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(Hypertension. 1995;26:1019-1023.)
© 1995 American Heart Association, Inc.

Articles

Effects of Long-term Nitric Oxide Synthesis Inhibition on Plasma Volume Expansion and Fetal Growth in the Pregnant Rat

Sofía P. Salas; Fernando Altermatt; Mauricio Campos; Andrea Giacaman; Pedro Rosso

From the Departments of Obstetrics and Gynecology, Pediatrics, and Center for Medical Research, School of Medicine, Catholic University of Chile, Santiago.

	Abstract

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Abstract We conducted the present study to investigate whether the vasodilator nitric oxide plays a role in plasma volume homeostasis during pregnancy. Pregnant Sprague-Dawley rats were randomly assigned to a control group (n=18) or to groups receiving 0.69 mmol/L (n=11) or 1.7 mmol/L (n=14) N-nitro-L-arginine, a competitive inhibitor of nitric oxide synthetase, from gestational days 7 through 21. On day 20 systolic pressure was measured. On day 21 blood samples were taken for plasma volume, hematocrit, and hormonal measurements. Fetal and placental weights also were determined. Systolic pressure was significantly higher in experimental rats (101±6 and 115±6 mm Hg in the 0.69 and 1.7 mmol/L groups, respectively) than in controls (79.7±7.5 mm Hg), and plasma volume was lower (18.4±1.1 and 17.1±0.5 mL) than in controls (21.5±0.8 mL). Both experimental groups had increased hematocrit levels. Plasma renin activity was significantly lower in the experimental groups (11.5±3 and 7.2±1.5 ng angiotensin I/mL per hour) than in controls (21.9±2.7 ng angiotensin I/mL per hour); however, no changes were observed in aldosterone levels. Experimental groups had lower fetal weight (4.6±0.1 and 5.1±0.1 g) than controls (5.5±0.1 g). In addition, fetal hindlimb hypoplasia was observed in the experimental groups. In conclusion, the present data indicate that long-term N-nitro-L-arginine administration to pregnant rats leads to increased blood pressure, reduced plasma volume expansion, lower plasma renin activity, and fetal growth retardation. These results suggest that nitric oxide may play an important role in maternal systemic vasodilatation and indirectly in plasma volume homeostasis and fetal growth.

Key Words: pregnancy • nitric oxide • aldosterone • renin • fetal growth retardation

	Introduction

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Early gestation is characterized by a systemic vasodilatation that stimulates the renin-angiotensin-aldosterone system, resulting in sodium and water retention and ultimately in plasma volume expansion.^{1 2 3} In turn, during the second half of gestation plasma volume expansion influences cardiac output and secondarily uterine blood flow. Thus, systemic vasodilatation would set in motion a series of hemodynamic changes that are important for fetal growth. Consistent with such a possibility, normotensive women with idiopathic fetal growth retardation⁴ as well as mothers with preeclampsia⁵ have a lower plasma volume expansion associated with a reduced cardiac output and increased total peripheral vascular resistance.

Despite its apparent importance, little is known about the mechanisms causing the systemic vasodilatation of pregnancy. Early increases in urinary excretion of prostacyclin⁶ and kallikrein⁷ have been observed in normal pregnancy, whereas decreased levels of these vasodilators have been reported in pregnant women with idiopathic fetal growth retardation or preeclampsia.^{6 7 8} Thus, prostacyclin and kallikrein may participate in maternal vasodilatation, but many aspects regarding the possible mechanisms of this physiological adaptation remain unknown.

In recent years the role of NO as a potent vasodilator has become well accepted.^{9 10} In pregnant rats urinary excretion and plasma levels of nitrate, the stable NO metabolite, are increased. Similarly, an increase in urinary excretion of cGMP, the second messenger of NO, has been observed, paralleling the rise in urinary nitrate excretion.¹¹ In addition, this rise in cGMP is associated with increased NO synthase activity in maternal tissues,¹² implying that NO may play a role in maternal systemic vasodilatation.

We conducted the present study to explore this possibility by observing the effects of long-term administration of NO-Arg, a competitive inhibitor of NO synthetase, in the pregnant rat.

	Methods

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Virgin Sprague-Dawley rats weighing 230 to 270 g were used and maintained at a constant temperature (24°C) in a 12-hour light/dark cycle. The procedures followed were in accordance with institutional guidelines.

