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ORIGINAL RESEARCH |
From the * Department of Obstetrics and Gynecology, University of Maastricht, Maastricht, Netherlands; and Department of Obstetrics and Gynecology, University of Bochum, Bochum, Germany.
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ABSTRACT |
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 ABSTRACT SUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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METHODS: Fifteen sheep with singleton pregnancies were chronically instrumented at 107 days of gestation (term is 147 days). Three days later, 8 of the fetuses received nitro-l-arginine methyl ester (L-NAME), an inhibitor of nitric oxide synthesis. Fifteen minutes after L-NAME administration, all 15 fetuses received lipopolysaccharides (LPS) from a strain of Escherichia coli. The 7 fetuses that received LPS only were used as controls. Sixty minutes after LPS was administered, the maternal aorta was occluded for 2 minutes in all fetuses. Organ blood flow and physiological variables were measured at 75 minutes before the start of occlusion (ie, at the time of L-NAME administration to the experimental group), at 1 minute before the start of occlusion, and at 2, 4, and 30 minutes after the start of occlusion.
RESULTS: Arterial pH was lower in the L-NAME group than in the control group at 1 minute before and 2 minutes after occlusion. Mean arterial pressure was higher in the L-NAME group than in the control group at 2 and 4 minutes after occlusion. Cardiac output fell in the L-NAME group and was lower than in the control group; the percentage of cardiac output to the cerebrum in the L-NAME group was 35% lower than that in the control group. Throughout the study, placental blood flow decreased by more than 80% in both groups and remained low. Blood flow to the fetal body decreased by 65% in the L-NAME group and was lower than in the control group. Blood flow to the carcass also decreased in the L-NAME group and was 36% of that in the control group.
CONCLUSION: Inhibition of nitric oxide synthesis causes a general vasoconstriction in practically all organs and leads to a reduction in LPS-induced circulatory decentralization. The changes in blood flow distribution in endotoxin-treated fetal sheep seem to be mediated in part by nitric oxide.
The exact mechanism by which asphyxia and infection are linked in the development of brain damage is not yet understood. Several products, such as lipopolysaccharides (LPS), may play a role in this process. Lipopolysaccharides stimulate astrocytes and microglia to produce various cytokines, such as tumor necrosis factor 
and interleukins 1ß and 6. Recent clinical studies have demonstrated that expression of these cytokines is much higher in brains with periventricular lesions than in those without such lesions.5 Newborns with lesions in brain white matter have been found to have higher concentrations of these cytokines in their amniotic fluid than did those without white-matter lesions.6
Hypoxemia and ischemia also induce an inflammatory response in the central nervous system of the immature rodent. This response is characterized by the very early expression of cytokines, which induce astrocytes to produce nitric oxide.7,8
Nitric oxide is a vascular and neuronal messenger and a cytotoxic and cytostatic agent.9 In a previous study on the effects of LPS on fetal circulation in preterm fetal sheep, we found that endotoxemia resulted in prolonged placental hypoperfusion and reduced oxygen delivery to the brain, effects that may contribute to perinatal brain damage. Furthermore, LPS blunted circulatory centralization, resulting in decreased blood flow to the placenta and brain and increased blood flow to the carcass, heart, lungs, and adrenals.10
On the basis of these and other results, we hypothesized that nitric oxide may mediate LPS-induced peripheral vasodilation and the circulatory decentralization that occurs during fetal hypoxemia. Nitric oxide is produced in large quantities after LPS administration and hence might be involved in the pathway that connects endotoxemia to circulatory failure.8 We therefore studied the effects of LPS after blocking nitric oxide synthesis with nitro-l-arginine methyl ester (L-NAME) in fetal sheep when gestation was 75% complete.
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SUBJECTS AND METHODS |
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ABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Fifteen pregnant ewes with singleton pregnancies were chronically instrumented at a mean gestational age of 107 ± 1 days (term is 147 days). Eight of the fetuses received L-NAME (Sigma Aldrich, Zwijndrecht, Netherlands), an inhibitor of nitric oxide synthesis. Fifteen minutes after L-NAME administration, 60 minutes before occlusion (t –60), all 15 fetuses received LPS from a strain of Escherichia coli. The 7 fetuses that received LPS only were used as controls. The ewes were 1 year old and had a mean (± standard error [SE]) weight of 64 ± 3.9 kg. All ewes underwent surgery with sterile techniques under general anesthesia. Thiopental sodium, 1 g per 70 kg of body weight intravenously, was used for induction of anesthesia, and 0.5–1.0% halothane in a 1:1 mixture of nitrous oxide and oxygen was used for maintenance. The ewes received 1 g of ampicillin (Pentrexyl; Bristol-Myers, Woerden, Netherlands) subcutaneously and 10 µg of buprenorphine (Temgesic; Schering, Utrecht, Netherlands) per kilogram of body weight twice a day for 3 consecutive postoperative days.
