| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1 Centre for Developmental Origins of Health & Disease, Princess Anne Hospital, Coxford Road, Southampton SO16 5YA, UK2 Fetal Health Research Group, Division of Obstetrics and Gynaecology, Guy's King's St Thomas Hospital, Lambeth Palace Road, London SE1 7EH, UK
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
(Received 26 July 2003;
accepted after revision 20 October 2003;
first published online 24 October 2003)
Corresponding author M. A. Hanson: Centre for Developmental Origins of Health & Disease, Princess Anne Hospital, Coxford Road, Southampton SO16 5YA, UK. Email: m.hanson{at}soton.ac.uk
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
During pregnancy, adaptations occur in the maternal circulation that include systemic vasodilatation and an increase in cardiac output (Gilson et al. 1992; Thornburg et al. 2000). The resulting rise in blood flow to the reproductive tract ensures a continuous nutrient supply to the growing fetus. Undernutrition during pregnancy impairs these maternal haemodynamic adaptations resulting in insufficient rises in cardiac output, plasma volume and uteroplacental flow (Rosso & Streeter, 1979; Ahokas et al. 1983; Ahokas et al. 1984). The reduction in systemic vascular tone via vasodilatation precedes and thus induces other critical adaptations in the maternal circulatory system during early pregnancy (Duvekot et al. 1993). Enhanced release of the endothelium-derived vasodilator nitric oxide (NO) is thought to account for the increased vasodilatation and fall in peripheral vascular resistance (Kopp et al. 1977; Conrad et al. 1993; Nathan et al. 1995; Poston et al. 1995; Williams et al. 1997). Reduced relaxation to endothelium-dependent vasodilators is evident in both uterine and mesenteric arteries from protein-restricted pregnant rats (Itoh et al. 2002; Koumentaki et al. 2002). Failure to make or sustain these cardiovascular alterations may result in complications in pregnancy and fetal outcome.
In the protein-restricted pregnant rat, reductions in the essential amino acids limit the effective utilization of the restricted diet. Supplementation with the non-essential amino acid glycine has been shown to restore the nitrogen balance (Snyderman et al. 1962; Kies, 1972; Jackson, 1995). In addition, since there is a large fetal requirement for glycine, reduction in fetal supply and/or biosynthesis adversely effect fetal development (Widdowson, 1979). Glycine thus becomes a conditionally essential amino acid in pregnancy. Recent evidence suggests that glycine may play an important role in maternal S-amino acid metabolism in pregnancy and/or fetal cardiovascular development since glycine supplementation, rather than urea or alanine supplementation, prevented elevated blood pressure in adult offspring of protein-restricted pregnant rats (Jackson et al. 2002). Glycine is a vital component of the S-amino acid metabolic pathway as it aids regulation of methionine and homocysteine levels (Bagley & Stipanuk, 1995) so that, in the face of fetal demands for glycine, the availability of these amino acids could be altered. Thus whilst current ideas focus on the direct effects on the developing fetus of sulphur amino acid imbalance the possibility also exists of indirect effects via an impaired maternal circulatory adaptation to pregnancy.
We therefore hypothesized that dietary glycine supplementation to the protein-restricted pregnant rat would improve vascular function in the maternal circulation. We compared the vasoreactivity of mesenteric arteries (MA) and the thoracic aorta (TA) from rats in late gestation (day 18/19) fed a protein restricted diet in the absence (PR) or the presence of glycine supplementation (PRG). We examined whether the vasorelaxation observed in each group was related to alterations in NO release by the vessels using chemiluminescence methods and, if so, whether this was associated with changes in endothelial nitric oxide synthase (eNOS) mRNA expression and plasma homocysteine (Hcy) levels.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Animals and dietary protein restriction
Thirty-six virgin female Wistar rats were mated (day of vaginal plug detection defined as day 0) and pregnant rats randomly assigned to three dietary groups: control (C, 18% casein, n= 14) and low protein ± 3% glycine (9% casein, PR, n= 15; 9% casein + glycine, PRG, n= 7) prepared as previously described by Jackson et al. (2002). Animals were humanely killed on day 18/19 of gestation by CO2 inhalation and cervical dislocation.
