Integrated Blood Pressure Control Dovepress open access to scientific and medical research Open access Full Text article O r I g I n a l r e s e a r C h nitric oxide dysregulation in the pathogenesis of preeclampsia among ghanaian women Kwame adu-Bonsaffoh1,2 Background: Preeclampsia (PE) is still a disease of theories as the exact cause remains Daniel ansong antwi1 uncertain. Widespread vascular endothelial cell dysfunction is thought to mediate the generalized samuel amenyi Obed3 vasospasm and hypertension characteristic of PE. Altered nitric oxide (NO) production has been Ben gyan4 associated with the endothelial dysfunction in the pathogenesis of PE but conflicting results have emerged from previous studies. 1Department of Physiology, University of ghana Medical school, accra, Objectives: To determine maternal serum levels of NO, a biomarker of endothelial function, ghana; 2Department of Obstetrics in nonpregnant, normal pregnant, and preeclamptic women. and gynecology, Korle Bu Teaching Materials and methods: This was a cross-sectional case–control study of 277 women com- hospital, accra, ghana; 3Department of Obstetrics and gynecology, prising 75 nonpregnant, 102 normal pregnant, and 100 preeclamptic women conducted at the University of ghana Medical school, Korle Bu Teaching Hospital between April and June 2011. About 5 mL of venous blood was accra, ghana; 4Department of Immunology, noguchi Memorial obtained from the participants for the various investigations after meeting the inclusion criteria Institute for Medical research, and signing to a written consent. Serum levels of NO were determined by Griess reaction. The University of ghana, accra, ghana data obtained were analyzed with SPSS version 20. Results: The study showed significantly elevated serum levels of NO in preeclamptic women (82.45±50.31 µM) compared with normal pregnant (33.12±17.81 µM) and nonpregnant (16.92±11.41 µM) women with P,0.001. The alteration in maternal serum NO levels was significantly more profound in early-onset (severe) PE (119.63±45.860 µM) compared to that of late-onset (mild) disease (62.44±40.44 µM) with P,0.001, indicating a more severe vascular endothelial cell dysfunction in the early-onset disease. Conclusion: This study has determined a profound NO upregulation in PE evidenced by sig- nificant elevation of NO metabolite levels compared to normal pregnancy. This might be due to deranged endothelial function with dysregulated production of NO to restore the persistent hypertension characteristic of PE. Keywords: preeclampsia, endothelial dysfunction, nitric oxide, Griess reagent Introduction Preeclampsia (PE) is defined as a new onset of hypertension and significant proteinuria in a previously normotensive woman after the 20th week of gestation.1–3 It is a common medical complication in pregnancy with increasing incidence globally, complicating 2%–8% of pregnancies worldwide.1,2 PE is associated with significant maternal and perinatal morbidity and mortality.1,4 Maternal complications of PE include eclampsia Correspondence: Kwame adu-Bonsaffoh Department of Obstetrics and (seizures), stroke, liver or renal failure, and disseminated intravascular coagulation, gynecology, Korle Bu Teaching hospital, and fetal problems include intrauterine growth restriction and preterm birth.2 In Korle PO box KB783, Korle Bu, accra, ghana Tel +233 20 630 0840 Bu Teaching Hospital (KBTH) where the current study was conducted, hypertensive email bonsaffoh@yahoo.com disorders in pregnancy including PE account for over 30% of maternal deaths.5 submit your manuscript | www.dovepress.com Integrated Blood Pressure Control 2015:8 1–6 1 Dovepress © 2015 Adu-Bonsaffoh et al. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) http://dx.doi.org/10.2147/IBPC.S68454 License. The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. Permissions beyond the scope of the License are administered by Dove Medical Press Limited. Information on how to request permission may be found at: http://www.dovepress.com/permissions.php Powered by TCPDF (www.tcpdf.org) 1 / 1 Integrated Blood Pressure Control downloaded from https://www.dovepress.com/ by 197.255.119.9 on 14-Jul-2018 For personal use only. adu-Bonsaffoh et al Dovepress PE is still a disease of theories as the exact cause remains utilized in devising more efficacious preventive measures. uncertain.3,6 There are no well-established strategies for The current study has aimed at determining and comparing primary prevention, and no consistent screening tests exist maternal serum levels of NO in nonpregnant, normal pregnant, for PE.6 However, the most widely held view is that PE is a and preeclamptic women using the Griess reagent. multisystem disorder with widespread vascular endothelial cell dysfunction. This vascular dysfunction is thought