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Role of nitric oxide in the pathophysiology of pregnancy-induced hypertension.


Pregnancy-induced Hypertension (PIH)

It is defined as the development of new onset of hypertension after 20 weeks of gestation without the onset of proteinuria or other features of pre-eclampsia. [1] A pregnant female is said to have PIH if her blood pressure is higher than 140/90 mm of Hg, measured on two separate visits or more than 6 h apart. [2]


It is defined as a combination of PIH plus proteinuria (i.e., >300 mg of protein in a 24-h urinary sample).

Severe Pre-eclampsia

It occurs when blood pressure exceeds 160/110 mmHg, with added abnormal signs and symptoms such as pedal edema.


It is defined as PIH plus proteinuria plus tonic-clonic seizures appearing in a pregnant female. Pre-eclampsia and eclampsia are at times treated as components of a common syndrome. [3]

In spite of being the important cause of maternal and infant mortality, the factors that are responsible for the development of PIH are very uncertain. An originating episode in PIH has been proposed to be a decrease in the placental perfusion that primes an extensive vascular endothelial dysfunction by certain unclear mechanisms. Certain studies propose the absence of the normal fall in the blood pressure seen in pregnancy in PIH. Some studies also propose that the increase in blood pressure is mainly due to placental hyperresponsiveness or placental vasoconstriction. Although the causes of PIH have not been fully interpreted, various mechanisms such as the renin-angiotensin-aldosterone system, local mediators, and platelets have all been associated. [4]

Nitric oxide (NO) which is a powerful mediator released by vascular endothelial cells impedes adhesion and aggregation of platelets. It also produces vasodilation of the placental bed. The primary objective of the present study was to find whether lower levels of NO in circulation could be associated with the increased placental vascular resistance and hence the high blood pressures observed in PIH.


The present study was conducted at the at Government Kilpauk Medical College Hospital, Chennai. After obtaining the permission from the Institutional Ethics Committee, 60 primiparous women in the second trimester of pregnancy with PIH and 60 healthy, normotensive primiparous women in second trimester matched with respect to maternal age, gestational age, and body mass index were selected. The scope of the study was explained to all the subjects, and an informed written consent was obtained. The women with PIH had persistently (measured on two separate occasions, more than 6 h apart) elevated blood pressure readings of [greater than or equal to] 140 mmHg systolic and 90 mmHg diastolic. Subjects with proteinuria of [greater than or equal to] 300 mg in 24 h were excluded from the study. Women with multiple pregnancies, other pregnancy-related complications such as gestational diabetes mellitus, and other pre-existing diseases were excluded from the study.

Study Design

This was cross-sectional case--control study

Collection of Data

The resting blood pressure of the subjects was recorded on 2 consecutive days, and the average of the two values was recorded. Fasting blood samples of the subjects were obtained for the estimation of serum NO levels. The serum levels of NO was measured using enzyme-linked immunosorbent assay kits, namely serum NO determination, using kit supplied by Intron Bio. The NO estimation kit is on the basis of diazotization (Griess method) technique and is capable of measuring in vitro concentration of NO. This estimation kit facilitates to overcome technical hitches in detecting NO attributable to the brief half-life of almost 5 s. NO concentration is indirectly measured by means of accurately quantifying the levels of nitrite (NO2-), the derivative of NO in live tissues. The chemical basis of the test is a color change that takes place when the compound naphthyl ethylenediamine is added to the offshoot of the reaction amid sulfanilamide and nitrite.


The mean serum NO levels of both the groups were compared. A decrease was observed in the mean serum NO levels ([micro]M) in subjects with PIH (18.5 [+ or -] 5.8) compared with the controls (36.9 [+ or -] 3.9). Student's t-test was used for the comparison of parameters. The difference was statistically significant at P < 0.05 [Figure 1].


The present study shows a significantly less level of serum NO in women in their second trimester of pregnancy with PIH compared to the controls.

Our study is supported by a study finding that inhibiting the synthesis of NO during the gestational period in rats resulted in high blood pressure and pre-eclampsia like features. [4, 5] Furthermore, in a similar study, it was proven that, in pregnant rats, the blockage in the production of NO synthase enzyme leads to a condition that is similar to PIH and the features were reverted by infusion of L-arginine. [6] This finding also supports the results of our study. A research study where small-sized blood vessels were isolated from pregnant women with pre-eclampsia and established an impaired endothelial-mediated vasodilatation [7] is also in concurrence with our results. However, the results of our study and studies of serum levels of metabolites of NO and the levels of cGMP through which NO exerts its action have been inconsistent, [8] wherein an increase in NO metabolites were reported. Our study is also supported by another article which reports previous study which found that lower levels of blood pressure were associated with higher levels of serum NO in elderly subjects. [9] Other similar studies also implicate the deficiency of or impaired responsiveness to NO in the genesis of preeclampsia [10, 11] which lend support to our findings. A recent finding suggests that NO synthase in the placenta has been found to be reduced in pre-eclampsia as well as the release of vasodilators (endotheliumderived relaxing factor) from umbilical vessels [12, 13] which strengthens our hypothesis.