Sample collection and homocysteine analysis
Plasma total homocysteine concentration (C, n= 6; PR, n= 9; PRG, n= 6) was measured by high pressure liquid chromatography with fluorescence detection as described by Araki & Sako, 1987) modified by the use of cysteamine as an internal standard. Heart, lungs, liver, kidneys, pancreas and adrenal glands were removed and weighed at postmortem and are expressed as percentage of body weight. The uterus was removed for determination of fetal and placental weights.
Vasomotor responses
Thoracic aortae (TA) (C, n= 6; PR, n= 8; PRG, n= 6) were suspended in 20 ml organ bath chambers (Linton Instrumentation, Norfolk, UK) and equilibrated for 60 min at resting tension of 1.5 g weight prior to experimental protocols as previously described by Dantas et al. (1999). Small mesenteric arteries (MA) (C, n= 14; PR, n= 15; PRG, n= 7) were mounted on a Mulvany-Halpern wire myograph (J.P.Trading, Denmark). Both preparations were mounted in physiological salt solution (PSS (mmol l-1): NaCl 119, KCl 4.7, CaCl2 2.5, MgSO4 1.17, NaHCO3 25, KH2PO4 1.18, EDTA 0.026 and D-glucose 5.5), at 37°C and gassed with 95% O2–5% CO2. Cumulative concentration response curves (CRCs) were conducted to the 
1 adrenoceptor agonist phenylephrine (PE). Following preconstriction with PE (EC80), cumulative CRCs to the endothelium-dependent vasodilator acetylcholine (ACh) and ß-adrenoceptor agonist isoprenaline (ISO) were conducted as previously described by Torrens et al. (2003). All drugs and chemical were obtained from Sigma (Poole, UK).
Determination of NO levels
Bath samples of PSS (C, n= 5; PR, n= 6; PRG, n= 7) were reduced using an acidic potassium iodide solution and NO concentration produced from nitrite was quantified as previously described by Clough (1999). NO concentration in the samples was calculated by integration of signal peaks against a standard curve constructed using sodium nitrite (Sievers NOA, Analytix Ltd, Durham, UK).
Analysis of aortic and mesenteric artery eNOS mRNA expression
Sections of third order MA (C, n= 8; PR, n= 10) and TA (C, n= 10; PR, n= 13) were dissected clean of connective and adipose tissue, snap frozen in liquid nitrogen and stored at –80°C. RNA was extracted and converted to cDNA by standard methods. The cDNA was amplified and evaluated for eNOS mRNA expression by real-time PCR relative to 18 s ribosomal RNA (Applied Biosystems, Warrington, U.K). The forward primer 5'-CCAATTACTGCCAAGGCTGACT-3', reverse primer 5'-GGGTGGATTTGCTGCTCTGT-3 and probe 5'-FAM-TCTCCACAGAAAGAATTGTAGCCTGGAACA TCT-TAMRA-3' were used for eNOS real-time PCR.
Calculations and statistical analysis
All data are expressed as means ±S.E.M. Constrictor responses were calculated as percentage of maximum contraction induced by 125 mM KPSS and relaxant responses calculated at percentage PE-induced preconstriction. Agonist CRCs obtained from the three dietary groups were analysed by fitting to a four-parameter logistic equation using non-linear regression to obtain the pEC50 (–log molar concentration to produce 50% of response) and maximum response, which were compared by one-way analysis of variance (Prism 3.0, GraphPad software Inc., San Diego, CA, USA). eNOS mRNA levels were compared by Student's t test. NO and Hcy concentrations were compared using a one-way analysis of variance (Prism 3.0, GraphPad Software Inc.). Significance was assumed if the P-value was < 0.05.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
All dams showed a significant weight gain during pregnancy, which did not differ between groups (Table 1). Nor were there significant differences in litter size, fetal and placental weight or fetal:placental weight ratio between groups (Table 1). The weight of organs collected from pregnant dams did not differ between dietary groups, except lung and liver which were slightly larger in the PRG group versus PR (Table 2).
|
|
There was no significant differences in plasma total Hcy levels between groups observed, although a trend of higher Hcy in PR versus C was observed (C, 7.38 ± 0.09, n= 6; PR, 10.24 ± 1.27, n= 8; PRG, 8.52 ± 0.87, n= 6; Fig. 1).