For the surgical procedure, a midline abdominal incision was made. A snare was placed around the maternal distal aorta below the renal artery to provide a means of temporarily arresting uterine and ovarian blood flow and inducing fetal asphyxia. The fetal limbs were identified and brought to the exterior through an incision in the uterus. Polyvinyl catheters (Maxxim Medical BV, Den Bosch, Netherlands) with an inner diameter of 0.75 mm and an outer diameter of 1.25 mm were inserted via both a fetal tibial vein and artery in each hind leg. The catheters in the tibial veins were then advanced into the caudal vena cava, and those in the tibial arteries were advanced into the abdominal aorta. Catheters were also placed into both brachial arteries. The fetal skin was closed with cyanoacrylate glue (Cyanolit; Eurobond Adhesives, Kent, UK). An intrauterine pressure catheter was placed, and the uterus was sutured after the amniotic fluid was replaced with a 39°C saline solution. Catheters were filled with heparin (100 IU/mL; Heparin-Natrium; Braun, Melsungen, Germany) and brought to the exterior through a small incision in the flank of the ewe. The catheters were protected by a pouch sewn to the skin of the ewe. A recovery period of 72 hours followed the operation before experiments were begun. Ewes were housed in individual cages and had free access to food and water.
The experiments were performed 3 days after the surgical procedure, at 110 ± 1 days of gestation, when gestation was 75% complete. Time points were designated in relation to the start of occlusion of the maternal aorta, which was designated as t = 0. After obtaining control measurements of blood flow and physiological variables, we selected 8 fetuses with a computer-generated, random-number table and injected them with a 30-mg intravenous bolus of L-NAME at 75 minutes before occlusion of the maternal aorta (t –75). This was followed by a continuous infusion of L-NAME at a rate of 6 mg/min. Adequate blockade of nitric oxide synthesis was confirmed by the intravenous injection of 2 µg of acetylcholine. Before the inhibition of nitric oxide synthesis, acetylcholine induced a decrease in mean arterial pressure (MAP) of ±15 mm Hg. This effect was completely abolished with the inhibition of nitric oxide synthesis.
Then, all 15 fetuses received LPS (51 ± 7 µg/kg) at 15 minutes after L-NAME administration, which is 60 minutes before occlusion of the maternal aorta (t –60). Lipopolysaccharide was administered in a dose of 50 µg/kg of estimated fetal weight, which was the same as that used in our previous study.11
To determine the effects of L-NAME and endotoxemia on the time course of circulatory centralization before, during, and after hypoxemia, we measured blood flow to fetal organs and the distribution of combined ventricular output by injecting suspensions of 16-µm-diameter microspheres labeled with 5 different radioisotopes (141Ce, 114In, 113Sn, 103Ru, and 46Sc; New England Nuclear Corporation, Boston, MA). The suspensions were prepared in 10% dextran containing 0.01% Tween 80. They were then sonicated and checked for size, shape, and aggregation. Depending on the specific activity, 0.7–1.8 x 106 microspheres per batch were injected at 5 different time periods over a period of 20 seconds. Using t = 0 as the start of the 2-minute occlusion of the maternal aorta, we injected the microsphere suspensions into the inferior vena cava11,12 of the control group at t –75 and t –1 (before the onset of hypoxemia), at t + 2 (at the end of the 2-minute period of hypoxemia), and at t + 4 and t + 30 (after the release of the snare). It was previously shown that injections of 6 different suspensions of 0.5–2.0 x 106 microspheres, 15 µm in diameter, can be administered without significant acute or chronic hemodynamic changes.12
Reference blood samples were drawn from the catheters, which were shifted upward to the carotid artery and a femoral artery, at a rate of 1.75 mL/min. Sampling was performed continuously for 390 seconds, from t –1 to t + 5.5. Separate samples were collected over a period of 90 seconds during the control period (t –75) and during recovery (t + 30). The volume of blood drawn was replaced by maternal blood that had been maintained at 39°C in a water bath.
