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University Laboratory of Physiology, University of Oxford, Parks Road, Oxford OX1 3PT, United Kingdom
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Hypoxia-inducible factor (HIF)-1 is stabilized by hypoxia and iron chelation. We hypothesized that HIF-1 might be involved in pulmonary vascular regulation and that infusion of desferrioxamine over 8 h would consequently mimic hypoxia and elevate pulmonary vascular resistance. In study A, we characterized the pulmonary vascular response to 4 h of isocapnic hypoxia; in study B, we measured the pulmonary vascular response to 8 h of desferrioxamine infusion. For study A, 11 volunteers undertook two protocols: 1) 4 h of isocapnic hypoxia (end-tidal PO2 = 50 Torr), followed by 2 h of recovery with isocapnic euoxia (end-tidal PO2 = 100 Torr), and 2) 6 h of air breathing (control). For study B, nine volunteers undertook two protocols while breathing air: 1) continuous infusion of desferrioxamine (4 g/70 kg) over 8 h and 2) continuous infusion of saline over 8 h (control). In both studies, pulmonary vascular resistance was assessed at 0.5- to 1-h intervals by Doppler echocardiography via the maximum pressure gradient during systole across the tricuspid valve. Results show a progressive rise in pressure gradient over the first 3-4 h with both isocapnic hypoxia (P < 0.001) and desferrioxamine infusion (P < 0.005) to increases of ~16 and 4 Torr, respectively. These results support a role for HIF-regulated gene activation in human hypoxic pulmonary vasoconstriction.
hypoxia inducible factor-1; hypoxic pulmonary vasoconstriction; pulmonary circulation
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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THERE IS EVIDENCE TO SUGGEST that the human pulmonary circulation responds to sustained hypoxia by developing a progressively more intense constriction over a period of a few hours. In anesthetized patients, Fiser et al. (4) observed a gradual decline in pulmonary venous admixture during unilateral atelectasis over 90 min, suggesting that blood flow diversion by hypoxic pulmonary vasoconstriction was intensifying during this time. Exposure of healthy humans to an 8-h isocapnic reduction in end-tidal oxygen partial pressure (PETO2) to 50 Torr, approximately half its normal value, results in a progressive rise in pulmonary vascular resistance (PVR) over 2 h to ~2.5 times its euoxic value as determined by right heart catheterization (3).
The mechanisms responsible for this slower component of the pulmonary
vascular response to hypoxia remain unclear (13, 22), but
one possibility is that the transcriptional regulator hypoxia-inducible factor (HIF)-1 is involved, as it is in some other homeostatic responses to hypoxia (18). Yu et al. (23)
examined the kinetics of induction of increased levels of the
subunit HIF-1
in isolated ferret lungs exposed to 8 h of
hypoxia. They found that HIF-1 was not detectable at 0 h,
increased at 1-2 h, peaked at 4 h, and remained elevated
thereafter (23). Furthermore, the work of Yu et al.
related the activity of HIF-1 to pulmonary vascular responses to
hypoxia in mice. They showed that mice that are heterozygous for the
HIF-1 gene, although apparently normally developed, have a
substantially impaired chronic pulmonary vascular response to 1-6
wk of hypoxia compared with wild-type mice (24).
The reaction by which oxygen regulates HIF-1 has an absolute requirement for iron as a cofactor (10, 11). In a recent study by Ren et al. (17), it was demonstrated that 8 h of desferrioxamine (DFO) infusion increased erythropoietin production in humans, which is a response to sustained hypoxia that is known to be regulated by HIF-1 (21). Thus, if hypoxic pulmonary vasoconstriction is regulated by HIF-1, then it might be anticipated that iron chelation would induce a rise in pulmonary arterial pressure.
The objective of the present study was to examine whether DFO-induced iron chelation in humans could mimic hypoxia by inducing an increase in PVR with a similar time course. In study A, we characterized the human pulmonary vascular response to 4 h of isocapnic hypoxia by using Doppler echocardiographic measurement of tricuspid regurgitation. In study B, we used the same monitoring to examine the pulmonary vascular response to an 8-h DFO infusion.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Subjects. Eleven healthy volunteers (3 women, 8 men) participated in study A. Nine healthy volunteers (5 women, 4 men) participated in study B. Subjects visited the laboratory once or twice before the experiment to become familiarized with the procedure and to confirm that they were suitable for echocardiographic measurement of tricuspid regurgitation. Female subjects only participated during the first 14 days of their menstrual cycle. The appropriate protocols were explained to all participants, but they were naive about the exact purpose of the studies. Informed, written consent was obtained from all subjects on each experimental day. Ethical permission was obtained from the Central Oxford Research Ethics Committee.