All rats had systolic pressure measured by tail-cuff plethysmography before mating.¹³ The day of conception (day 0 of pregnancy) was determined by the presence of spermatozoa in vaginal smears. On day 7 of gestation the rats were randomly assigned to either a control group or experimental groups (Exp). For the rest of gestation the latter had their drinking water replaced by either 0.69 mmol/L (Exp 1) or 1.7 mmol/L (Exp 2) solution of NO-Arg (Sigma Chemical Co) in tap water. Eighteen rats were used for the control group, 11 for Exp 1, and 14 for Exp 2. Based on water intake, the estimated NO-Arg average daily dose received by the experimental groups was 10 and 25 mg/kg, respectively.

For determination of a possible role for NO in the implantation process, eight additional rats received 1.7 mmol/L NO-Arg dissolved in their drinking water from day 0 through day 7 of gestation.

Systolic pressure was measured again on day 20 of gestation. On day 21 the rats were weighed and anesthetized with pentobarbital sodium (4 mg/kg), and plasma volume was determined as previously described.¹⁴ Briefly, approximately 1 mg/kg of body weight of T-1824 dye (Evans blue) diluted in normal saline was injected into the femoral vein. Ten minutes later both renal pedicles were ligated, and blood was obtained from the abdominal aorta and placed in ice-cold tubes containing either liquid EDTA (for PRA determinations) or sodium heparin (for plasma volume and aldosterone determinations). Rats were then killed, and the uterus and its content were removed; the maternal net body weight (after removal of all major organs) and the weights of individual fetuses and placentas were recorded. An aliquot of the blood sample taken from each rat was used for microhematocrit determinations, and the remaining was centrifuged at 4°C to separate plasma. These samples were immediately frozen for later hormonal determinations. For plasma volume estimates an aliquot of plasma was diluted 1:9 (vol/vol) with normal saline.¹⁴

Hormonal determinations were performed with commercially available radioimmunoassay kits (New England Nuclear for PRA and Diagnostic Products Corp for aldosterone). PRA results are expressed as nanograms Ang I per milliliter per hour.

Statistical analysis was done by a single-factor factorial design ANOVA with STATVIEW II (Abacus Concepts, Inc). Differences between group means were determined by Fisher's protected least-significant differences test, with a significance level of 95%.

	Results

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Maternal body weight at term was significantly lower in the experimental rats than in the control group (control, 418±12.4 g, mean±SEM; Exp 1, 385±11 g; Exp 2, 383±9.7 g; P<.05). In contrast, net maternal weight was similar in all groups (Table 1).

View this table: [in this window] [in a new window]   Table 1. Maternal Effects of Long-term NO-Arg Administration During Pregnancy

Systolic pressure was higher in the experimental groups (P<.01, Table 1), but values remained below the range observed before mating (126±3.3 mm Hg). Plasma volume was lower in both experimental groups than in the control group (P<.001, Table 1). By contrast, hematocrit values were higher in rats treated with NO-Arg (P<.01, Table 1). PRA levels were significantly lower in the experimental groups (P<.001); however, aldosterone values were similar in all groups (Table 1). Pooled data from the three groups revealed a positive and significant correlation between PRA and aldosterone levels (r=.48, P<.01); when only control rats were considered, this correlation increased to .64. Weak, although significant, correlations were observed between PRA and plasma volume (r=.43, P<.01) and fetal weight (r=.38, P<.03) as well as between plasma volume and fetal weight (r=.36, P<.03). None of these maternal variables exhibited significant differences between the two experimental groups.

Litter size was significantly reduced only in the group receiving 1.7 mmol/L NO-Arg (P<.001, Table 2). This reduction was due to early fetal death, as reflected by an increased number of fetal reabsorption sites (P<.001, Table 2). Fetal weight was lower in both experimental groups (P<.001), particularly in the group that received 0.69 mmol/L NO-Arg (Table 2). However, average placental weight was similar in all groups (Table 2).

View this table: [in this window] [in a new window]   Table 2. Fetal Effects of Long-term NO-Arg Administration During Pregnancy

Hindlimb hypoplasia, either unilateral or bilateral, not associated with other malformations, was observed in 6.5% and 12.7% of the fetuses of the Exp 1 and Exp 2 groups, respectively. The weight of the malformed fetuses was similar to that of the rest of the litter. Additional pregnant rats (n=8) that received 1.7 mmol/L NO-Arg were allowed to deliver. In three of them, hindlimb hypoplasia was present in one or more of the fetuses; these newborns had normal postnatal growth. The Figure shows a photograph of a 3-month-old male offspring depicting the characteristic anomaly. As revealed by the x-ray film, the alteration was a complete absence of toe development.