to Materials and methods mediate the characteristic generalized vasospasm manifesting This was a cross-sectional case–control study conducted as hypertension, a central feature of established PE.3,7 The at the Maternity Unit of KBTH in Accra, Ghana, between major features of endothelial dysfunction include vasospasm, April and June 2011. KBTH is the largest tertiary hospital increased platelet aggregation, and leukocytes activation, in Ghana with about 11,000 deliveries per year. It serves as and there is evidence that nitric oxide (NO) inhibits all these a referral center for most of the peripheral hospitals, clinics, processes.3 and maternity homes in southern Ghana. NO is a potent vasodilator and is thought to have a major The study participants were recruited in their third trimes- effect on gestational vasodilation.2,7,8 Previous studies sug- ters after 26 weeks of gestation. The criteria used for diag- gest that the physiologic vascular adaptation to pregnancy nosis of PE include a diastolic blood pressure of 90 mmHg is accompanied by an increase in endogenous NO produc- or higher, and/or systolic blood pressure of 140 mmHg or tion and enhanced responsiveness of the vascular smooth higher after 20-week gestation in a previously normotensive muscle to NO.7,8 Alteration or dysregulation of NO produc- woman associated with significant proteinuria of 300 mg tion is thought to be associated with the pathogenesis of PE, or more in a 24-hour urine collection or $1+ dipstick on a although conflicting results showing elevation, decrease, random urine sample.6 Early-onset PE was defined as PE that or no change in NO levels have emerged from previous develops prior to 34 weeks of gestation, whereas late-onset studies.4,8,9 PE develops at or after 34 weeks of gestation.12 NO deficiency or downregulation may be associated with The normotensive pregnant women and those diagnosed PE, and NO donors have been hypothesized to prevent PE, of PE were approached and evaluated for eligibility to be although the evidence is contradictory.2 Accordingly, serum included in the study immediately after the diagnosis has been NO level is considered as a valuable biomarker of endothelial made. The study protocol was explained to eligible women, function, and this represents the basis of the current study. and those who consented were recruited into the study. The Generally, NO levels are difficult to quantify due to their study included preeclamptic, normotensive nonpregnant, and relatively short half-life in the presence of oxygen and other normal pregnant women between the ages of 18 years and scavenging molecules such as hemoglobin. Therefore, deter- 42 years and without any preexisting disease. The study par- mination of NO levels in biological samples is usually done ticipants were selected using a systematic random sampling. by measuring the nitrite and nitrate levels, which are stable The nonpregnant normotensive controls were recruited from products of the NO oxidation, since the concentration of these the gynecology clinic of KBTH, after satisfying the inclu- metabolites directly depends on NO production.10 sion criteria in the same manner. All the pregnant women In PE, the primary disturbance appears to result from included in the study must have done ultrasound scan during reduced uteroplacental circulation due to abnormal tropho- the first half of their pregnancies for pregnancy confirmation blastic invasion of the maternal spiral arteries resulting in poor and accurate pregnancy dating. The cases and controls were placentation.11 These spiral arteries retain their endothelial matched for age, parity, and gestational age. Exclusion criteria lining and the underlying smooth muscles, which make them consisted of patients with a history of chronic hypertension, reactive to vasoactive agents expressed by the endothelial smoking, renal disease, diabetes mellitus, chronic inflam- cells. Extensive angiogenesis is vital in ensuring adequate matory diseases, urinary infection, cardiac disease, thyroid blood supply to the developing fetus in normal pregnancy, dysfunction, and infectious diseases, and women on any but this angiogenic process is impaired in PE.11 medical treatment other than iron and folic acid. Patients who Significant attempt has been made in the developed world to were not able to grant informed consent and those who were determine the serum level of NO in PE,5,7,9 but there are limited unwilling to comply with the requirements of the protocol data in Ghana. The outcome of this work might give more clues were also excluded from the study. to clinicians as to whether the pathogenesis of PE is linked to The study population was interviewed by means of maternal serum NO levels and how such knowledge can be structured questionnaire to obtain their basic