Protocols for study A. Subjects undertook two protocols. Protocol A1 consisted of 4 h of isocapnic hypoxia with PETO2 maintained at 50 Torr and end-tidal carbon dioxide partial pressure (PETCO2) maintained at each subject's normal value, followed by 2 h of isocapnic euoxia (PETO2 = 100 Torr). Protocol A2 consisted of 6 h of air breathing (control). In protocol A1, during hypoxia, echocardiography measurements were obtained every 30 min for the first 2 h and every 60 min for the remaining 2 h. During euoxia, echocardiography measurements were obtained every 30 min. In protocol A2, echocardiographic measurements were taken at the same times as in protocol A1.
Subjects were asked to refrain from alcohol and caffeine intake on experimental days. For every visit to the laboratory, subjects were allowed at least 30 min to settle before measurements were obtained. During the experiments, food and drinks were provided frequently but in small quantities in an effort to minimize the effects of digestion on cardiac variables. Subjects were free to watch television, read, write, or relax, according to their own preference.Protocols for study B. Subjects undertook two protocols. Protocol B1 consisted of 8 h of DFO infusion (4 g/70 kg body wt). Protocol B2 consisted of 8 h of saline infusion (control). Both infusions were followed by 4 h of observation without infusion (early recovery). During the infusion, echocardiography measurements were made every 30 min for the first 2 h and every 60 min for the remaining 6 h. Measurements were obtained again every 30 min for the first 2 h of the recovery period and finally every 60 min until the end of the experiment. All subjects returned to the laboratory the next day for a final set of measurements at 24 h (late recovery) after the start of the infusion. In other respects, subjects were treated similarly to those who underwent study A.
Control of end-tidal gases (study A). Subjects undergoing study A were seated in a chamber in which the inspired gas partial pressures could be controlled so as to maintain desired end-tidal levels. Respired gas was sampled continuously via a nasal cannula and analyzed with a mass spectrometer. The inspired and end-expired values were recorded breath by breath on a computer. Computer-automated control of PETO2 and PETCO2 was achieved by adjustment of the chamber gas composition every 5 min, as described elsewhere (7). During the control protocol for study A, subjects were seated in the chamber and breathed air.
DFO infusion (study B). DFO (Desferal, Ciba-Geigy, Cheshire, UK) was dissolved in water (0.1 g/ml) and diluted with saline to a total volume of 50 ml. For the control infusion, 50 ml of saline were used. A vein in the back of the hand or the forearm was used for the infusions. The vein was cannulated aseptically, and an infusion pump was used to infuse the contents of the syringe at a constant rate over 8 h.
Echocardiographic measurements. Echocardiographic measurements were performed by using a Hewlett-Packard Sonos 5500 ultrasound machine with an S4 two-dimensional transducer (2-4 MHz). Heart rate and respiratory waveform were both recorded. Subjects were examined on a suitably modified couch while rolled slightly onto their left side. For each view, enough time was allowed for a consistent waveform and heart rate to appear before data from a series of consecutive heart cycles were stored to optical disk. At least three beats at end expiration were analyzed and averaged at a later time.
Tricuspid valve maximal pressure difference.
The majority of people have detectable regurgitation through their
tricuspid valve during systole. Doppler echocardiography is able to
detect the jet and measure the velocity with which it travels back into
the right atrium. On the assumption that the flow within the jet may be
regarded as steady, Bernoulli's equation (Eq. 1) can be
used to calculate the pressure difference between the right ventricle
and right atrium
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(1) |
Pmax is maximal pressure difference, 
is the density
of blood, and v is the peak velocity of the jet. From this, systolic
pulmonary arterial pressure (SPAP) is given by
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(2) |
Pmax will be equal to changes in SPAP.
Furthermore, as it has been shown previously that SPAP and PVR
correlate well within individual subjects (3), changes in
Pmax can be used as an index of changes in PVR.
