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J Physiol (2003), 548.2, pp. 519-526
© Copyright 2003 The Physiological Society
DOI: 10.1113/jphysiol.2002.034470
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ABSTRACT |
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Ductus venosus (DV) sparing means the maintenance of blood flow through the DV following reduction of liver venous blood supply during fetal hypoxia. The present study compared the reactions of the isthmic portion of the DV and intrahepatic veins (IHVs) to catecholamines in vitro. Vessel rings of 1 mm width and 3 mm diameter were obtained from 17 fetal sheep (88-136 days gestational age, median 120 days). The immunohistochemical examination of the DV and IHV was performed in eight cases using an antibody against-smooth muscle actin and an antibody against
(Received 15 October 2002; accepted after revision 29 January 2003; first published online 7 March 2003)
Corresponding author M. Tchirikov: Klinik für Frauenheilkunde und Geburtshilfe, Martinistraße 52, 20246 Hamburg, Germany. Email: tchiriko{at}uke.uni-hamburg.de
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INTRODUCTION |
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In the fetus, normally one-third of the umbilical blood flow passes through the ductus venosus (DV) whilst the other two-thirds supply the liver (Rudolph, 1983). Experiments in sheep have demonstrated that during acute fetal hypoxia the ratio of DV to umbilical vein blood flow (DV/UV ratio) increases (Reuss & Rudolph, 1980; Tchirikov et al. 1998a, 2001). Flow rates in these experiments were measured using the microsphere technique or using Doppler ultrasound methodology. Thus DV flow tends to be maintained and this 'ductus venosus sparing effect' contributes to the preservation of the oxygen supply to the fetal brain and heart during hypoxia (Reuss & Rudolph, 1980). Paulick et al. (1991) reproduced DV sparing by intravenous infusion of catecholamines into fetal sheep. The authors also showed that the maintenance of DV flow was associated with a reduction of umbilical liver blood supply. Because catecholamine concentrations in fetal plasma increase markedly during hypoxia (Jensen et al. 1987; Tchirikov et al. 1998a) and because these hormones are long-established powerful vasoconstrictors, the mechanism for DV sparing may be hypothesised to be mediated by rising plasma concentrations of adrenaline and noradrenaline. In addition to these systemic actions, Pearson et al. (1980) demonstrated sympathetic innervation of the DV in human fetuses, a finding consistent with local catecholamine effects.
Umbilical blood flow redistribution as measured by Doppler ultrasound and the alteration of blood flow profiles in the DV and in liver veins has been used in clinical perinatal practice as a sign of fetal hypoxia (Hecher et al. 1995; Kiserud et al. 1994). However, the mechanisms by which central venous blood flow is redistributed during hypoxia are not fully understood.
The DV and the intrahepatic veins (IHVs) are arranged in parallel. (The IHVs are defined as afferent liver veins which accept blood from the umbilical and portal veins and enter the liver; they are to be distinguished from the hepatic veins carrying blood out of the liver.) Thus, from a haemodynamic viewpoint, changes of the DV/UV flow ratio must reflect changes of the ratio of the resistance to blood flow through the IHVs relative to the resistance to blood flow through the DV. An increase of the DV/UV flow ratio then indicates that resistance to flow through the DV has decreased more (or increased less) than the resistance to flow through the IHV. This may be achieved in several ways. For example, using B-scan ultrasound, Bellotti et al. (1998) were able to demonstrate the increase of the DV diameter in growth-retarded human fetuses, which would reduce the resistance of the DV. Kiserud et al. (2000) also demonstrated a substantial increase in the diameter of the DV during hypoxaemia. We could not, however, detect a significant increase of the DV diameter (isthmic region) in fetal sheep during acute hypoxia or in human intrauterine growth-retarded fetuses (Tchirikov et al. 1998a,b).