demographic 2 submit your manuscript | www.dovepress.com Integrated Blood Pressure Control 2015:8 Dovepress Powered by TCPDF (www.tcpdf.org) 1 / 1 Integrated Blood Pressure Control downloaded from https://www.dovepress.com/ by 197.255.119.9 on 14-Jul-2018 For personal use only. Dovepress nitric oxide dysregulation in preeclampsia and clinical characteristics after signing an informed consent gravidity, parity, blood pressures, and NO were recorded in form. Other important information such as blood pressure at means ± standard deviation (SD). The above parameters were booking (first antenatal care) were extracted from the medical compared between the nonpregnant, normotensive pregnant, records of the patients. However, the normotensive nonpreg- and preeclamptic women using analysis of variance followed nant women had their blood pressures measured at the time of by a post hoc analysis using the Bonferroni’s test to deter- recruitment into the study, and they were tested for proteinuria mine the specific differences between the parameters with using dipsticks. Ethical clearance for the study protocol was significant statistical differences. The demographic, clinical, obtained from the Ethical and Protocol Review Committee of and laboratory parameters of the participants with early- the University of Ghana Medical School. An informed consent and late-onset PE were compared using the independent was obtained from all the study participants after meeting Student’s t-test. A P-value of , 0.05 was considered as sta- the inclusion criteria. The potential risks to the participants tistically significant. The correlation between gestational age for taking part in the study were explained to the study par- and NO levels, and between mean arterial pressure (MAP) ticipants individually. Furthermore, they were informed that and NO was determined using Pearson’s moment correlation failure to take part in the study would not in any way affect coefficient. MAP was calculated as diastolic blood pressure the normal management of their clinical conditions. (BP) plus 1/3 (systolic BP minus diastolic BP). Blood sampling Results About 5 mL of venous blood was obtained through veni- During the study period, 277 women were enrolled in the puncture from all the study participants and controls after study comprising 100 preeclamptic, 102 normal pregnant application of a tourniquet. The blood sample was centrifuged (control group 1), and 75 nonpregnant women (control for 15 minutes at 3,000 rpm, and the serum was decanted and group 2). The basic demographic, clinical, and laboratory stored at a temperature of −80°C, until the laboratory assays characteristics of the subjects are presented in Table 1. There were done. The sera were analyzed using Biosystems reagents were no statistically significant differences observed in the in a semi-automated analyzer for parameters of relevance to mean age and gravidity (number of pregnancies) among PE such as urea, uric acid, and creatinine. Maternal serum the nonpregnant, normotensive pregnant, and preeclamptic NO was determined using the Griess reagent.13 women. Significant differences were, however, observed in the mean parity (number of deliveries) and MAP at the Data analysis time of recruitment among the normotensive nonpregnant, The data were analyzed using SPSS version 20. Descriptive normotensive pregnant, and preeclamptic women. Similarly, analysis was done, and the demographic, clinical, and significant differences were seen among the three groups of laboratory parameters of the participants such as age, women regarding the mean serum levels of creatinine, urea, Table 1 Demographic, clinical, and some basic laboratory data of the study participants Parameter Nonpregnant group Normotensive pregnant group Preeclamptic group P-value (mean ± SD) (mean ± SD) (mean ± SD) age (years) 29.53±5.74 28.11±5.58 29.64±5.48 ns gravidity 2.44±1.54 2.75±1.68 2.38±1.58 ns Parity 0.83±1.08 1.26±1.30 0.75±1.20a 0.006* Booking diastolic BP (mmhg) na 65.67±8.07 68.41±7.23 0.012* Booking systolic BP (mmhg) na 107.95±11.69 110.26±8.91 ns Booking MaP (mmhg) na 79.76±8.24 82.36±6.71 0.015* Diastolic BP at recruitment (mmhg) 71.16±8.02 69.42±8.59 106.28±11.70a,b ,0.001* systolic BP at recruitment (mmhg) 113.12±7.63 111.23±9.13 165.67±20.97a,b ,0.001* MaP at recruitment (mmhg) 85.15±6.13 83.36±6.99 126.08±13.42a,b ,0.001* serum creatinine (µmol/l) 94.84±13.77 68.24±10.76b 115.08±41.44a,b ,0.001* serum urea (mmol/l) 4.96±1.28 2.52±1.06b 6.55±2.90a,b ,0.001* serum uric acid (µmol/l) 286.65±59.32 224.78±75.18b 379.26±96.58a,b ,0.001* Notes: The results are presented as mean ± sD. Post hoc analysis: asignificantly different from normotensive pregnant group; bsignificantly different from nonpregnant group. *Significant. Abbreviations: SD, standard deviation; BP, blood pressure; MAP, mean arterial pressure; NA, not applicable; NS, nonsignificant. Integrated Blood Pressure Control 2015:8 submit your manuscript | www.dovepress.com 3 Dovepress Powered by TCPDF (www.tcpdf.org) 1 / 1 Integrated Blood Pressure Control downloaded from https://www.dovepress.com/ by 197.255.119.9 on 14-Jul-2018 For personal use only. adu-Bonsaffoh et al Dovepress uric acid, and proteins (Table 1). The mean gestational age 140 (weeks ± SD) at diagnosis of PE and recruitment of normo- 120 tensive pregnant women were 33.96±2.93 and 34.63±2.74 P<0.001 (P=0.096). 