View larger version (95K): [in this window] [in a new window]   Figure 1. Top, Photograph of 3-month-old male offspring of a dam treated with 1.7 mmol/L NO-Arg during pregnancy shows the late effects of the hindlimb alteration. Bottom, X-ray film of the same rat.

Another rat group (n=8) received 1.7 mmol/L NO-Arg in drinking water from gestational day 0 through day 7. When compared with the control group no significant changes in maternal hemodynamics or fetal growth were observed (data not shown). Litter size was not affected, and none of the fetuses had hindlimb hypoplasia or any other malformation. No maternal death was observed in any of the groups.

	Discussion

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In this study we describe the effects of long-term administration of an NO synthesis inhibitor during pregnancy on maternal blood pressure, plasma volume, PRA, serum aldosterone levels, and fetal growth. Administration of NO-Arg from day 7 of pregnancy to term caused a dose-dependent increase in systolic pressure, although blood pressure values remained below the nonpregnant range. This result suggests that NO may play an important role in the vasodilatation of pregnancy.

Other researchers have reported that short-term administration of NO-Arg in the pregnant rat increases blood pressure and reverses the pregnancy-induced refractoriness to vasopressor agents.^{15 16} Moreover, L-NAME, another specific inhibitor of NO synthesis, administered for a few days either in drinking water¹⁷ or intravenously¹⁸ causes an increase in maternal blood pressure that can be prevented by the administration of the NO precursor L-arginine. The previous information indicates that prolonged blockade of NO synthesis in gravid rats may cause changes in blood pressure ranging from a dampening of the normal drop observed during pregnancy to hypertension. Clinical studies have shown that circulating levels of nitrite are decreased in patients with preeclampsia, supporting the concept that diminished NO synthesis contributes to the pathophysiological changes seen in preeclampsia.¹⁹

Additionally, the observation that NO synthesis inhibition during pregnancy is associated with a limited plasma volume expansion and fetal growth retardation, also reported in some of the studies in the literature,¹⁸ is in line with our hypothesis that plasma volume expansion is a crucial hemodynamic adjustment for fetal growth. According to this possibility, plasma volume expansion is necessary to increase cardiac output and indirectly uteroplacental blood flow, further indicating that a decreased vasodilatation may interfere with normal fetal growth.

With respect to the fetal effects, reduced litter size and fetal weight have been reported in rats receiving L-NAME^{17 18 20} but were not observed when the inactive enantiomer D-NAME was used,²⁰ indicating that fetal growth retardation is secondary to NO inhibition.

The mechanisms of fetal growth retardation associated with blockade of NO synthesis inhibition are still unknown. As mentioned above, it can be secondary to the reduced vasodilatation and lower plasma volume expansion. Since it is known that the placental villus vascular tree has the ability to both generate and respond to NO,²¹ fetal growth retardation also can be related to a compromised placental circulation.

Fetal hindlimb hypoplasia was reported after maternal treatment with L-NAME, another NO synthase inhibitor; was not present when D-NAME, the inactive enantiomer of L-NAME, was given; and was reduced with the coadministration of the NO donor nitroprusside sodium to the pregnant rats, indicating that this defect is most likely related to the ability of the drug to inhibit NO formation.²⁰ However, we cannot rule out the possibilities that the drug itself could cause birth defects and that NO, working outside its capacity to produce vasodilation, may be important in fetal development. The absence of fetal malformations after administration of the drug during the first week of pregnancy suggests that this alteration would be secondary to necrosis of mesenchymal tissues that had been fully differentiated.

Mothers with growth-retarded infants have lower plasma volume expansion, reduced cardiac output, and increased total peripheral vascular resistance.⁴ Similarly, in animal models interference with plasma volume expansion leads to a reduced uteroplacental blood flow and fetal growth retardation.^{22 23} In the present study both experimental groups had a smaller plasma volume and reduced fetal weight. In this respect, it seems paradoxical that the group that received 1.7 mmol/L NO-Arg had higher fetal weight than the group that received the lower dose. However, this fact can be explained by the reduced litter size observed in these rats. We believe that the early reduction in litter size may have favored a greater uteroplacental blood flow per unit of body weight in the surviving fetuses.