Another possibility is that during hypoxia there is an increase of the resistance in both IHVs and the DV, but to a lesser extent in the DV than in the IHV. If this were to occur, umbilical venous blood flow as well as hepatic parenchymal flow would be reduced, but DV flow could be maintained or even increased. There is experimental evidence that central venous flows indeed change in fetal sheep as described (Paulick et al. 1990) but it is unknown why the resistance increases are different.
In this in vitro study we tested the hypothesis that DV sparing is caused by different responses of IHVs and of the DV to circulating adrenaline and noradrenaline.
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METHODS |
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The experimental procedures were approved by the board on animal studies of the State Authority for Labour, Health and Social Issues of the State of Hamburg, Germany. The experiments were performed on vessel rings from the isthmic portion of the DV and from intrahepatic afferent veins (IHV) isolated from the right and the left lobes of the fetal liver. The vessel rings were obtained from 17 fetal sheep at gestational ages between 88 and 136 days (median 120 days). The animals were included in studies on the effects of the obstruction of umbilical-placental vessels, or of the DV published elsewhere (Tchirikov et al. 2001, 2002). The vascular rings were isolated from fetuses at the termination of those experiments.
Preparation of the vessels
The animals were killed by injection of 0.3 ml kg-1 T61 (1 ml T61: 0.2 g embutramide, 0.05 g mebezoniumjodid, 0.005 g tetracaine hydrochloride; Intervet Deutschland GmbH, D-85701 Unterschleißheim, Germany) into the external jugular vein of the maternal sheep and, if necessary, into the fetal heart. The fetal abdomen was opened and the sternum was removed. The intra-abdominal portion of the umbilical vein was ligated. A polyethylene catheter with an outer diameter of 2 mm was inserted into the inferior caval vein (IVC) and directed towards the liver. After ligation of both ends of the IVC, caudally and cranially to the liver, the organ was excised. The umbilical vein was opened with scissors up to the sinus venae portae. Then, Tyrode solution (37 ° C) was injected through the catheter into the IVC to identify the DV by the extruding fluid. A ring taken from the isthmic portion of the DV and a ring from IHVs were cut free within 5-15 min and placed immediately in Tyrode solution (37 °C; mM: NaCl 132.2; KCl 4.8; MgCl2 0.49; NaHCO3 11.9; NaH2PO4 0.36; glucose 5.05; and sodium pyruvate 2.0; gassed with 95 % O2/5 % CO2; pH 7.3 and PO2 about 500 mmHg). The rings were of 1 mm width, each of about 3 mm diameter and weighed about 15 mg. Each of the rings was then transferred within 10 min into an individual thermostable bath filled with Tyrode solution. The rings were secured by ties between a force transducer (Swema 45, Stockholm, Sweden) and a Ling 101 vibrator (Ling Dynamik Systems Ltd, Royston, Herts, UK). The resting tension was set to 2 mN (because of preliminary studies) by adjusting the length of the rings. The preparations were allowed to stabilise for 1 h.
Experimental procedures
Vessel contractions were first induced with K+-Tyrode solution (KCl max, equimolar replacement of Na+ by 124 mM K+) as shown in Fig. 1. The tonic contractions were completely removed by flushing the chambers with normal Tyrode solution and resting tension was readjusted, if necessary, to 2 mN (Fig. 1). Next, noradrenaline (Sigma) was added in a sequence of eight increasing steps (0.006, 0.03, 0.3, 0.6, 3, 6, 30 and 60 µM per step). At each step, the maximum force was measured. When the vessels had reached a stable maximum contraction force at the highest concentration of catecholamines, they were vibrated (100 Hz, duration 1 s) so as to cause a rapid and transient relaxation of the contracted vessels (Fig. 1). The baths were then flushed with normal Tyrode solution to remove noradrenaline and thus no longer stimulate tonic contractions. After adjustment of the resting vessel tension to 2 mN, the KCl-induced vessel contraction was repeated in some cases. Subsequently, adrenaline (Sigma) was added stepwise to both baths (0.002, 0.02, 0.2, 2 and 40 µM per step). Vessel tensions were recorded continuously as shown in Fig. 1.
