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From the *Department of Anesthesiology, Providence Milwaukie Hospital, Milwaukie, Oregon; 
Department of Anesthesiology, Vanderbilt University, Nashville, Tennessee; and 
Department of Anesthesiology, Columbia University, New York, New York.
Address correspondence and reprint requests to John W. Downing, MD, Department of Anesthesiology & Division of Obstetric Anesthesia, Vanderbilt University School of Medicine, 4202 Vanderbilt University Hospital, 1211 22ndAvenue South, Nashville, TN 37232-7580. Address e-mail to john.downing{at}vanderbilt.edu.
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Abstract |
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Introduction |
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TopAbstractIntroductionMETHODSRESULTSDISCUSSIONREFERENCES |
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Uteroplacental hypoxemia causes the previllous umbilical arterioles to constrict. Umbilical arterial (Ua) blood flow is shunted away from poorly perfused, hypoxemic areas of the intervillous space towards better perfused, oxygenated regions (2–5). HFPV adjustment of maternal/fetal (Qm/Qf) perfusion balance favors more efficient transplacental exchange of oxygen (O2) with carbon dioxide (CO2) as well as nutrients with fetal metabolic waste products. HFPV has been elicited in the dual perfused, single isolated human placental cotyledon (5–9). We investigated the effects of graduated reductions in O2 availability on HFPV using the same well established in vitro placental model (10).
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METHODS |
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A fetal chorionic artery and a vein serving a discrete, intact cotyledon were cannulated with polyethylene infant feeding tubes (Sherwood Medical Corp., St. Louis, MO) and perfused with KRB solution. The outgoing umbilical venous effluent had to match the incoming Ua flow rate to prove the absence of placental leaks. The cotyledon was mounted in a plexiglas chamber and positioned with the maternal surface facing upward. The intervillous surface was perfused with KRB solution using 3 blunt-tipped 19Fg needles inserted 2–3 mm into the maternal plate.
Maternal and fetal perfusates were stored in non-recycling reservoirs common to both circuits connected to the plexiglas perfusion chambers by Tygon (R/3603) tubes. The first reservoir was equilibrated with a control gas mixture consisting of 21% O2 and 5% CO2 in nitrogen (N2). The second reservoir was exposed to different O2 concentrations mixed with 5% CO2 and N2. The desired combinations of gases were determined by monitoring their concentrations in the reservoir effluent gases (Datex Capnomac Monitor, Tewksbury, MA).
The pH of the perfusate was kept constant at 7.4. All experiments were conducted at 37°C. Peristaltic roller pumps maintained constant maternal (12 mL/min) and fetal circulatory flow rates. Fetal flow rates were adjusted for each individual placenta to maintain a basal fetal arterial blood pressure (FAP) of 60–70 mm Hg and therefore varied overall between 2–4 mL/min depending on the size of the cotyledon in use. Perfusate volumes were monitored to ensure the absence of leak-induced fluid shifts between the two circuits. Perfusion pressures were measured using in-line electronic pressure transducers previously calibrated against a mercury manometer and linked to a Hewlett Packard monitor (78342A; Hewlett Packard, Palo Alto, CA). Flow rate (Q) was assumed to be directly proportional to FAP and inversely related to Ua previllous vascular resistance (UaVR); Q = FAP ÷ UaVR then FAP = Q x UaVR. Thus, FAP changes with Q constant were assumed to reflect increases or decreases in "upstream" UaVR (FAP 
UaVR).
Fifteen placentae were harvested. Three were discarded because they leaked. Intact cotyledons were perfused with KRB buffer solution equilibrated with the control gas mixture for 30 min to establish a baseline FAP. Four cotyledons (Group 1) were subsequently exposed to a perfusate purged of O2 (5% CO2 and 95% N2). The peak FAP value was recorded. Thereafter O2 (21%) was reintroduced into the perfusate. Eight more cotyledons (Group 2) were challenged sequentially with perfusates equilibrated with O2 concentrations of 15%, 12%, 5%, and 0% in 5% CO2 and N2 respectively for 15 min and peak FAP was recorded. Hypoxemic episodes were separated by 15-min recovery intervals of aeration with the control gases.
Baseline FAP (mm Hg) was compared with the maximum FAP measured under hypoxemic conditions using the paired Student's t-test for significant differences. Data are expressed as mean (± sd). A P value 
0.05 was considered significant.