The present results support the concept that plasma volume expansion is a consequence of maternal vasodilation, most probably mediated by NO.^{8 24} In keeping with this hypothesis, several studies have provided evidence that maternal hemodynamic adaptation to pregnancy is triggered by a primary fall in systemic vascular tone.^{2 25} This vasodilation would reduce systemic vascular resistance and produce secondary stimulation of the renin-angiotensin-aldosterone system, with subsequent renal sodium and water retention.¹ The present study did not explore the possibility that other vasodilators, such as prostaglandins and kallikrein, may participate in this hemodynamic adjustment. However, short-term cyclooxygenase inhibition in unstressed, conscious rats did not alter the rise in renal hemodynamics and did not attenuate the systemic and renal pressor responsiveness observed during pregnancy, providing evidence against the hypothesis that prostaglandins are the vasodepressor agents of pregnancy.²⁶ On the other hand, pregnant women with idiopathic fetal growth retardation or with preeclampsia have reduced urinary kallikrein activity.^{7 8} Kallikrein exerts its vasodilator action through bradykinin formation, which in turn releases NO from endothelial cells.^{10 27} Therefore, NO inhibition also may interfere with the vasodilator response to kinins.

To the best of our knowledge, this is the first study that measures the effects on PRA and aldosterone levels produced by long-term NO synthesis inhibition during pregnancy. The administration of NO synthase inhibitors on renin release has yielded conflicting results. In anesthetized dogs NO-Arg reduced renin release stimulated by renal arterial constriction but had no effect on basal renin release.²⁸ In Wistar rats treated on a long-term basis with NO-Arg, PRA was not significantly different from that of control rats, despite increased systolic pressures. However, the subgroup of rats with left ventricular hypertrophy had higher PRA than the rats without hypertrophy.²⁹ In another study long-term NO-Arg administration to conscious rats reduced PRA.³⁰ Our data suggest that in pregnancy, which is characterized by high renin activity,^{13 14} NO-Arg administration inhibits renin secretion. It is interesting to note that preeclamptic women have reduced PRA and increased sensitivity to Ang II infusion.³¹ In addition, NO-Arg administration to pregnant rats reverses the pregnancy-induced refractoriness to vasopressor agents, supporting the view that NO plays a key role in the regulation of blood pressure during pregnancy.¹⁶

Despite lower plasma volume values observed in the NO-Arg–treated groups, the normal aldosterone levels are in apparent contradiction with the current theories about the role of this hormone in volume homeostasis during pregnancy.¹ However, since the experimental groups had only a relative reduction in plasma volume, the present results do not rule out a role of aldosterone in this hemodynamic change. More surprising is the fact that in both experimental groups PRA was markedly reduced without affecting aldosterone levels. It is well known that PRA, through changes in Ang II levels, is one of the main determinants of aldosterone secretion.³² Several mechanisms can explain this apparent dissociation. One possibility is that NO-Arg administration may increase Ang II receptor number or affinity in the glomerulosa zone. Alternatively, other factors that are important mediators of aldosterone release, such as potassium and atrial natriuretic peptide levels, may increase as a result of NO synthesis inhibition.³² Finally, consistent with the finding that long-term NO-Arg administration in the rat leads to severe glomerular injury,¹⁸ renal metabolism of aldosterone might be reduced in the experimental animals.

In conclusion, the present data indicate that in the pregnant rat inhibition of NO synthesis by NO-Arg administration interferes with normal maternal systemic vasodilatation, limiting plasma volume expansion and causing fetal growth retardation. These results support our hypothesis that normal plasma volume expansion during pregnancy is secondary to maternal vasodilation and suggest that interference with this physiological adjustment may produce fetal growth retardation. In addition, the data provide a caveat regarding the use of NO-Arg in pregnant women.

	Selected Abbreviations and Acronyms

 

Ang I, II = angiotensin I, II D-NAME = NG-nitro-D-arginine methyl ester L-NAME = NG-nitro-L-arginine methyl ester NO = nitric oxide NO-Arg = N-nitro-L-arginine PRA = plasma renin activity

	Acknowledgments

 
This work was partially supported by grants 92-0657 and 194-0603 from the Fondo Nacional de Ciencias (Chile), FONDECYT. The authors wish to thank Carolina Kunstmann and Christian Zárate for their invaluable help in performing the experiments.

	Footnotes

 
Reprint requests to Dr Sofía P. Salas, Center for Medical Research, Catholic University of Chile, PO Box 114-D, Santiago, Chile. E-mail ssalas@osler.med.puc.cl.

Received June 19, 1995; first decision August 1, 1995; accepted August 23, 1995.

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