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Figure 1. Response of the ductus venosus and of intrahepatic veins to KCl, noradrenaline and adrenaline Typical response of the ductus venosus (DV) and an intrahepatic vein (IHV) to KCl (124 mM) and to noradrenaline (0.006, 0.03, 0.3, 0.6, 3, 6, 30 and 60 µM, added stepwise, double-headed arrows) and adrenaline (0.002, 0.02, 0.2, 2 and 40 µM). The effects were reversible after flushing. Note the different time course of force development in response to KCl. At the end of each contraction, vessel vibrations (V, 100 Hz, 1 s) reversibly decreased the vessel tonus. | ||
The kinetics of the actin-myosin interaction were analysed based on the vibration method (Klemt et al. 1981). The time(s) of vessel recovery after vibration to re-attain one-third of the muscle force prior to vibration was measured and used as an index of cross-bridge cycle kinetics.
Histological methods
Nineteen tissue samples (1-2 cm3) containing the DV and IHVs from an additional eight fetuses with gestational ages between 114 and 135 days (median 126 days) were immersion-fixed with buffered 4 % formaldehyde solution (pH 7.4). In four cases, tissue samples were frozen in liquid nitrogen. Serial cryostat sections (12 µm) were prepared at -21 °C. The formalin-fixed specimens were dehydrated in a graded series of ethanol and embedded in paraffin.
Immunohistochemical reactions were performed on serial paraffin sections using an antibody against -smooth muscle actin (Sigma). They were also carried out on serial cryostat sections using an antibody against - and 
-adrenergic receptors (Chemicon International, Inc.,Temecula, CA, USA; MAB399 and AB5122). A standardised streptavidin-biotin technique (Frank et al. 1994) was used. Control reactions were performed omitting the primary antibodies. The control experiments did not reveal any staining (Fig. 6B). The same serial sections were used to investigate the vessel structure using Masson's trichrome stain.
Data acquisition and analysis
The force signals were recorded at a sampling rate of 100 Hz with an MP100WSW Biopac system (Goleta, CA, USA) and the data were stored on disk. In three cases the force signal was digitised with an analog/digital converter (DAS 1600, Metra Byte Corp, Taunton, MA, USA) at a sampling rate of 40 Hz. Mean tension during about 15 s before vessel contraction was accepted as the basic tension (approximately 2 mN). The maximum force of vessel contractions at each catecholamine concentration was derived from the mean value within 1 s observation time. Dose-response curves for each vessel (with tension as a percentage of the maximum tension obtained at the highest catecholamine concentration) were derived by fitting to Hill's equation, (% force = (concentrationnH)/(a + concentrationnH)] and the catecholamine concentrations for half-maximal effect (EC50) were calculated. Mean values of exponent nH and constant a were used to construct average dose-response curves (Fig. 4). The maximum force development in response to noradrenaline (100 µM) and to adrenaline (42 µM) was also expressed as a percentage of the maximum force development induced by KCl (124 mM). Data are presented as means ± S.E.M. Means were compared by Student's paired and unpaired t tests as well as ANOVA. Differences were considered significant at P < 0.05.
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RESULTS |
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Figure 1 shows an example of the vascular reactions to KCl and to catecholamines. Vessel rings from IHVs always responded to potassium and catecholamine stimulation. Five out of 10 vessel rings from the DV obtained from fetuses at gestational ages between 88 and 111 days (median 95 days) did not respond to KCl depolarisation, or their maximum force development was less than 0.2 mN. These five experiments (both DV and IHV data) were not included in the analysis. Later in gestation (119-126 days, median 124 days, n = 7), all rings responded to potassium stimulation, though with different time courses.
