcGMP during pregnancy we postulate peripheralacting mediators that contribute to the decreasingarterial resistance in physiologic pregnancy.Schiessl et al, Decreasing arterial resistance is unrelated to NO-metabolites during pregnancy 285J. Perinat. Med. 31 (2003)Table I. Correlation between pulsatility index (PI) and concentration of nitrite/nitrate and plasma and urinary cyclicguanosinmonophosphate (cGMP)Placental artery Nonplacental artery Cubital arteryPlasma nitrite/nitrate P = 0,7 P = 0,56 P = 0,35Plasma cGMP P = 0,25 P = 0,19 P = 0,93Urinary nitrite/nitrate P = 0,68 P = 0,37 P = 0,76Urinary cGMP P = 0,90 P = 0,52 P = 0,51Abstract Aims: The aim of the presented study was to clarify therelationship between the pulsatility index of the uterinearteries and the maternal cubital artery and peripheralconcentrations of the metabolites of nitric oxide (NO)and its second messenger cyclic guanosinmonophophate(cGMP) during the normal course of pregnancy andpostpartum.Methods: 49 uncomplicated pregnancies were investi-gated every 4–6 weeks until delivery, 29 of them wereadditionally investigated postpartum. Paralleling eachDoppler sonografic investigation maternal blood andurine samples were taken. The measurements of ni-trite/nitrate and cGMP were performed with a colori-metric and radio immuno assay.We demonstrate a significant decrease of the PI of theuterine arteries and of the cubital artery with inversecorrelation to advancing gestational age.Results: The concentrations of nitrite/nitrate and cGMPremain stable during gestation and do not correlate tothe PI of the uterine and cubital artery. Postpartum a re-Bereitgestellt von | Universitaetsbibliothek der LMU MuenchenAngemeldet | 129.187.254.47Heruntergeladen am | 18.11.13 12:36increase in the uterine and peripheral resistance can beshown. The concentrations of urinary cGMP and ni-trite/nitrate as well as plasma cGMP remain unchanged,whereas plasma nitrite/nitrate decreases postpartum.Conclusions: The status of NO biosyntheses in normalpregnancy remains controversial. We hypothesize fur-ther systemically acting mediators which contribute tothe decreasing vascular resistance.286 Schiessl et al, Decreasing arterial resistance is unrelated to NO-metabolites during pregnancy J. Perinat. Med. 31 (2003)Keywords: Doppler sonography, nitric oxide, peripheral resistance, pregnancy, uterine resistance.References[1] Ayala DE, RC Hermida: Influence of parity and ageon ambulatory monitored blood pressure duringpregnancy. Hypertension 38 (2001) 753[2] Begum S, M Yamasaki, M Mochizuki: Urinary levelsof nitric oxide metabolites in normal pregnancy andpreeclampsia. J Obstet Gynaecol Res 22 (1996) 551[3] Beinder E, MG Mohaupt, D Schlembach, T Fischer,RB Sterzel, N Lang et al: Nitric oxide synthase activ-ity and Doppler parameters in the fetoplacental anduteroplacental circulation in preeclampsia. Hyper-tens Pregnancy 18 (1999) 115[4] Curtis NE, M.Gude, RG King, PJ Mariott: Nitric ox-ide metabolites in normal human pregnancy andpreeclampsia. Hypertens Pregnancy 14 (1995) 339 [5] Davidge ST, CP Stranko, JM Roberts: Urine but notplasma nitric oxide metabolites are decreased inwomen with preeclampsia. Am J Obstet Gynecol174 (1996) 1008[6] Di Iorio R, E Marinoni, S Emiliani, B Villaccio, EVCosmi: Nitric oxide in preeclampsia: lack of evi-dence for decreased production. Eur J Obstet Gy-necol Reprod Biol 76 (1998) 65[7] Hafner E, M Metzenbauer, B Dillinger-Paller, DHoefinger, K Schuchter, H Sommer-Wagner et al:Correlation of first trimester placental volume andsecond trimester uterine artery Doppler flow. Pla-centa 22 (2001) 729[8] Hermida RC, DE Ayala, M Iglesias: Predictableblood pressure variability in healthy and complicat-ed pregnancies. Hypertension 38 (2001) 736[9] Kurjak A, S Kupesic, T Hafner, M Kos, L Kostovic-Knezevic, D Grbesa: Conflicting data on intervillouscirculation in early pregnancy. J Perinat Med 25(1997) 225[10] Lyall F, JN Bulmer, H Kelly, E Duffie, SC Robson:Human trophoblast invasion and spiral arterytransformation: the role of nitric oxide. Am JPathol 154 (1999) 1105[11] Norris LA, JR Higgins, MR Darling, JJ Walshe, JBonnar: Nitric oxide in the uteroplacental, fetopla-cental, and peripheral circulations in preeclampsia.Obstet Gynecol 93 (1999) 958[12] Schiessl B, CJ Strasburger, M Spannagl, F Kainer:Decreasing peripheral resistance during the courseof normal pregnancy monitored at the cubital ar-tery by Doppler sonography. Eur J Clin Invest 33(2003) 346[13] Seligman SP, JP Buyon, RM Clancy, BK Young, SBAbramson: The role of nitric oxide in the patho-genesis of preeclampsia. Am J Obstet Gynecol 171(1994) 944[14] Sladek SM, RR Magness, KP Conrad: Nitric oxideand pregnancy. Am J Physiol 272 (1997) R441Received August 26, 2002. Revised February 11,2003. Accepted February 12, 2003.B. Schiessl, MDDepartment of Obstetrics and GynecologyPrenatal Medicine UnitLudwig-Maximilians-UniversityMaistr. 1180337 MunichGermanyTel.: +49 89 5160 4111Fax: +49 89 5160 4913e-mail: bsc@fk-i.med.uni-muenchen.deBereitgestellt von | Universitaetsbibliothek der LMU MuenchenAngemeldet | 129.187.254.47Heruntergeladen am | 18.11.13 12:36

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King,PJ Mariott:Nitric oxide metabolites in normal human pregnancy and preeclampsia.Hypertens

KostovicKnezevic,D Grbesa:Conflicting data on intervillous circulation in early pregnancy.

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Decreasing resistance in the maternal uterine and peripheral arterial system is apparently unrelated to plasma and urinary levels of nitrite/nitrate and cyclic-guanosinmonophosohate during the course of normal pregnancies

Decreasing resistance in the maternal uterine and peripheral arterial system is apparently unrelated to plasma and urinary levels of nitrite/nitrate and cyclic-guanosinmonophosohate during the course of normal pregnancies

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