Objective:To compare second-trimester, third-trimester, and postpartum arginine flux and nitric oxide production using infusions of the stable isotope L-[15N2]-arginine in normal human gestation.
Methods:Kinetic measurements were made in pregnant volunteers with uncomplicated singleton gestations in mid gestation, late gestation, and more than 8 weeks postpartum. A bolus of 4.95 μmol/kg of labeled arginine was administered, followed by an infusion at 4.95 μmol/kg per hour for 6 hours. The isotopic enrichment of plasma arginine and nitrite or nitrate (NOx) was determined by gas chromatography, mass spectrometry, or both. We used the Kolmogorov-Smirnov test for normality, repeated-measures analysis of variance, and Newman-Keuls test. P < .05 denoted statistical significance.
Results:The rate of turnover of the intravascular NOx pool was significantly higher in midgestation compared with late gestation and almost reached statistical significance when compared with postpartum values (6.2 ± 0.9 versus 4.3 ± 0.8 [P < .02] versus 3.7 ± 2.1% pool/hour; P = .08). Arginine flux was significantly higher in early compared with late gestation and postpartum (107.8 ± 13.9 versus 72.5 ± 16.1 versus 82 ± 8.8 μmol/kg per hour, respectively; p < .01).
Conclusion:Arginine and nitric oxide production is higher in mid gestation. This suggests a role for nitric oxide in early cardiovascular adaptation in human gestations.
1. Gant NF, Daley GL, Whalley P, MacDonald PC. A study of angiotensin II pressor response throughout primigravid pregnancy. J Clin Invest1973;52:2682-2689.
2.
2. Ito M, Nakamura T, Yoshimura T, Koyama H, Okamura H. The blood pressure response to infusions of angiotensin II during normal pregnancy: Relation to plasma angiotensin II concentration, serum progesterone level, and mean platelet volume. Am J Obstet Gynecol1992;166:1249-1253.
3.
3. Everett RB, Worley RJ, MacDonald PC, Gant NF. Modification of vascular responsiveness to angiotensin II in pregnant women by intravenously infused 5 alpha-dihydroprogesterone. Am J Obstet Gynecol1978;131:352-357.
4.
4. Mithcell MD. Endothelins in perinatal biology. Semin Perinatol1991;15:79-85.
5.
5. Brown CE, Gant NF, Cox K, Spitz B, Rosenfeld LR, Magnes RR. Low-dose aspirin II. Relationship of angiotensin II pressor responses, circulating eicosanoids, and pregnancy outcome. Am J Obstet Gynecol1990;163:1853-1861.
6.
6. Fuchgott RF, Zawadzki JV. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature1980;288:373-376.
7.
7. Barton JR, Sibai Bm, Ahokas RA, Whybrew WD, Mercer BM. Magnesium sulfate therapy in preeclampsia is associated with increased urinary cyclic guanosine monophophate excretion. Am J Obstet Gynecol1992;167:931-934.
8.
8. Conrad KP, Joffe GM, Kruszyna H, et al. Identification of increased nitric oxide biosynthesis during pregnancy in rats. FASEB J1993;7:566-571.
9.
9. Ignarro LJ, Byrns RE, Buga GM, Wood KS. Endothelium-derived relaxing factor (EDRF) released from artery and vein appears to be nitric oxide (NO) or a closely related radical species. Proc Fed Am Soc Exp Biol1987;46:644-644.
10.
10. Palmer RMJ, Ashton DS, Moncada S. Vascular endothelial cells synthesize nitric oxide from L-arginine. Nature1988;333:664-666.
11.
11. Wennmalm A, Lanne B, Peterson AS. Detection of endothelial-derived relaxing factor in human plasma in the basal state and following ischemia using electron para-magnetic resonance spectrometry. Anal Biochem1990;187:359-363.
12.
12. Roberts JM, Redman CG. Preeclampsia: More than pregnancy-induced hypertension. Lancet1993;341:1447-1453.
14. Moncada S, Higgs A. The L-arginine nitric oxide pathway. N Engl J Med1993;329:2002-2012.
15.
15. Castillo L, DeRojas C, Chapman E, et al. Splanchnic metabolism of dietary arginine in relation to nitric oxide synthesis in normal adult man. Proc Natl Acad Sci U S A1993;90:193-197.
16.
16. Macallan DC, Smith LM, Ferber J, et al. Measurement of NO synthesis in humans by L[15N2]arginine: Application ot the response to vaccination. Am J Physiol1997;272:R1888-R1896.
17.