On average, rings from IHVs (n = 12) required 4.1 ± 0.8 min to reach their maximum tension with KCl depolarisation; then, after slight relaxation, a stable muscle contraction was established (Fig. 1). DV vessel rings slowly developed a steady contraction within 14.5 ± 4.0 min (n = 12, P = 0.023). Maximum force development in response to potassium was significantly greater in IHV rings than in DV rings (Fig. 2). Responses increased with gestational age for both DV rings (r = 0.53, force (mN) = -6.17 + 0.07 
days, n = 12, not significant) and IHV rings (r = 0.63, force (mN) = -15.54 + 0.18 days, n = 12, P = 0.03). We did not find any difference between the IHV from the left and right liver lobes.
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Figure 2. Maximum tension of DV and IHV rings in response to KCl, noradrenaline and adrenaline Cell depolarisation of vessel rings was induced with 124 mM KCl (KClmax, n = 12). The concentration was 100 µM for noradrenaline (n = 9) and 42 µM for adrenaline (n = 12). Bars show S.D. Boxes represent S.E.M. values. Means are indicated by squares inside the boxes. Dashed lines connect both vessels of individual fetuses. DV, open circles; IHV, filled circles; * P < 0.05. | ||
The maximum tension developed by IHV rings in response to noradrenaline and adrenaline (Fig. 2) was about sixfold higher than the respective maximum tension of DV rings (P = 0.003, n = 9). The force amplitude in response to catecholamines as a percentage of KClmax force was significantly higher in the IHV than in the DV (Fig. 3).
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Figure 3. Force development of DV and IHV rings in response to noradrenaline and adrenaline Vessel reaction to 124 mM KCl (KClmax) was accepted as 100%. The maximum force development in response to catechoamines is presented as a percentage of vessel force amplitude in response to KClmax. Bars show S.D. Boxes represent S.E.M. values. The means are indicated by squares inside the boxes. Dashed lines connect both vessels of individual fetuses. DV, open circles;. IHV, filled circles; * P < 0.05. | ||
Figure 4 illustrates the average, fitted dose-response curves of DV and IHV rings in response to catecholamines. The EC50 values of the DV and the IHV rings in response to noradrenaline were 5.9 ± 1.3 µM and 5.0 ± 1.3 µM, respectively (n = 9, P = 0.03). The EC50 values of adrenaline responses were 2.5 ± 0.5 µM for the DV and 2.2 ± 0.7 µM for the IHV (n = 12, n.s.).
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Figure 4. Dose-response curves of the DV and of the IHV to noradrenaline and adrenaline Relative force development of vessel rings in the presence of noradrenaline (A) and adrenaline (B). Values were fitted to Hill's equation (y = xnH/(a + xnH), where a is a constant). Filled circles present the mean reactions of the IHV (continuous curves) to catecholamines. Mean values of reaction of the DV (dashed curves) are represented by open circles. Means ± S.E.M. * P < 0.05. | ||
The time for force recovery after vibration (see Methods) during KCl-induced contraction was 59.4 ± 13.8 s for IHV rings and 55.4 ± 14.7 s for DV rings (n = 12, not significant). During noradrenaline-induced tonic contraction, force recovery was significantly shorter for DV rings than for IHV rings (47.9 ± 24.4 and 163.9 ± 42.0 s, respectively). With noradrenaline, DV rings also needed less time (40.1 ± 6.1 s) than the IHV rings (88.6 ± 21.3 s, P < 0.05, n = 12) for recovery.
Morphology of the vessel wall
The isthmic portion of the DV mainly contained connective tissue and small amounts of smooth muscle tissue (Fig. 5A). The smooth muscle -actin could be identified in the subendothelial layer of the vessel wall.
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Figure 5. DV isthmus and IHV sections depicting the morphological characteristics of the vessel wall Top, Masson's trichrome staining (a) shows the vessel wall of the DV isthmus containing a tight network of connective tissue in the subendothelial zone ( | ||
IHVs typically had three layers as shown by Masson's staining in Fig. 5B. The intima consisted of a single layer of endothelial cells with a loose network of connective tissue underneath. The media was formed by well-organised smooth muscle cells, identified with immunostaining with antibodies against smooth muscle -actin. The muscle cells were embedded in small amounts of connective tissue, which became denser in the adventitia.