A standard technique was used for the measurement of Pmax
(16). Two-dimensional echocardiography allowed
visualization of the tricuspid valve in an apical four-chamber view,
and then color Doppler format allowed for the regurgitant jet to be
detected. After proper alignment with the Doppler beam, continuous-wave spectral analysis at a sweep speed of 50 mm/s was used to record the
velocity profile of the jet. During analysis, the maximal velocity of
the jet was measured by placing an electronic caliper tool at the most
distal part of the envelope. Pmax values were then computed automatically.
Cardiac output. An apical five-chamber view was obtained, and by using color Doppler mode the flow through the aortic valve during systole was identified. Once this had been done, the velocity profile was obtained in pulsed-wave spectral mode at a display screen sweep speed of 100 mm/s. Doppler sampling of the flow was made just below the orifice of the aortic valve. An automated procedure was then used to calculate the velocity time integral (VTI) of the flow. VTI, measured in centimeters, represents the distance through which blood travels in the outflow tract with each ventricular contraction.
The diameter of the aortic valve was measured from a parasternal long axis view, and the area of the aortic valve (AoVarea) was calculated. The product of VTI and AoVarea gives the stroke volume (SV). Cardiac output (
) can then be calculated by multiplying SV and heart
rate (HR). These calculations are shown in Eq. 3
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(3) |
Statistical analysis. Repeated-measures ANOVA was undertaken to determine whether there was an interaction between time and protocol. This analysis was undertaken separately for the data from study A (hypoxia vs. air-breathing control) and study B (DFO infusion vs. control infusion). Separate repeated-measures ANOVA were then performed on the data from just the control protocols to check that time did not have a significant effect in these protocols.
To determine the time at which steady state had been reached after the induction of hypoxia (study A) or the start of DFO infusion (study B), a family of linear models was used where the next model differed from the previous model by the inclusion of the next additional factor for time, starting from time t = 0. The models are given by
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(4) |
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1 are the factors that indicate the contribution of each time point, 
is the number of time
points at which data were collected, and 
is the residual error.
Because each model was introduced sequentially, the reduction in
squared error over the previous model was assessed for statistical significance (F-ratio test). The time at which steady state
had been reached was taken as the first time point for which a
significant reduction in squared error did not arise.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Gas control during study A.
Figure 1 illustrates values for
inspiratory and end-tidal PO2 and
PCO2 for study A. For protocol
A1, it may be seen that the steps into and out of hypoxia were
achieved rapidly and that isocapnia was maintained with considerable
precision throughout. For protocol A2, the end-tidal gases
changed little over the 6-h period.
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Pulmonary vascular response to hypoxia in study A.
The changes in Pmax during isocapnic hypoxia and the ensuing period
of isocapnic euoxia (protocol A1) are presented in Fig. 2, together with data from the
air-breathing control (protocol A2). Pmax was
significantly affected by hypoxia compared with euoxia
(P < 0.001). No change in Pmax was seen during the
air-breathing control protocol. A progressive rise in Pmax was
observed during hypoxia that had not reached steady state by 3 h
(P < 0.001). During the period of euoxia that followed
4 h of hypoxia, Pmax had not reached steady state by 1.5 h
of euoxia (P < 0.02).
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Heart rate, stroke volume, and cardiac output responses to hypoxia
in study A.
Figure 3 shows heart rate,
stroke volume, and cardiac output for the two protocols of
study A. Heart rate was significantly and substantially
elevated by hypoxia (repeated-measures ANOVA P < 0.001). Little change was seen in stroke volume, and so changes in
heart rate were reflected in changes in cardiac output (Eq. 3). The rise in heart rate between 2 and 3 h coincides with
the time at which most subjects ate a small lunch during both
protocols. In Fig. 4 are plotted
the absolute differences between the measurements of heart rate, stroke
volume, and cardiac output shown in Fig. 3, making the effects of
hypoxia alone easier to appreciate.
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Study B: Pulmonary vascular response to DFO.
The changes in Pmax during DFO infusion and saline infusion are
shown in Fig. 5. DFO induced a
significant change in Pmax compared with control (P < 0.005). During DFO infusion, Pmax reached steady state by 3 h (P = 0.1) but not by 2 h (P < 0.02) and remained elevated until the end of the DFO infusion at 8 h. Although not significant, there appeared to be a decrease in Pmax in the early recovery period. At 24 h after the start of DFO
infusion, Pmax had returned to control levels.
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Study B: Heart rate, stroke volume, and cardiac output responses to
DFO.