100 There was a moderate degree of negative association between the gestational age at diagnosis and NO levels in 80 PE (r=0.576, P=0.005) with a coefficient of determination of 33.18%. However, there was no statistically significant 60 association between the MAP at diagnosis and NO levels in = = 40PE (r 0.164, P 0.104) with a coefficient of determination of 1.08%. There was a significant difference between the mean 20 serum levels of NO in nonpregnant (16.92±11.41 µM), preec- lamptic (82.45±50.31 µM), and normal pregnant women 0 (33.12±17.81 µM) with a P-value ,0.001 (Figure 1). Post Early-onset preeclampsia Late-onset preeclampsia hoc analysis using the Bonferroni’s method showed statisti- Figure 2 Mean serum levels of nO in early-onset and late-onset preeclampsia. Abbreviation: nO, nitric oxide. cally significant difference between the three groups relative to each other (Table 1). Discussion early-onset and late-onset Pe In this study, maternal serum NO levels were found to Among the 100 preeclamptics studied, early-onset and be significantly elevated in normotensive pregnant and in late-onset PE occurred in 35 and 65 women, respectively. preeclamptic women compared to the nonpregnant state. There was no statistically signif icant difference with The elevation in serum NO levels seen in PE was markedly respect to age, gravidity, parity, height, and booking greater than that seen in normal pregnancy, and this finding 9,14,15 systolic blood pressures between the early- and late-onset is consistent with other previous studies. Norris et al groups (P.0.05). The MAP at diagnosis was significantly reported that the production of NO was significantly higher higher in early-onset PE (132.36±16.91 mmHg) compared in the uteroplacental, feto-placental, and peripheral circula- to the late-onset PE (122.68±9.65 mmHg) (P,0.001). tion in PE compared to normotensive pregnancies. They The mean maternal serum level of NO (±SD) was signifi- attributed the marked increase in NO levels to compensatory ± µ mechanism to the pathological effect of PE.14cantly higher in early-onset PE (119.63 45.86 M) than Similarly, the in late-onset disease (62.44±40.44 µM) with P,0.001 marked elevation of NO levels in the PE determined in the (Figure 2). current study might be attributable to compensatory reaction to restore the persistently elevated blood pressure. Normal pregnancy is characterized by a profound increase 100 in cardiac output and circulating intravascular volume.14 90 P<0.001 Blood pressure in normal pregnancy decreases from early 80 pregnancy due to decreased peripheral resistance as a result 70 of marked systemic vasodilatation.3 NO, a potent vasodila- 60 tor, is thought to have a significant effect on gestational 50 vasodilatation. Reduced NO synthase (NOS) activity result- ing in decreased levels of NO may contribute significantly to 40 the widespread vasoconstriction and hypertension in PE.14,16 30 However, NOS was not measured concomitantly with serum 20 NO levels in this study. Although nitrate and nitrite levels 10 were found to be markedly elevated in PE, it is possible that 0 the amount of bioavailable NO needed to restore the elevated Nonpregnant state Preeclampsia Normal pregnancy BP was insufficient. Figure 1 Mean serum levels of nO in normal pregnant, preeclamptic, and However, a recent study has shown that constitutive nonpregnant women. Abbreviation: nO, nitric oxide. endothelial NOS could be upregulated by a factor present in 4 submit your manuscript | www.dovepress.com Integrated Blood Pressure Control 2015:8 Dovepress Powered by TCPDF (www.tcpdf.org) 1 / 1 Integrated Blood Pressure Control downloaded from https://www.dovepress.com/ by 197.255.119.9 on 14-Jul-2018 For personal use only. Serum levels of NO (µM) Serum levels of NO (µM) Dovepress nitric oxide dysregulation in preeclampsia the sera of preeclamptic women.14 It has been demonstrated of NO in early-onset PE might represent a compensatory that endothelial cells exposed to 2% of plasma from preec- mechanism to offset the pathologic effect of PE epitomized by lamptic women resulted in greater amounts of NO production generalized vasoconstriction and hypertension.14,18 The MAP and NOS activity compared to endothelial