During these procedures, fetal heart rate (FHR) and MAP were continuously recorded on a personal computer, using a customized hemodynamic data acquisition system. Blood samples were collected from the fetal descending aorta before each blood flow measurement and again at t –30 minutes. These were analyzed for blood gases, acid-base balance (AVL 993; Radiometer, Copenhagen, Denmark), hemoglobin concentration, and arterial oxygen saturation of hemoglobin (OSM 2 Hemoximeter; Radiometer, Copenhagen, Denmark). Glucose and lactate concentrations were measured at the same sampling points (YSI, 2300 Statplus Analyzer/2; Yellow Springs Instruments, Yellow Springs, OH).
After these measurements were completed, the each ewe was administered a lethal dose of sodium pentobarbitone (Euthesate; Apharmo, Duiven, Netherlands), and the fetuses were perfused with 200 mL of 10% formalin in saline. Fetal organs were weighed and placed in vials, which were filled to the same height to reduce variations in geometry. The intestines were separated from the mesentery and then opened and cleared of all contents. Paired organs (lungs, kidneys, and adrenals) were weighed separately, as were the right and left sides of the cerebrum. No significant preferential streaming of microspheres was detected in the right or left sides of the fetal cerebrum. Samples of skin and muscle tissue were collected from the fetuses' hips and shoulders. Cotyledons from the placenta, along with the upper and lower fetal body, were homogenized in a meat chopper, and the samples were placed into vials.
An applied solid-state semiconductor gamma counter (thallium activated, sodium iodine crystal) with a high-energy resolution of about 2 keV was connected to a multichannel (1,024) pulse-height analyzer (LKB 1282, Compugamma; Wallac, Turku, Finland). The results were normalized with respect to time and sample weight.
Fetal combined ventricular output and blood flow to the various fetal organs were calculated from counts of the injected nuclide that was recovered in fetal organs, placenta, and the appropriate reference samples and from the withdrawal rate of the reference samples.12,13 The percentage of combined ventricular output distributed to a given organ was calculated by measuring the absolute blood flow to that organ and the combined ventricular output. Oxygen delivery to the various organs (DO2), expressed as milliliters per minute per 100 g, was calculated according to the following formula:
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The data were analyzed for intra- and intergroup differences by 2-way multivariate analysis for repeated measures. The Games-Howell test was used as a post hoc testing procedure.14 Statistical analysis was performed with the Super Anova Statistical Package (Abacus, Monrovia, CA).
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RESULTS |
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During the immediate recovery, or postocclusion, phase, there was no improvement in the metabolic status of the control group, and mixed acidosis persisted (Table 1). Cardiac output did not recover (Table 4) during this phase in controls, and placental blood flow remained low but showed a tendency to recover (Table 2). Cerebral oxygen delivery also remained low during the recovery phase in controls (Table 4).
In the L-NAME group, measurements of blood gases were not significantly different from those in the control group during normoxia (t –75 and t –1). Injection of L-NAME resulted in a lower arterial pH and base excess than in the control group during normoxia. Glucose concentration was higher in the L-NAME group during normoxia. Partial bicarbonate pressure, oxygen saturation, and lactate concentrations were not statistically different between the 2 groups during normoxia (Table 1).
Mean arterial pressure tended to increase after L-NAME administration, whereas after LPS administration the hypotensive effect eclipsed this effect and there was no difference in MAP between the 2 groups (Fig. 1). Fetal heart rate in the L-NAME group tended to decrease in the normoxic period, whereas it increased in the control group (Fig. 2). During normoxia, cardiac ventricular output decreased in the L-NAME group to 39% of the value in the control group at t –1 (Table 2). Placental blood flow decreased to about the same level in both groups during normoxia (Table 2). Blood flow to the fetal body decreased by 65% after L-NAME administration and was significantly lower in this group than in controls at t –1 (Table 2). Blood flow to the carcass also decreased after L-NAME administration, to 36% of that in the control group (Table 3). After L-NAME administration, the percentage of cardiac output to the heart increased to twice the level in the control group at t –1 (Table 4). The rate of increase in adrenal blood flow during normoxia was lower in the L-NAME group than in the control group (Table 3). The percentage cardiac output to the brain was lower in the L-NAME group, especially in the recovery phase (Table 4). Cerebral oxygen delivery showed the same pattern in both groups, decreasing by about 50% during normoxia (Tables 3 and 4).