17. Tsikas D, Boger RH, Bode-Boger SM, Gutzki FM, Frolich JC. Quantification of nitrite and nitrate in human urine and plasma as penatfluorobenzyl derivatives by gas chromatography-mass spectrometry using 15N-labelled analogs. J Chromatog B1994;666:185-191.
18.
18. Jahoor F, Wykes LJ, Reeds PJ, Henry JF, Del Rosario MP, Frazer ME. Protein-deficient pigs cannot maintain reduced glutathione homeostasis when subject to the stress of inflammation. J Nutr1995;125:1-11.
19.
19. Weiner CP, Thompson LP, Liu KZ, Herring JE. Endothelium-derived relaxing factor and indomethcin-sensitive contracting factor alter arterial contractile responses to thromboxane during pregnancy. Am J Obstet Gynecol1992;166:1171-1181.
20.
20. Greggs KC, Conrad KP, MacKay K, McLaughlin MK. Endothelial modulation of renal interlobar arteries from pregnant rats. Am J Physiol1993;265:F309-F315.
21.
21. Weiner CP, Thompson LP, Liu KZ, Herrig JE. Pregnancy reduces serotonin-induced contractions of guinea pig uterine and carotid arteries. Am J Physiol1992;263:H1764-H1769.
22.
22. Weiner CP, Liu KZ, Thompson LP, Herrig JE, Chestnut D. Efect of pregnancy on endothelium and sooth muscle: Their role in reduced adrenergic sensitivity. Am J Physiol1991;262:H1275-H1283.
23.
23. Chu ZM, Beilin LJ. Mechanisms of vasodilation in pregnancy: Studies of the role of prostaglandins and nitric oxide in changes of vascular reactivity in the in-situ blood perfused mesentery of pregnant rats. Br J Pharmacol1993;109:322-329.
24.
24. Fern EB, Garlick PJ, McNurlin MA, WAterlow JC. The excretion of isotope in urea and ammonia for estimating protein turnover in man with 15N glycine. Clin Sc1981;61:217-228.
25.
25. Jackson AA, Persaud C, Badeloo V, deBenoist B. Whole body protein turnover in man determined in three hours with oral or intravenous 15N-glycine and enrichment in urinary ammonia. Hum Nutr Clin Nutr1987;416:263-276.
26.
26. Chien PW, Smith K, Watt PW, Serimgeour CM, Taylor DJ, Rennie MJ. Protein turnover in the human fetus studied at term using stable isotope tracer amnio acids. Am J Physiol1993;265:E31-E35.
27.
27. Whittaker PG, LInd T, Williams JG. Iron absorption during normal human pregnancy: A study using stable isotopes. Br J Nutr1991;65:457-463.
28.
28. Conrad KP, Kerchner LJ, Mosher MD. Plasma and 24-h NOx and cGMP during normal pregnancy and preeclampsia in women on a reduced NOx diet. Am J Physiol1999;277:F48-F57.
29.
29. Nobunaga T, Tokugawa Y, Hachinoto T, et al. Plasma nitric oxide levels in pregnant patients with preeclampsia and essential hypertension. Gynecol Obstet Invest1996;41:189-193.
30.
30. Silver RK, Kupfemine MJ, Russell TL, Adler L, Mullen TA, Caplan MS. Evaluation of nitric oxide as a mediator of severe preeclampsia. Am J Obstet Gynecol1996;175:1013-1017.
31.
31. Davidge ST, STranko CP, Roberts MJ. Urine but not plasma nitric oxide metabolites are decreased in women with preeclampsia. Am J Obstet Gynecol1996;174:1008-1013.
32.
32. Lopez-Daranillo P, Narvaez M, Calle A, et al. Cyclic guanosine 3′, 5′ monophosphate concentrations in preeclampsia: Effects of hydralazine. Br J Obstet Gynecol1996;103:33-38.
33.
33. Cameron IT, Van Papendorp CL, Palmer RMJ, Smith Sk, Moncada S. Relationship between nitric oxide synthesis and increase in systolic blood pressure in women with hypertension in pregnancy. Hypertens Preg1993;12:85-92.
34.
34. Sumararon AK, Aelman KG, Young D, Redman CWG. Elevated levels of serum nitrate, a stable end product of nitric oxide, in women with preeclampsia. Br J Obstet Gynecol1997;104:358-343.
35.
35. Curtis NE, Gude NM, King RG, Marriott PJ, Rook TJ, Brennecke SP. Nitric oxide metabolites in normal human pregnancy and preeclampsia. Hypertens Preg1995;1995:339-349.