cells treated with was found to be significantly elevated in the preeclamptic plasma from normotensive uncomplicated pregnancies.17 group compared with the control groups (Table 1). Similarly, This suggests that endothelial cell dysfunction due to certain the mean arterial blood pressure was also significantly higher substances released from the placenta plays a significant role in early-onset disease compared to the late-onset PE. These in the pathogenesis of PE. Ranta et al also reported that NO findings might partly explain why the serum NO levels were production was increased in PE.18 Although the biologic also markedly elevated in the early-onset disease as a means significance of the increase is unknown, it might be a com- of compensatory reaction to restore the ongoing pathological pensation for the generalized vasoconstriction occurring in process. The markedly high serum levels of NO could still PE. They stated that their result was unexpected, since PE is not restore the persistently elevated blood pressure, indicat- associated with marked vasoconstriction, which is generally ing a possible decoupling of signaling in endothelial cells considered as an evidence of decreased NO production.18 or a consequence of generalized endothelial dysfunction. With the persistent hypertension, maternal serum levels of Intriguingly, there was no significant association between NO were expected to be reduced or deficient, but the converse the MAP at diagnosis and maternal serum NO levels. This was found in the current study. finding might be explained by the dysregulation of NO physi- Conversely, other researchers have indicated that maternal ology in PE, probably from impaired endothelial function. serum NO levels are reduced in PE.19 Sahu et al reported a However, significant negative correlation was found between reduction in NO production in preeclamptic women com- the gestational age at diagnosis and NO levels suggesting pared with normotensive pregnant women.19 In their study, that early-onset disease might be associated with marked they measured uric acid levels in plasma and urine concomi- endothelial damage. tantly to address the possible impact of alteration in renal Various analytical methods for quantitative measurement clearance on plasma NO metabolites in PE. In the current of nitrite and nitrate in plasma, serum, and urine of humans study, urinary uric acid levels were not measured concomi- are available.22 In this study, concentration of nitrite and tantly with the serum NO levels. However, the renal function nitrate, which are stable products of the NO oxidation, was of the participants was assessed using serum creatinine, urea, determined using Griess reagent.13 This assay measured the and uric acid levels concomitantly. Although there were concentration of the serum nitrites and nitrates as a represen- significant differences in the mean serum creatinine, urea, tation of total NO production. Griess reaction is simple and and uric acid levels in the study population, the values were straightforward and has a long history with significant valid- generally within normal limits indicating that renal function ity and reliability equivalent to contemporary methods.14 was not significantly impaired to affect NO clearance. The limitation of this study includes the fact that deter- On the other hand, other researchers have reported that mination of proteinuria was performed using a semiquanti- circulating nitrate and nitrite levels are not reduced in patients tative dipstick testing instead of a 24-hour urinary protein with severe PE compared with normotensive controls.20,21 or urinary albumin/creatinine ratio, which is more accurate Silver et al demonstrated that sera obtained from preec- and reliable. Also, any inherent limitation of Griess reagent lamptic women did not suppress endothelial cell synthesis is considered a limitation of the current study. Despite of NO in vitro as reported by other studies.20 The researchers the above limitations, the findings of this study serve as evaluated the possibility that circulating factors in PE could a baseline data for further longitudinal studies to better suppress endothelial cells NO synthesis, but their study did understand the contribution of NO alteration and endothelial not identify any significant suppressive effect on endothelial dysfunction to the pathogenesis of PE. cell NO production in vitro. It was concluded that the absence of compensatory rise in NO synthesis in PE might also sug- Conclusion gest a relative deficiency of NO due to impaired endothelial In conclusion, the current study has determined significantly cell function.20 elevated NO levels in normal pregnancy, and more so, in The current study also showed markedly elevated serum PE, compared to the nonpregnant state. The