During the 2-minute period of hypoxemia, oxygen saturation declined to the same extent in both groups (Table 1). Po2 and glucose concentration were higher in the L-NAME group than in controls, whereas arterial pH and base excess were lower in the L-NAME group (Table 1). At the end of occlusion (t + 2), MAP increased in the L-NAME group but decreased further in the control group (Fig. 1), whereas FHR was not significantly different between the groups (Fig. 2). In both groups, cardiac output decreased equally during occlusion. Although absolute flow in the placenta decreased by more than 80% in both groups and thus was not different between the 2 groups, the percentage cardiac output to the placenta was 3 times higher in the L-NAME group during hypoxemia (Table 2). Blood flow to the fetal body decreased by 83% after L-NAME injection and was significantly lower in this group than in controls (Table 2). The rate of increase in percentage cardiac output to the fetal body was lower in the L-NAME group than in the control group, and this difference reached significance at the end of the occlusion (Table 2). During occlusion, blood flow to the adrenals increased in the control group but decreased in the L-NAME group (Table 3). Also during hypoxemia, the percentage cardiac output to the cerebrum was 35% lower in the L-NAME group than in the control group (P < .01 at t + 2) (Table 3). Cerebral oxygen delivery decreased to the same extent in both groups, reaching almost zero at the end of the 2-minute period of asphyxia (Table 4).
During the recovery phase, oxygen saturation was reduced to significantly lower levels in both groups, and arterial pH and base excess were not significantly different between the 2 groups (Table 1). Po2 and glucose concentration remained higher in the L-NAME group than in controls (Table 1). Mean arterial pressure also increased in the L-NAME group but decreased in the control group during this phase (Fig. 1). Fetal heart rate increased in the L-NAME group and was higher than in the control group (Fig. 2).
Although cardiac output remained significantly lower throughout the experiment in the L-NAME group than in the control group, the percentage of cardiac output to the placenta was higher during recovery in the L-NAME group (Table 2). Blood flow to the fetal body remained significantly lower in the L-NAME group than in controls during the immediate recovery period (t + 4 minutes) (Table 2), and the rate of increase in percentage cardiac output to the fetal body was lower in the L-NAME group during recovery. Blood flow to the adrenals and carcass remained lower in the L-NAME group (Table 3). The lower percentage of cardiac output to the cerebrum persisted in the L-NAME group during recovery (Table 3). The expected increase in cerebral blood flow after hypoxemia was absent in both groups (Tables 3 and 4).
Prolonged hypotension, combined with bradycardia, led to the death of 5 of the 7 control animals after t + 4. Six of 8 animals in the L-NAME group survived until the end of the experiment, when the animals were killed.
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DISCUSSION |
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The changes in fetal cardiovascular control seen in these experiments were of the same order and magnitude as those we have described previously.10 Other studies have also described fetal hypertension and bradycardia immediately after L-NAME administration in fetal sheep.16 The initial transient rise in MAP in the L-NAME group, although not significant, is most likely caused by systemic and umbilico-placental vasoconstriction due to inhibition of nitric oxide synthesis.17
The more pronounced hypotension seen in the control group during maternal aorta occlusion might indicate that the LPS-induced changes in FHR are mediated by nitric oxide. Cardiac output, which decreased steeply in the L-NAME group, showed a tendency to recover after hypoxemia, although it remained significantly lower than during normoxia. Cardiac output in the L-NAME group was approximately 40% of that in the control group at the end of the period of asphyxia. This finding can be ascribed to an increase in MAP, which in turn leads to an increase in afterload.18 In addition, the lower blood flow to the fetal body in the L-NAME group might lead to a lower venous return, in turn causing a lower cardiac output. These alterations contribute to the decrease in combined ventricular output that is evident with the inhibition of nitric oxide synthesis.19
Lipopolysaccharide endotoxin inhibited peripheral vasoconstriction, causing a higher blood flow to the fetal body. This measurement was lower in the animals pretreated with L-NAME. Thus, blood flow to the fetal body in the L-NAME group was lower than that in the control group. Previous studies have shown evidence for a role of nitric oxide in the regulation of resting tone in renal, mesenteric, hindquarter, carotid, and cerebral vascular beds and, thus, in blood pressure homeostasis.20,21 Our results suggest that the vascular bed of the premature fetal body is also mediated via nitric oxide and remains nitric oxide–dependent during hypoxemia and even under endotoxemic conditions.