The sample size of the study is less, and the findings may not represent the findings in the general population. Furthermore, prospective studies on interventions for improving NO levels during pregnancy, such as physical activity, diet, and mild aerobic training, could enhance the value of this study.

To conclude, PIH is a major cause of morbidity and mortality during pregnancy, affecting both the mother and the fetus. It is of great public health importance, and an exact pathophysiology has to be identified for its prevention, early diagnosis, and management.


[1.] August P, Lindheimer MD. Pathophysiology of preeclampsia. Hypertension 1995;142:2407-26.

[2.] Lindheimer MD, Katz AI. Renal physiology and disease in pregnancy. In: Seldin DW, Giebisch G, editors. The Kidney: Physiology and Pathophysiology. 2nd ed. New York: Raven Press; 1992. p. 3371-431.

[3.] Chesley LC. Hypertensive Disorders in Pregnancy. New York: Appleton-Century-Crofts; 1978.

[4.] Dekker GA, Kraayenbrink AA, Zeeman GG, van Kamp GJ. Increased plasma levels of the novel vasoconstrictor peptide endothelin in severe pre-eclampsia. Eur J Obstet Gynecol Reprod Biol 1991;40:215-20.

[5.] Nathan L, Cuevas J, Chaudhuri G. The role of nitric oxide in the altered vascular reactivity of pregnancy in the rat. Br J Pharm 1995;114:955-60.

[6.] Roberts JM, Taylor RN, Musci TJ, Rogers GM, Hubel CA, McLaughlin MK. Preeclampsia: An endothelial cell disorder. Am J Obstet Gynecol 1989;161:1200-4.

[7.] Roberts JM. Pregnancy related hypertension. In: Creasy RK, Resnik R, editors. Maternal Fetal Medicine. 4th ed. Philadelphia, PA: W.B. Saunders Company; 2003. p. 833-54.

[8.] Williams DJ, Vallance PJ, Neild GH, Spencer JA, Imms FJ. Nitric oxide-mediated vasodilation in human pregnancy. Am J Physiol 1997;272:H748-52.

[9.] Udayakumar RK, Muthupandian A. A study of serum nitric oxide levels and pulse pressure in aging. Natl J Physiol Pharm Pharm 2018;9: Doi: 10.5455/njppp.2018.8.0416903052018.

[10.] Jirecek S, Joura EA, Tempfer C, Knofler M, Husslein P, Zeisler H, et al. Elevated serum concentrations of androgens in women with pregnancy-induced hypertension. Wien Klin Wochenschr 2003;115:162-6.

[11.] James WH. Hormone levels in pre-eclampsia. Acta Obstet Gynecol Scand 2002;81:1152.

[12.] Diamant YZ, Rimon E, Evron S. High incidence of preeclamptic toxemia in patients with polycystic ovarian disease. Eur J Obstet Gynecol Reprod Biol 1982;14:199-204.

[13.] Simoncini T, Mannella P, Fornari L, Varone G, Caruso A, Genazzani AR. Dehydroepiandrosterone modulates endothelial nitric oxide synthesis via direct genomic and nongenomic mechanisms. Endocrinology 2003;144:3449-55.

Rathna Kumari Udayakumar, Anita Muthupandian

Departmet of Physiology, Kilpauk Medical College, Chennai, Tamil Nadu, India

Correspondence to: Anita Muthupandian, E-mail:

Received: September 07, 2018; Accepted: October 02, 2018

DOI: 10.5455/ijmsph.2019.0926002102018
Figure 1: Serum nitric oxide levels ([micro]M) in
subjects with pregnancy-induced hypertension
compared with the controls

Serum NO level ([micro]M)

PIH        18.5
Controls   36.9

Note: Table made from bar graph.
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Title Annotation:Research Article
Author:Udayakumar, Rathna Kumari; Muthupandian, Anita
Publication:International Journal of Medical Science and Public Health
Article Type:Report
Date:Jan 1, 2019
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