high levels of levels of NO in early-onset PE compared to late-onset PE that NO might be attributable to a dysregulated compensatory is considered as a mild disease. The significantly high levels reaction to restore the generalized endothelial damage and Integrated Blood Pressure Control 2015:8 submit your manuscript | www.dovepress.com 5 Dovepress Powered by TCPDF (www.tcpdf.org) 1 / 1 Integrated Blood Pressure Control downloaded from https://www.dovepress.com/ by 197.255.119.9 on 14-Jul-2018 For personal use only. adu-Bonsaffoh et al Dovepress persistently elevated hypertension characteristic of PE. The 6. American College of Obstetricians and Gynecologists, ACOG. Diagnosis and management of preeclampsia and eclampsia. ACOG blood pressure elevation and serum NO levels were markedly Practice Bulletin. 2002;2:33. higher in early-onset PE (severe disease) compared to the 7. Buhimschi IA, Saade GR, Garfield RE. The nitric oxide pathway in late-onset type (mild disease), suggesting a more severe preeclampsia: pathophysiological implications (review). Hum Reprod Update. 1998;4:25–42. endothelial dysfunction in the former. The findings from the 8. Sladek SM, Magness RR, Conrad KP. Nitric oxide and pregnancy. current study and other previous studies show conflicting Am J Physiol. 1997;272:R441–R463. 9. Shaamash AH, Elsnosy ED, Makhlouf AM, Zakhari MM, Ibrahim OA, results in terms of NO production in PE. However, the base- Eldien HM. Maternal and fetal serum nitric oxide (NO) concentrations in line findings suggest that vascular endothelial cell dysfunc- normal pregnancy, preeclampsia and eclampsia. Int J Gynaecol Obstet. tion plays a pivotal role in the pathogenesis of PE. 2000;68:207–214. 10. Giustarini D, Rossi R, Milzani A, Dalle-Donne I. Nitrite and nitrate Acknowledgments measurement by Griess reagent in human plasma: evaluation of interfer-ences and standardization. Methods Enzymol. 2008;440:361–380. The authors are grateful to the College of Health Sciences 11. George EM, Granger JP. Recent insights into the pathophysiology of preeclampsia. Expert Rev Obstet Gynecol. 2012;5(5):557–566. for funding this research work through the Bench Fee 12. Raymond D, Peterson E. A critical review of early-onset and late-onset Award and a small grant for thesis and dissertations from preeclampsia. Obstet Gynecol Surv. 2011;66(8):497–506. the Association of African Universities. The authors are also 13. Granger DL, Taintor RR, Boockvar KS. Measurement of nitrate and nitrite in biological samples using nitrate reductase and Gries reaction. grateful to the staffs of the Departments of Obstetrics and Methods Enzymol. 1996;268:142–151. Gynecology, Physiology, and Biochemistry of the University 1 4. Norris AA, Higgins JR, Darling MRN, Walshe JJ, Bonnar J. Nitric oxide in the uteroplacental, fetoplacental, and peripheral circulations of Ghana Medical School, labor wards of the KBTH, and in preeclampsia. Am J Obstet Gynecol. 1999;93:958–963. the Noguchi Memorial Institute for Medical Research for 1 5. Nobunaga AK, Allman KG, Young D, Redman CWG. Elevated levels facilitating the research. We also thank Mr Emmanuel of serum nitrate, a stable end product of nitric oxide, in women with preeclampsia. Br J Obstet Gynaecol. 1997;104:538–543. Dwamena-Asare for his immense contribution to the data 1 6. Choi JW, Im MW, Pai SH. Nitric oxide production increases during collection. normal pregnancy and decreases in preeclampsia. Ann Clin Lab Sci. 2002;32(3):2002. Disclosure 17. Davidge ST, Baker PN, Roberts JM. NOS expression is increased in endothelial cells exposed to plasma from women with preeclampsia. The authors report no conflicts of interest in this work. Am J Physiol. 1995;269:H1106–H1112. 18. Ranta V, Viinikka L, Halmesmaki E, Ylikorkala O. 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Cochrane Database Syst Rev. 2007;18(2):CD006490. Gynecol. 1996;174:1008–1013. 4. Diejomaoh FME, Omu AE, Al-Busiri N, et al. Nitric oxide production 22. Tsikas D. Methods of quantitative analysis of the nitric oxide is not altered in preeclampsia. Arch Gynecol Obstet. 2004;269: metabolites nitrite and nitrate in human biological fluids. Free Radic 237–243. Res. 2005;39:797–815. 5. Adu-Bonsaffoh K, Oppong SA, Binlinla G, Obed SA. Maternal deaths attributable to hypertensive disorders in a tertiary hospital in Ghana. Int J Gynecol Obstet. 2013;123(2):110–113. Integrated Blood Pressure Control Dovepress Publish your work in this journal Integrated Blood Pressure Control is an international, peer-reviewed features of the journal. This journal is indexed on American Chemical open-access journal focusing on the integrated approach to managing Society’s Chemical Abstracts Service (CAS). The manuscript manage- hypertension and risk reduction. 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