|
Both ACh and ISO produced concentration-dependent relaxation of PE-constricted MA and TA. In the MA, sensitivity to ACh was significantly reduced in the PR (pEC50 values: C, 7.71 ± 0.05, n= 14; PR, 7.42 ± 0.03, n= 15, P < 0.01) with no change in maximum relaxation (Fig. 2A). Maximum relaxation (% maximum relaxation, C, 98 ± 1, n= 11; PR, 74 ± 7, n= 14; P < 0.01) and sensitivity to ISO were significantly blunted in the PR versus C (pEC50 values: C, 8.08 ± 0.04, n= 11; PR, 7.79 ± 0.05, n= 14; P < 0.001; Fig. 2B). Glycine supplementation in the PR group reversed the impaired relaxation to ACh (pEC50 values: ACh, PR, 7.42 ± 0.03, n= 15; PRG, 7.84 ± 0.05, n= 7, P < 0.001) and ISO (% maximum relaxation, PR, 74 ± 7, n= 14; PRG, 97 ± 1, n= 7; P < 0.05) in MA (Fig. 2A and B). Protein deprivation ± glycine repletion did not alter the vascular function in the TA (Fig. 3).
|
|
Basal NO production was lower in MA between PR versus C (C, 0.39 ± 0.07 µM, n= 5; PR, 0.16 ± 0.07 µM, n= 6; P= 0.05) as were NO levels induced by 0.1 µM ACh (C, 1.45 ± 0.42 µM, n= 5; PR, 0.31 ± 0.07 µM, n= 6, P < 0.01) and 1 µM ACh; (C, 1.09 ± 0.22 µM, n= 5; PR, 0.30 ± 0.09 µM, n= 6, P < 0.05) but these levels were restored in PRG (basal, 0.52 ± 0.12 µM, n= 7; ACh 0.1 µM, 0.61 ± 0.09 µM, n= 7; ACh 1 µM, 0.66 ± 0.16 µM, n= 7, Fig. 4A).
|
In both TA and MA there was no difference in mRNA expression of eNOS observed between C and PR groups (TA; C, 0.87 ± 0.44, n= 10; PR, 0.91 ± 0.42, n= 13; P= 0.949; MA; C, 5.51 ± 1.22, n= 8; PR, 4.86 ± 1.29, n= 10; P= 0.726; Fig. 4B). It was noted that eNOS mRNA expression was significantly elevated in MA compared to TA in both C and PR groups.
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
No differences were observed in maternal weight gain, litter size or fetal and placental weight, confirming previous observations by Itoh et al. (2002). Nor were significant differences in organ weights between the C, PR or PRG pregnant dams observed, with the exception of heavier lungs and livers in the PRG versus PR. This suggests that the dietary insult had minimal effects on the dams throughout their pregnancy. It is therefore clear that the effects on the offspring are independent of gross changes in fetal growth (Brawley et al. 2003a).
Disturbances in maternal peripheral vascular function through an imbalance in the local production and/or action of constrictors and dilators may result in abnormal cardiovascular adaptations in pregnancy (Sladek et al. 1997). In normal pregnancy, enhanced NO release is vital as it precedes and influences other haemodynamic changes, such as the fall in peripheral resistance, which are crucial for cardiovascular homeostasis (Duvekot et al. 1993). Dietary restriction or NO synthase inhibition are reported to result in disruptions in cardiovascular control in pregnancy (Rosso & Streeter, 1979; Ahokas et al. 1983, 1984; Zhang & Kaufman, 2000). In the present study, responses to the endothelium-dependent vasodilator, acetylcholine (ACh) were impaired in MA from the PR group, in agreement with Koumentaki et al. (2002). The blunting of ACh-induced relaxation in PR may be attributed to a reduction in synthesis or bioavailability of endothelial-derived vasodilators, NO, prostacyclin and/or endothelium-derived hyperpolarizing factor. ISO-induced relaxation was also attenuated in the PR group in MA, suggesting that ß-adrenoceptor signalling pathways are affected by protein deprivation: this is a novel observation. The defect in ISO-mediated relaxation may be associated with a decrease in basal NO release or reduced NO bioavailability, since ISO responses are potentiated by basal NO-mediated increases in cyclic guanosine monophosphate (Delpy et al. 1996). In MA, basal and ACh-induced NO release were indeed reduced in PR versus C, suggesting that NO bioavailability is reduced in the PR group. However, the effect seems unlikely to be due to reduced production of eNOS mRNA, since no differences in levels were observed between C and PR groups in MA. This indicates that changes in eNOS protein levels, eNOS activity and/or substrate deficiency account for the endothelial dysfunction observed in this model. Glycine supplementation to PR reversed the reduced NO levels and improved ACh and ISO relaxation in MA. Glycine therefore exerts a protective role on the maternal vasculature in part by enhancing NO release. One possibility is that this is due to a glycine-mediated increase in the formation of the antioxidant glutathione (Jackson, 1991).