Absolute placental blood flow was the same in both groups in our study; these values declined to almost zero at the end of the period of asphyxia and did not recover. The normal umbilico-placental circulation of sheep receives 40% of the fetal combined ventricular output at term.22 In our study, this percentage was about 45% during normoxia and decreased during occlusion, recovering slightly in the L-NAME group. Absolute placental blood flow also decreased in both groups, and there was no significant difference between the 2 groups. Premature fetal sheep exposed to LPS endotoxin have been shown to have profound reductions in placental blood flow and cerebral oxygen delivery.23 The regulation of umbilical and placental blood flow must depend on circulating or locally released vasoactive substances,24,25 because these vessels lack autonomic innervation.26 In fetal sheep, the microcirculation of the placenta is remarkably inert to many vasoconstrictors, whereas the umbilical artery and vein are more vasoactive.27,28 The inhibition of nitric oxide synthesis seems to only partially influence the changes in placental blood flow seen in endotoxin-treated fetal sheep. This decrease in placental blood flow could also result from endothelin-mediated vasoconstriction of the umbilical arteries. Endothelin-1 is a strong endothelium-derived vasoconstrictor peptide that constricts fetoplacental microcirculation and decreases fetal oxygen consumption in sheep. Activation of the endothelin-ß1 receptor, which is located on vascular endothelium, causes the release of vasoactive substances such as nitric oxide, leading to vasodilation.29,30 Activation of the endothelin-ß2 receptor, located on vascular smooth muscle, leads to vasoconstriction. Thus, placental blood flow changes might be attributed to a combination of the effects of endothelin-ß2 and endothelin-ß1.
The reduced cerebral blood flow observed in the L-NAME group might be caused by increased vascular resistance in the brain. Neither group experienced a rise in cerebral blood flow after hypoxia, as was previously observed in control animals undergoing hypoxemia.13 In our study, this lack of recovery in cerebral blood flow was probably due to hypotension after occlusion in the control group, whereas in the L-NAME group the lack of nitric oxide was involved. Nitric oxide mediates resting tone in the fetal cerebral vascular bed and is required for hypoxemia-induced cerebral vasodilation.31 In a previous study in fetal sheep at 60% and 90% of complete gestation, the posthypoxemia rise in cerebral blood flow was not lower in L-NAME–treated animals than in the control group.32 In addition, inhibition of nitric oxide synthesis has been shown to attenuate the delayed rise in cerebral blood volume and to increase the extent of cerebral injury.15,33 In our study, endotoxemia resulted in a constant cerebral blood flow but coincided with a severe fall in oxygen saturation. Previous studies have shown a positive correlation between cerebral blood flow and oxygen saturation.34 The normally occurring response of cerebral blood flow to hypoxemia might be altered by endotoxemia. In our study, cerebral blood flow was reduced by 50% in the L-NAME group, although oxygen saturation was the same in both groups. This result may be due to a normalizing effect of the inhibition of nitric oxide synthesis on the altered response during endotoxemia, thus leading to higher vascular resistance in the cerebrum.
Studies in the literature have shown that severe hypoxemia in the newborn lamb induces impairment of the autoregulatory ability of the cerebral vascular bed. Inhibition of nitric oxide synthesis by the administration of even a low dose of N
-nitro-l-arginine, started at reperfusion, restored autoregulation.35 These findings suggest a role for nitric oxide–induced vasodilation in the impairment of autoregulation of the cerebral blood flow after birth asphyxia.
Findings from a recent study do not provide strong evidence for cerebral hypoperfusion or hypoxemia as the primary etiological factor in brain injury after bacterial infection.36 Nonetheless, the authors of that study found damage to focal white matter after LPS injection, supporting epidemiological data that the antenatal brain is indeed susceptible to LPS.
From our data, we conclude that nitric oxide plays a role in the process of fetal cardiovascular decentralization after LPS injection. Inhibition of nitric oxide synthesis causes a collapse in combined ventricular output and a general vasoconstriction in practically all organs. The changes in blood flow distribution in endotoxin-treated fetal sheep seem to be mediated in part by nitric oxide. Certain changes in organ blood flow seem less influenced by nitric oxide synthesis inhibition, such as in the placenta, where other mediators might be more important. Furthermore, we conclude that inhibition of nitric oxide synthesis partially overrides LPS-induced peripheral vasodilation and leads to a reduction in LPS-induced circulatory decentralization.
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Footnotes |
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Received November 11, 2003. Received in revised form August 17, 2004. Accepted August 25, 2004.
doi:10.1097/01.AOG.0000146640.45530.69
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REFERENCES |
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