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RESULTS |
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DISCUSSION |
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Power et al. (11) used labeled albumin microaggregates to show that Qm/Qf placental blood flow patterns matched better when pregnant animals inhaled 12% O2. It has been conjectured that HFPV may play a pivotal role regulating human fetoplacental blood flow in vivo and contribute to poor fetal outcome in preeclampsia (5), and others have postulated that "Impaired placental oxygenation may contribute to the development and severity of vasoconstriction in the placenta associated with preeclampsia" (6). Byrne et al. (7) concluded from their study that reduced basal nitric oxide (NO) activity triggers HFPV, and that placental NO production is governed by Ua Po2.
Chronic hypoxemia causes pulmonary arterial hypertension through unrelenting HPV (12). Howard et al. (5) wondered if uteroplacental hypoxemia likewise promotes unremitting HFPV. Notably Khalid et al. (13) concluded from their investigations that "the low birth weight observed at high altitude compared to low altitude appeared mainly secondary to placental hypoxia resulting from maternal hypoxia.caused by high altitude."
Oxygen-sensing potassium (Kv) channels in the pulmonary arterial mesothelial myocytes may control HPV (2,14). Hampl et al. (8) suggested that HFPV is also Kv channel dependent and that "understanding the mechanism of HFPV thus might ultimately facilitate new treatments to prevent or minimize IUGR."
Pierce et al. (9) studied hypoxia and FAP in the dual perfused human cotyledon but in addition surrounded the tubing supplying the Ua with a N2 purged copper jacket. Their Po2 values were <25 mm Hg: "just before the placental artery" and <60 mm Hg: "just before the intervillous space." Paradoxically, they observed a modest decrease in FAP with hypoxia.
We used 21% rather than 40%–95% O2 for our control experiments, believing this to be more physiological. Fetal umbilical venous effluent O2 levels were not measured. However, our use of 21% O2 and the brisk HFPV responses obtained suggest that placental hypoxemia was achieved. Group 2 experiments might have been better served by longer exposures to hypoxemia randomly applied. The shorter exposure time to low O2 tensions (15 versus 30 minutes) could account for the less intense HFPV response noted in Group 2. However, increased exposure of cotyledons repeatedly subjected to hypoxia might have fatigued or damaged the fetoplacental vasculature, and prolongation of each experiment beyond the 6–8 hours it took to set up and breakdown the apparatus would have been overly time-consuming and expensive.
Unremitting HFPV increases upstream resistance to Ua blood flow and fetal right ventricular impedance leading to right heart failure or "cor placentale." (15). Clinically, this manifests as absent or reversed Ua diastolic blood flow velocity patterns, both hallmarks of severe preeclampsia that predicate a poor outcome (16). Less profound HFPV would likely compromise fetal oxygenation and nutrition to restrict fetal growth and development.
NO inhalation and phosphodiesterase-5 (PDE-5) inhibition modulate neonatal and adult pulmonary arterial hypertension (17,18). O2 sensing KV3.1b channel blockade in the lungs might do likewise (14). Similar logic is applicable to persistent HFPV (19). NO donors promote vasodilatory cyclic guanine monophosphate expression to relieve fetal stress in preeclampsia (20). Hypothetically PDE-5 inhibition may also offer relief by slowing the breakdown of placental cyclic guanine monophosphate (19). Pregnant rats fed a NO synthase inhibitor develop hypertension, proteinuria and runt litters (21). Notably IUGR is prevented by PDE-5 inhibition (22). Theoretically, specific KV channel blockers could do the same (8).
Talbert and Sebire (23,24) designed a computer model of a mechanism that hypothetically matched local fetal blood flow with prevailing intervillous O2 delivery to study transplacental water balance in polyhydramnios with fetal hydrops. The opposite, oligohydramnios, is pathognomonic of preeclampsia. It is possible that Talbert and Sebire's (23,24) computer model could be used to investigate the therapeutic potential of selective PDE-5 inhibition and specific KV channel blockade in preeclampsia.
In conclusion, our results suggest that HFPV intensity in the dual perfused, isolated human cotyledon is proportional to the degree of O2 lack. A graded HFPV response would theoretically provide the stressed fetus with a survival mechanism akin to HPV ex utero. Persistent HPV increases pulmonary arterial resistance, causing pulmonary hypertension and cor pulmonale (2,12). Likewise unrelenting HFPV by increasing Ua upstream resistance may precipitate fetoplacental hypertension and life threatening cor placentale (15). Further laboratory studies are needed to determine whether or not HFPV, like HPV, can be manipulated pharmacologically to the ultimate benefit of both mother and infant.
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Footnotes |
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This article has been cited by other articles:
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  V. Jakoubek, J. Bibova, J. Herget, and V. Hampl Chronic hypoxia increases fetoplacental vascular resistance and vasoconstrictor reactivity in the rat Am J Physiol Heart Circ Physiol, April 1, 2008; 294(4): H1638 - H1644. [Abstract] [Full Text] [PDF]
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