Figure 6 shows heart rate, stroke volume,
and cardiac output for study B. Stroke volume was lower at
the commencement of the DFO infusions than at the beginning of the
saline infusions and remained so throughout the 24 h of the study.
This appears likely to be entirely a chance finding because the
subjects and starting conditions for both protocols were identical.
There was no statistically significant difference between the two
protocols with regard to any of the three physiological variables in
Fig. 6.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The main finding of study A was that the human pulmonary vascular response to hypoxia, as measured by use of Doppler echocardiography, increased progressively over at least 3 h and was several times greater after 4 h than after 30 min. The main finding of study B was that an 8-h infusion of DFO in humans induced a modest rise in tricuspid valve maximal pressure gradient that had a very similar pattern over time to the more pronounced rise induced by hypoxia in study A. The findings suggest that HIF-1 may be involved in the pulmonary vascular responses to hypoxia over times of 0.5-4 h. We are unable to comment on responses over a shorter period than 0.5 h, because measurements were not made within this period, although others have seen very rapid responses (14). Because both the response to hypoxia and the response to DFO are likely to be dependent on the dose used, interpretation of the relative magnitudes of the pulmonary vascular responses seen in study A and study B is difficult to undertake without further studies.
Echocardiographic assessment of SPAP.
Our results from study A may be compared with a very similar
study in humans at the same level of (isocapnic) hypoxia in which pulmonary arterial pressures together with PVR were obtained directly by right heart catheterization (3). In that study, there
was a progressive rise in SPAP over the first 2 h of isocapnic
hypoxia, with SPAP remaining relatively constant over the rest of the
hypoxic exposure. In the present study, Pmax also rose progressively over the first 2 h of exposure, but in this case a steady state was not obtained until at least 3 h had elapsed. The absolute values for SPAP from the previous study compare rather poorly with the
absolute values for Pmax from the present study. One possible reason
for this is that the subjects were seated in the former study, but
lying down in the present study. The average change in SPAP over 4 h of hypoxia in the previous study was 17 Torr, and this compares
closely with the average change in Pmax in the present study of 15 Torr. These data provide support for the use of changes in Pmax
assessed by echocardiography as measures of changes in SPAP.
Measures of pulmonary vascular tone.
None of the measures relating to the whole human lung (Pmax, SPAP,
PVR) is a direct measure of the pulmonary vascular smooth muscle
activity that is the variable of principal concern. In particular,
there is a strong body of evidence supporting the notion that PVR
varies substantially as a function of cardiac output in the absence of
any underlying variations in pulmonary vascular smooth muscle activity.
During exercise in humans, there is relatively little change in the
arteriovenous pressure difference across the lung as cardiac output
increases three- to fourfold (12). Similar results have
been obtained for SPAP assessed by echocardiography (6).
Quantitatively, these results suggest that there is an approximately
hyperbolic relationship between PVR and cardiac output when other
factors that might affect pulmonary vascular tone remain constant.
|
(5) |
1. The presence of the
intercept in this relation means that any given percentage change in
PVR will result in smaller percentage change in SPAP. However, it
should also be realized that this relationship was determined against a
background of some increase in cardiac output over the course of the
hypoxic exposure. Changes in cardiac output necessarily induce an
alteration in the relationship between SPAP and PVR because for any
particular PVR higher values of cardiac output will be associated with
higher values of SPAP.
Interestingly, the combination of factors discussed in the
preceding two paragraphs may mean that SPAP (or Pmax) may be a better measure of underlying pulmonary vascular smooth muscle tone than
PVR itself because it is less influenced by changes in cardiac output.
At its most simple, we may consider SPAP to be related through an
Ohm's law type of relationship to PVR and cardiac output such
that SPAP = k × × PVR,
where k is a constant. This is precise if SPAP remains
proportional to mean pulmonary arterial pressure. If PVR is related to
cardiac output through a hyperbolic relationship as discussed above
(PVR = m/, where m is the underlying vascular tone), then
substituting for PVR in the first relationship from the second yields
SPAP = km. Under these simple conditions, SPAP (or
Pmax) becomes a direct measure of pulmonary vascular smooth muscle
tone (i.e., m) that is invariant with changes in cardiac output.
DFO and pulmonary vascular tone.