Responses to ACh or ISO in the maternal TA were similar in all groups even though NO plays an important role in relaxation in this vessel (Bobadilla et al. 1997). Hence nutritional restriction in pregnancy induces vascular abnormalities which differ between conduit and resistance arteries. The physiological importance of this selective impairment in pregnancy is unknown but it may be a compensatory mechanism where a fall in peripheral vascular resistance is ensured, thereby preventing an increase in blood pressure. Cardiovascular disorders such as atherosclerosis are associated with endothelial dysfunction but not all vascular beds are affected (Luscher, 1992), which suggests that preservation of endothelium-dependent relaxation in certain vascular beds may be protective.
Hcy is a metabolite of methionine metabolism of the S-amino acid pathway (Medina et al. 2001). Elevated Hcy plasma levels are associated with an increasing risk of atherosclerotic plaque formation (Christen et al. 2000) and even small increments are reported to contribute to endothelial damage (Selhub, 1999). It is unclear how Hcy mediates vascular damage although increased oxidative stress resulting in decreased NO bioavailability has been proposed (Welch & Loscalzo, 1998). No significant differences in total Hcy were observed between the groups but Hcy levels did tend to be higher in the PR group. Petrie et al. (2002) reported significant elevations in total Hcy levels in protein-restricted dams at day 3 of gestation, but this did not persist into late gestation. It is therefore possible that elevated Hcy levels may have been present in the PR dams earlier in gestation but further work is required to confirm this. Glycine is involved in Hcy clearance by remethylation in the folate cycle of S-amino acid metabolism (Bagley & Stipanuk, 1995). In the present study, glycine repletion improved maternal vascular function, but this was not accompanied with reduced circulating levels of Hcy. Therefore glycine may induce beneficial effects on the maternal circulation which are unrelated to alterations in Hcy at this stage of pregnancy, although other components of the S-amino acid metabolic pathway may be implicated. This is supported by our recent work which indicates that folate supplementation of the low protein diet also improves maternal vascular function (Brawley et al. 2003b). Moreover, the degree of DNA methylation and hence epigenetic effects on gene expression can be affected by this pathway and this is known to be influenced by dietary composition in both fetal and adult rats (Pogribny et al. 1995a,b; Rees et al. 2000). Maternal S-amino acid metabolic status may therefore affect the level of fetal DNA methylation and have longer-term consequences. This provides another route by which glycine provision may affect fetal development.
In conclusion, we have shown that protein restriction in pregnancy selectively impairs vasodilator responses in maternal MA, but not in the TA. The vascular defect in MA is accompanied by impaired NO release but not in reduced eNOS mRNA levels. Glycine supplementation of PR restores NO release and ACh-induced vasorelaxation. Our study provides evidence that the dietary supply of the conditionally essential amino acid glycine appears to play a pivotal role in the adaptations of the maternal circulation during pregnancy, although it will be important to determine whether this effect is shared with other amino acids. Impairment of these adaptations by dietary imbalance provides an additional potential mechanism for fetal programming.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Ahokas RA, Reynolds SL, Anderson GD & Lipshitz J (1984). Maternal organ distribution of cardiac output in the diet-restricted pregnant rat. J Nutr 114, 2262–2268.