The -adrenergic receptors were abundantly present in the media of the IHV, but were less distinctive in the wall of the DV. -Adrenergic receptors could be identified in hepatic arterial vessels (Fig. 6A) but in neither IHVs nor in the DV.
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Figure 6. Expression of A, layers of muscle cells are shown in the media of a hepatic artery. The stratum stains positively with an antibody against | ||
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DISCUSSION |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The maintenance of flow through the DV during hypoxia has been termed DV sparing. It requires changes of resistance to flow in the DV and/or in those parts of the hepatic vascular bed that receive blood from the umbilical vein. Regardless of which vessel or group of vessels is involved, the ratio of DV resistance to IHV resistance must decrease to allow blood to flow preferentially through the DV. This may happen in three different scenarios, wherein the combined resistance of the DV and IHVs remains constant (scenario I), is decreased (scenario II) or is increased (scenario III). Total umbilical vein blood flow will reflect which of the three scenarios prevails (for example, one would expect the total umbilical flow to be reduced in scenario III). Umbilical flow will also depend, of course, on the arterial-venous pressure difference and placental vascular resistance.
Geometric factors (vessel diameter and length) and blood viscosity (mainly haematocrit) determine vascular resistance. Evidence has been presented (Bellotti et al. 1998) that the isthmus of the DV widens in growth-retarded human fetuses. This response would exert a pronounced influence on flow as resistance varies strongly with vessel diameter. In vitro perfusion of the fetal sheep liver has also provided evidence that increases of haematocrit in the UV may contribute to preferential streaming of the DV (Kiserud et al. 1997).
Intravenous infusion of noradrenaline (Paulick et al. 1991) as well as acute hypoxaemia (Reuss & Rudolph, 1980) have elicited DV sparing in fetal sheep. The responses observed have been combined with a reduction of total umbilical flow and the maintenance (absolute or relative) of DV flow (Tchirikov et al. 1998a,b, 2001). This pattern of response is consistent with scenario III above, and could be based on increases of resistance of both the DV and IHVs, but with IHV resistance increasing to a greater extent than DV resistance. The morphological and functional differences between the two types of vessel demonstrated in the present report strongly support this view.
Morphology
It is evident from Fig. 5 that the isthmic region of the DV contains relatively little smooth muscle, a finding in agreement with earlier work (Mavrides et al. 2002). We did not find well-organised smooth muscle layers in the isthmic portion of the DV as described by Coceani et al. (1984). IHVs, on the other hand, displayed a structured vascular wall with a muscular media. Thus vascular rings of comparable size from both vessel types differ in their capability to generate force simply because the contractile machinery is differently developed. -Adrenergic receptors were detected in both vessel types in the present study, which is again in agreement with previous reports (Coceani et al. 1984). Immunohistochemistry does not permit precise quantification of receptor density, but -receptor staining was less pronounced in the DV than in IHVs. This finding may reflect solely a difference in the number of smooth muscle cells. -Receptors were not detected in the vessel rings here, though Coceani et al. (1984) demonstrated a relaxing effect of noradrenaline on the pre-constricted DV. Because hepatic arterial vessels did stain for -receptors in the present study (Fig. 6A) it seems unlikely that our methods used to detect -receptors were insufficient.