DFO has been shown repeatedly to stabilize HIF in vitro by iron
chelation and to induce HIF-regulated gene expression
(21). Recently, an oxygen-sensitive mechanism for the
degradation of HIF has been described, whereby a prolyl hydroxylase
hydroxylates a proline residue in HIF, which tags the protein for
proteosomal degradation (10, 11). This prolyl hydroxylase
requires the presence of iron for its activity. In a human study, it
has been shown that DFO may also induce HIF-dependent gene expression, in the sense that an 8-h infusion of DFO resulted in a dramatic increase in erythropoietin in the plasma (17). Thus, it
would seem a reasonable proposition that DFO can stimulate other
HIF-dependent gene expression in vivo in humans. In mice, it has
recently been shown by Shimoda et al. (19) that partial
deficiency of HIF-1 is sufficient to impair hypoxia-induced
depolarization and reduction of membrane potassium currents within
pulmonary artery smooth muscle cells. This evidence provides another
possible link between DFO induction of HIF and increased PVR. An
important factor in favor of such a link in our own study is that the
time course of the pulmonary vascular response to DFO in study
B is very similar to that to hypoxia in study A. This
is illustrated in Fig. 7, where Pmax
for study A has been plotted against Pmax for study B. In this figure, differences in the speed of response of Pmax to the two stimuli would appear as deviations from linearity. Although
the magnitude of the response to hypoxia is approximately four times
greater than that to DFO, the correlation coefficient between the two
responses is very high at 0.99.
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FOOTNOTES |
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Address for reprint requests and other correspondence: P. A. Robbins, Univ. Laboratory of Physiology, Parks Rd., Oxford OX1 3PT, United Kingdom (E-mail: peter.robbins{at}physiol.ox.ac.uk).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
First published February 15, 2002;10.1152/japplphysiol.00965.2001
Received 18 September 2001; accepted in final form 8 February 2002.
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REFERENCES |
|---|
|
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
1.
Archer, SL,
Peterson D,
Nelson DP,
DeMaster EG,
Kelly B,
Eaton JW,
and
Weir EK.
Oxygen radicals and antioxidant enzymes alter pulmonary vascular reactivity in the rat lung.
J Appl Physiol
66:
102-111,
1989
2.
Clar, C,
Dorrington KL,
Fatemian M,
and
Robbins PA.
Effects of 8 h of isocapnic hypoxia with and without muscarinic blockade on ventilation and heart rate in humans.
Exp Physiol
86:
529-538,
2001[Abstract].
3.
Dorrington, KL,
Clar C,
Young JD,
Jonas M,
Tansley JG,
and
Robbins PA.
Time course of the human pulmonary vascular response to 8 hours of isocapnic hypoxia.
Am J Physiol Heart Circ Physiol
273:
H1126-H1134,
1997
4.
Fiser, WP,
Friday CD,
and
Read RC.
Pulmonary circulatory adaptation to acute atelectasis in man.
Tex Rep Biol Med
39:
235-245,
1979[Web of Science][Medline].
5.
Fogg, S,
Agarwal A,
Nick HS,
and
Visner GA.
Iron regulates hyperoxia-dependent human heme oxygenase 1 gene expression in pulmonary endothelial cells.
Am J Respir Cell Mol Biol
20:
797-804,
1999
6.
Grünig, E,
Mereles D,
Hildebrandt W,
Swenson ER,
Kübler W,
Kuecherer H,
and
Bärtsch P.
Stress Doppler echocardiography for identification of susceptibility to high altitude pulmonary edema.
J Am Coll Cardiol
35:
980-987,
2000
7.
Howard, LSGE,
Barson RA,
Howse BPA,
McGill TR,
McIntyre ME,
O'Connor DF,
and
Robbins PA.
Chamber for controlling gas tensions over sustained periods in humans.
J Appl Physiol
78:
1088-1091,
1995
8.
Hu, J,
Discher DJ,
Bishopric NH,
and
Webster KA.
Hypoxia regulates expression of the endothelin-1 gene through a proximal hypoxia-inducible factor-1 binding site on the antisense strand.
Biochem Biophys Res Commun
245:
894-899,
1998[Web of Science][Medline].
9.
Hyman, AL,
Lippton HL,
Dempsey CW,
Fontana CJ,
Richardson DE,
Rieck RW,
and
Kadowitz PJ.
Autonomic control of the pulmonary circulation.
In: Pulmonary Vascular Physiology and Pathophysiology, , edited by Weir EK,
and Reeves JT.. New York: Dekker, 1988, p. 291-324.
10.