Araki A & Sako Y (1987). Determination of free and total homocysteine in human plasma by high-performance liquid chromatography with fluorescence detection. J Chromatogr 422, 43–52.[Medline]
Bagley PJ & Stipanuk MH (1995). Rats fed a low protein diet supplemented with sulfur amino acids have increased cysteine dioxygenase activity and increased taurine production in hepatocytes. J Nutr 125, 933–940.
Barker DJ, Gluckman PD, Godfrey KM, Harding JE, Owens JA & Robinson JS (1993). Fetal nutrition and cardiovascular disease in adult life. Lancet 341, 938–941.[CrossRef][Medline]
Bobadilla RA, Henkel CC, Henkel EC, Escalante B & Hong E (1997). Possible involvement of endothelium-derived hyperpolarizing factor in vascular responses of abdominal aorta from pregnant rats. Hypertension 30, 596–602.
Brawley L, Dance CS, Dunn RL, Anthony FW, Wheeler T, Jackson AA, Poston L & Hanson MA (2003b). Dietary folate supplementation prevents the attenuated relaxation to vascular endothelial growth factor (VEGF) in the uterine artery of protein-restricted in pregnant rats. Pediatr Res 53, 37A.
Brawley L, Itoh S, Torrens C, Barker AC, Bertram C, Poston L & Hanson MA (2003a). Dietary protein restriction in pregnancy induces hypertension and vascular defects in rat male offspring. Pediatr Res 54, 83–90.[CrossRef][Medline]
Christen WG, Ajani UA, Glynn RJ & Hennekens CH (2000). Blood levels of homocysteine and increased risks of cardiovascular disease: causal or casual?Arch Intern Med 160, 422–434.
Clough GF (1999). Role of nitric oxide in the regulation of microvascular perfusion in human skin in vivo. J Physiol 516, 549–557.
Conrad KP, Joffe GM, Kruszyna H, Kruszyna R, Rochelle LG, Smith RP, Chavez JE & Mosher MD (1993). Identification of increased nitric oxide biosynthesis during pregnancy in rats. FASEB 7, 566–571.[Abstract]
Dantas MF, Urban M, Spray D, Catelli De Carvalho MH & Passaglia RD (1999). Increased acetylcholine-induced vasodilation in pregnant rats: a role for gap junctional communication. Hypertension 34, 937–942.
Delpy E, Coste H & Gouville AC (1996). Effects of cGMP elevation on isoprenaline-induced increase in cAMP and relaxation in rat aortic smooth muscle: role of phosphodiesterase 3. Br J Pharmacol 119, 471–478.[Medline]
Duvekot JJ, Cheriex EC, Pieters FA, Menheere PP & Peeters LH (1993). Early pregnancy changes in hemodynamics and volume homeostasis are consecutive adjustments triggered by a primary fall in systemic vascular tone. Am J Obstet Gynecol 169, 1382–1392.[Medline]
Gilson GJ, Mosher MD & Conrad KP (1992). Systemic hemodynamics and oxygen transport during pregnancy in chronically instrumented, conscious rats. Am J Physiol 263, H1911–1918.[Medline]
Itoh S, Brawley L, Wheeler T, Anthony FW, Poston L & Hanson MA (2002). Vasodilation to vascular endothelial growth factor in the uterine artery of the pregnant rat is blunted by low dietary protein intake. Pediatr Res 51, 485–491.[Medline]
Jackson AA (1991). The glycine story. Eur J Clin Nutr 45, 59–65.[Medline]
Jackson AA (1995). Salvage of urea-nitrogen and protein requirements. Proc Nutr Soc 54, 535–547.[CrossRef][Medline]
Jackson AA, Dunn RL, Marchand MC & Langley-Evans SC (2002). Increased systolic blood pressure in rats induced by a maternal low- protein diet is reversed by dietary supplementation with glycine. Clin Sci 103, 633–639.[Medline]
Kies C (1972). Nonspecific nitrogen in the nutrition of human beings. Fed Proc 31, 1172–1177.[Medline]
Kopp L, Paradiz G & Tucci JR (1977). Urinary excretion of cyclic-3',5'-adenosine monophosphate and cyclic-3',5'-guanosine monophosphate during and after pregnancy. J Clin Endocrinol Metab 44, 590–594.[Abstract]
Koumentaki A, Anthony F, Poston L & Wheeler T (2002). Low-protein diet impairs vascular relaxation in virgin and pregnant rats. Clin Sci 102, 553–560.[Medline]
Langley SC & Jackson AA (1994). Increased systolic blood pressure in adult rats induced by fetal exposure to maternal low protein diets. Clin Sci 86, 217–222.[Medline]
Luscher TF (1992). Heterogeneity of endothelial dysfunction in hypertension. Eur Heart J 13 (Suppl. D), 50–55.