Functions
Figure 1 illustrates the responses of vascular rings from the DV and from IHVs to catecholamines and to KCl. Both membrane depolarisation and receptor stimulation were able to provoke contractile reactions that were reversible. In addition, the vascular rings from both types of vessel responded to the stepwise increase of noradrenaline and adrenaline concentrations in a dose-response fashion. Irregularities of responses (including unstable tension at baseline and at increased catecholamine levels, and incomplete recovery of tension after vibration) were noted in some preparations, but significant quantitative differences between the two vessel types remained apparent. For example, the maximum force developed after stimulation with KCl was about twofold greater in IHVs than in the DV. Noradrenaline and adrenaline stimulation led to a sixfold larger contraction in IHVs than in the DV. In contrast to the DV, in IHVs the receptor-mediated activation of contraction with catecholamines was more effective than membrane depolarisation with KCl. The greater tension developed by rings from the IHV is in agreement with the morphological findings described above. These include a well differentiated wall of the IHVs with a high muscle cell number and -receptor density in the media.
At a given wall tension in situ (which depends, among other things, on transmural pressure and vascular diameter), the IHVs might be more able to constrict than the isthmus of the DV, though transmural pressure or wall tension in the DV may be reduced due to high blood flow velocity. It also seems possible that increases of intravenous (Paulick et al. 1990) and thus transmural pressure during hypoxia are more likely to passively expand the DV isthmus than the IHV. The high constrictive power of IHVs will allow increases of their resistance to flow that are larger (on stimulation) than in the isthmus of the DV. This effect may be enforced by the increase of blood viscosity in IHVs because flow velocity is less than in the DV.
IHVs were more sensitive to noradrenaline than the isthmus of the DV, as shown by differences in EC50 in Fig. 4. Our data do not absolutely establish a basis for this difference, but the higher density of -receptors in the IHV is likely to be a major factor.
The ability of DV and IHV vessel rings to develop tension was found in this study to depend on gestational age. At about day 95, five (50 %) vascular rings from the DV had negligible responses to KCl whereas the IHV developed tension. If these values are to be included in the analysis, the positive correlation of KCl-induced DV force development with gestational age becomes significant (r = 0.66). Later in gestation, the vessel reactions following depolarisation increased with gestational age for both the DV and IHVs. However, the differences in constrictive power between the IHV and the DV were maintained. DV sparing has indeed been observed at these early gestational ages (Tchirikov et al. 2001).
Differences in the dynamic properties of the DV and IHVs were also observed in the present study. The time required for maximal force development following stimulation with KCl to peak response was less in IHV rings than in the DV. On the other hand, DV rings required less time to reattain one-third of the previous muscle tension after vibration than the IHV rings during catecholamine treatment, but not during KCl-induced cell depolarisation. The reason for the kinetic differences remains uncertain, but may relate to differences in time-dependent properties of the cross-bridge cycle.
Simply stated, the mechanism proposed here for DV sparing is greater constriction of IHVs than of the DV with diversion of flow to the weakly constricted DV. By this means, during hypoxia the better oxygenated blood from the placenta would be directed preferentially to the fetal heart and brain, while the oxygen supply to the liver parenchyma would be reduced. Clearly, this could have an important short-term survival value. The proposed mechanism does not exclude other factors that may influence DV flow and its importance could change during hypoxia and sympathetic stimulation. For example, expansion of the isthmus (Bellotti et al. 1998) may follow an increase of the central venous pressure during severe and final fetal hypoxia (Paulick et al. 1990).
Changes of blood volume content of the liver and central veins may also be speculated to evoke alterations of the vascular geometry of the DV, which affect its resistance to flow. Because of the anatomical position of the DV in the liver and sometimes below the liver, the decrease of liver volume during stress situations could change the DV diameter and/or stretch the vessel. The intrahepatic vessels could also shorten with their reaction to catecholamines. This could distend the isthmic portion of the DV and modulate the form of the shunt.
In conclusion, DV sparing can be explained by increased resistance of IHVs to catecholamines compared with the DV. The different responses are well explained by different anatomical and functional properties of the two vessel types. A number of other mechanisms are also likely to play a role in blood flow redistribution in the fetal liver.
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Acknowledgements
We would like to thank Dr G Power, Perinatal Biology, Loma Linda, CA, USA, for his editorial help.
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