Ivan, M,
Kondo K,
Yang H,
Kim W,
Valiando J,
Ohh M,
Salic A,
Asara JM,
Lane WS,
and
Kaelin WG.
HIF targeted for VHL-mediated destruction by proline hydroxylation: implications for oxygen sensing.
Science
292:
464-468,
2001
11.
Jaakkola, P,
Mole DR,
Tian YM,
Wilson MI,
Gielbert J,
Gaskell SJ,
von Kriegsheim A,
Hebestreit HF,
Mukherji M,
Schofield CJ,
Maxwell PH,
Pugh CW,
and
Ratcliffe PJ.
Targeting of HIF- to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation.
Science
292:
468-472,
2001
12.
Linehan, JH,
and
Dawson CA.
Pulmonary vascular resistance (P:Q relations).
In: The Pulmonary Circulation, , edited by Fishman AP.. Philadelphia, PA: University of Philadelphia Press, 1990, p. 41-55.
13.
Madden, JA.
Focus on "Hypoxic constriction of porcine distal pulmonary arteries: endothelium and endothelin dependence."
Am J Physiol Lung Cell Mol Physiol
280:
L853-L855,
2001
14.
Morrell, NW,
Nijran KS,
Biggs T,
and
Seed WA.
Magnitude and time course of acute hypoxic pulmonary vasoconstriction in man.
Respir Physiol
100:
271-281,
1995[Web of Science][Medline].
15.
Palmer, LA,
Semenza GL,
Stoler MH,
and
Johns RA.
Hypoxia induces type II NOS gene expression in pulmonary artery endothelial cells via HIF-1.
Am J Physiol Lung Cell Mol Physiol
274:
L212-L219,
1998
16.
Peacock, AJ,
Challenor V,
and
Sutherland G.
Estimation of pulmonary artery pressure by Doppler echocardiography in normal subjects made hypoxic.
Respiratory Med
84:
335-337,
1990.
17.
Ren, X,
Dorrington KL,
Maxwell PH,
and
Robbins PA.
Effects of desferrioxamine on serum erythropoietin and ventilatory sensitivity to hypoxia in humans.
J Appl Physiol
89:
680-686,
2000
18.
Semenza, GL.
HIF-1: mediator of physiological and pathophysiological responses to hypoxia.
J Appl Physiol
88:
1474-1480,
2000
19.
Shimoda, LA,
Manalo DJ,
Sham JS,
Semenza GL,
and
Sylvester JT.
Partial HIF-1 deficiency impairs pulmonary arterial myocyte electrophysiological responses to hypoxia.
Am J Physiol Lung Cell Mol Physiol
281:
L202-L208,
2001
20.
Tenenbein, M,
Kowalski M,
Sienko A,
Bowden DH,
and
Adamson IY.
Pulmonary toxic effects of continuous desferrioxamine administration in acute iron poisoning.
Lancet
339:
699-701,
1992[Web of Science][Medline].
21.
Wang, GL,
and
Semenza GL.
Desferrioxamine induces erythropoietin gene expression and hypoxia-inducible factor 1 DNA-binding activity: implications for models of hypoxia signal transduction.
Blood
82:
3610-3615,
1993
22.
Ward, JPT,
and
Aaronson PI.
Mechanisms of hypoxic pulmonary vasoconstriction: can anyone be right?
Respir Physiol
115:
261-271,
1999[Web of Science][Medline].
23.
Yu, AY,
Frid MG,
Shimoda LA,
Wiener CM,
Stenmark K,
and
Semenza GL.
Temporal, spatial, and oxygen-regulated expression of hypoxia-inducible factor in the lung.
Am J Physiol Lung Cell Mol Physiol
275:
L818-L826,
1998
24.
Yu, AY,
Shimoda LA,
Iyer NV,
Huso DL,
Sun X,
McWilliams R,
Beaty T,
Sham JSK,
Wiener CM,
Sylvester JT,
and
Semenza GL.
Impaired physiological responses to chronic hypoxia in mice partially deficient for hypoxia-inducible factor 1.
J Clin Invest
103:
691-696,
1999[Web of Science][Medline].
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G. M. Balanos, N. P. Talbot, K. L. Dorrington, and P. A. Robbins Human pulmonary vascular response to 4 h of hypercapnia and hypocapnia measured using Doppler echocardiography J Appl Physiol, April 1, 2003; 94(4): 1543 - 1551. [Abstract] [Full Text] [PDF]
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