Medina M, Urdiales JL & Amores-Sanchez MI (2001). Roles of homocysteine in cell metabolism: old and new functions. Eur J Biochem 268, 3871–3882.[Medline]
Nathan L, Cuevas J & Chaudhuri G (1995). The role of nitric oxide in the altered vascular reactivity of pregnancy in the rat. Br J Pharmacol 114, 955–960.[Medline]
Petrie L, Duthie SJ, Rees WD & McConnell JM (2002). Serum concentrations of homocysteine are elevated during early pregnancy in rodent models of fetal programming. Br J Nutr 88, 471–477.[CrossRef][Medline]
Pogribny IP, Basnakian AG, Miller BJ, Lopatina NG, Poirier LA & James SJ (1995b). Breaks in genomic DNA and within the p53 gene are associated with hypomethylation in livers of folate/methyl-deficient rats. Cancer Res 55, 1894–1901.
Pogribny IP, Poirier LA & James SJ (1995a). Differential sensitivity to loss of cytosine methyl groups within the hepatic p53 gene of folate/methyl deficient rats. Carcinogenesis 16, 2863–2867.
Poston L, McCarthy AL & Ritter JM (1995). Control of vascular resistance in the maternal and feto-placental arterial beds. Pharmacol Ther 65, 215–239.[CrossRef][Medline]
Reddy KS (2002). Cardiovascular diseases in the developing countries: dimensions, determinants, dynamics and directions for public health action. Public Health Nutr 5, 231–237.[CrossRef][Medline]
Rees WD, Hay SM, Brown DS, Antipatis C & Palmer RM (2000). Maternal protein deficiency causes hypermethylation of DNA in the livers of rat fetuses. J Nutr 130, 1821–1826.
Rosso P & Streeter MR (1979). Effects of food or protein restriction on plasma Volume expansion in pregnant rats. J Nutr 109, 1887–1892.
Selhub J (1999). Homocysteine metabolism. Annu Rev Nutr 19, 217–246.[CrossRef][Medline]
Sladek SM, Magness RR & Conrad KP (1997). Nitric oxide and pregnancy. Am J Physiol 272, R441–463.[Medline]
Snyderman S, Holt L, Dancis J, Roitman E, Boyer A & Balis M (1962). Unessential nitrogen: a limiting factor for human growth. J Nutr 78, 57–72.
Thornburg KL, Jacobson SL, Giraud GD & Morton MJ (2000). Hemodynamic changes in pregnancy. Semin Perinatol 24, 11–14.[CrossRef][Medline]
Torrens C, Brawley L, Barker AC, Itoh S, Poston L & Hanson MA (2003). Maternal protein restriction in the rat impairs resistance artery but not conduit artery function in pregnant offspring. J Physiol 547, 77–84.
Welch GN & Loscalzo J (1998). Homocysteine and atherothrombosis. N Engl J Med 338, 1042–1050.
Widdowson EM (1979). Nutritional requirement and its assessment, with special reference to energy, protein and calcium. Bibl Nutr Dieta 148–154.
Williams DJ, Vallance PJ, Neild GH, Spencer JA & Imms FJ (1997). Nitric oxide-mediated vasodilation in human pregnancy. Am J Physiol 272, H748–752.[Medline]
Zhang Y & Kaufman S (2000). Effect of nitric oxide synthase inhibition on cardiovascular and hormonal regulation during pregnancy in the rat. Can J Physiol Pharmacol 78, 423–427.[CrossRef][Medline]
|
Acknowledgements |
|---|
This article has been cited by other articles:
|
|
 |
|
  M. P. Koeners, E. E. van Faassen, S. Wesseling, M. de Sain-van der Velden, H. A. Koomans, B. Braam, and J. A. Joles Maternal Supplementation With Citrulline Increases Renal Nitric Oxide in Young Spontaneously Hypertensive Rats and Has Long-Term Antihypertensive Effects Hypertension, December 1, 2007; 50(6): 1077 - 1084. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Bogdarina, S. Welham, P. J. King, S. P. Burns, and A. J.L. Clark Epigenetic Modification of the Renin-Angiotensin System in the Fetal Programming of Hypertension Circ. Res., March 2, 2007; 100(4): 520 - 526. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. D. Rees, F. A. Wilson, and C. A. Maloney Sulfur Amino Acid Metabolism in Pregnancy: The Impact of Methionine in the Maternal Diet J. Nutr., June 1, 2006; 136(6): 1701S - 1705S. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Torrens, L. Brawley, F. W. Anthony, C. S. Dance, R. Dunn, A. A. Jackson, L. Poston, and M. A. Hanson Folate Supplementation During Pregnancy Improves Offspring Cardiovascular Dysfunction Induced by Protein Restriction Hypertension, May 1, 2006; 47(5): 982 - 987. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. A. Lillycrop, E. S. Phillips, A. A. Jackson, M. A. Hanson, and G. C. Burdge Dietary Protein Restriction of Pregnant Rats Induces and Folic Acid Supplementation Prevents Epigenetic Modification of Hepatic Gene Expression in the Offspring J. Nutr., June 1, 2005; 135(6): 1382 - 1386. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. A. Hanson and P. D. Gluckman Developmental processes and the induction of cardiovascular function: conceptual aspects J. Physiol., May 15, 2005; 565(1): 27 - 34. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. C. Mcmillen and J. S. Robinson Developmental Origins of the Metabolic Syndrome: Prediction, Plasticity, and Programming Physiol Rev, April 1, 2005; 85(2): 571 - 633. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. G. Hemmings, S. Veerareddy, P. N. Baker, and S. T. Davidge Increased Myogenic Responses in Uterine but not Mesenteric Arteries from Pregnant Offspring of Diet-Restricted Rat Dams Biol Reprod, April 1, 2005; 72(4): 997 - 1003. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Racasan, B. Braam, H. A. Koomans, and J. A. Joles Programming blood pressure in adult SHR by shifting perinatal balance of NO and reactive oxygen species toward NO: the inverted Barker phenomenon Am J Physiol Renal Physiol, April 1, 2005; 288(4): F626 - F636. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E Zambrano, G. L Rodriguez-Gonzalez, C Guzman, R Garcia-Becerra, L Boeck, L Diaz, M Menjivar, F Larrea, and P. W Nathanielsz A maternal low protein diet during pregnancy and lactation in the rat impairs male reproductive development J. Physiol., February 15, 2005; 563(1): 275 - 284. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. A Armitage, I. Y Khan, P. D Taylor, P. W Nathanielsz, and L. Poston Developmental programming of the metabolic syndrome by maternal nutritional imbalance: how strong is the evidence from experimental models in mammals? J. Physiol., December 1, 2004; 561(2): 355 - 377. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. D. Gluckman and M. A. Hanson Living with the Past: Evolution, Development, and Patterns of Disease Science, September 17, 2004; 305(5691): 1733 - 1736. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H.-C. Han, K. J. Austin, P. W. Nathanielsz, S. P. Ford, M. J. Nijland, and T. R. Hansen Maternal nutrient restriction alters gene expression in the ovine fetal heart J. Physiol., July 1, 2004; 558(1): 111 - 121. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
); protein-restricted (PR, 9% casein, •) and protein-restricted with glycine supplementation (PRG, 9% casein + glycine, 
). Cumulative concentration relaxation response curve induced by A, endothelium-dependent dilator, acetylcholine (C, n= 14; PR, n= 15; PRG, n= 7; *P < 0.01 versus pEC50 C and PRG), and B, ß-adrenoceptor agonist, isoprenaline (C, n= 11; PR, n= 14; PRG, n= 5; *P < 0.05 versus maximum relaxation C and PRG) in phenylephrine preconstricted small mesenteric arteries from pregnant rat dams. Results are expressed as percentage relaxation of tone induced by phenylephrine (EC80).
