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1 Department of Pediatrics, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157; and 2 Departments of Neurology and Pharmacology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Pulmonary hypertension and blunted pulmonary vascular responses to ACh develop when newborn pigs are exposed to chronic hypoxia for 3 days. To determine whether a cyclooxygenase (COX)-dependent contracting factor, such as thromboxane, is involved with altered pulmonary vascular responses to ACh, newborn piglets were raised in 11% O2 (hypoxic) or room air (control) for 3 days. Small pulmonary arteries (100-400 µm diameter) were cannulated and pressurized, and their responses to ACh were measured before and after either the COX inhibitor indomethacin; a thromboxane synthesis inhibitor, dazoxiben or feregrelate; or the thromboxane-PGH2-receptor antagonist SQ-29548. In control arteries, indomethacin reversed ACh responses from dilation to constriction. In contrast, hypoxic arteries constricted to ACh before indomethacin and dilated to ACh after indomethacin. Furthermore, ACh constriction in hypoxic arteries was nearly abolished by either dazoxiben, feregrelate, or SQ-29548. These findings suggest that thromboxane is the COX-dependent contracting factor that underlies the constrictor response to ACh that develops in small pulmonary arteries of piglets exposed to 3 days of hypoxia. The early development of thromboxane-mediated constriction may contribute to the pathogenesis of chronic hypoxia-induced pulmonary hypertension in newborns.
thromboxane; neonatal pulmonary hypertension; acetylcholine; thromboxane synthesis inhibitors
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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PULMONARY HYPERTENSION DEVELOPS when newborn pigs are exposed to chronic hypoxia for either 3 days (short hypoxia) or 10 days (long hypoxia) (10). Identifying the changes in the pulmonary circulation that occur with short hypoxia may be key to understanding the pathogenesis of pulmonary hypertension and to developing therapies to intervene with its progression (17). We have previously found that ACh dilation is blunted in lungs from piglets exposed to short hypoxia (11). Why this occurs is not clear, but one possibility is that the amount of vasodilators normally released in response to ACh stimulation is reduced in these animals (7, 18). Another possibility is that vasoconstrictors are released (27, 31). Supportive of this latter possibility is evidence that contracting metabolites of the cyclooxygenase (COX) pathway underlie the altered responses to ACh seen in a number of vascular beds of adult animals with systemic hypertension (13, 14, 22, 31). Whether a similar mechanism is operative in lungs of newborns with pulmonary hypertension is not known. The purpose of this study was to test the hypothesis that a COX-dependent contracting factor, such as thromboxane, is involved with the altered pulmonary vascular responses to ACh that develop in newborn piglets with pulmonary hypertension resulting from short hypoxia.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Animals. A total of 40 hypoxic piglets and a total of 45 control piglets were studied. For the hypoxic piglets, newborn pigs (2-3 days old; both sexes; Yorkshire, Landrace, or mixed York-Landrace) were placed in a hypoxic normobaric chamber for 3-4 days so that they were 5-7 days old when studied. Normobaric hypoxia was produced by delivering compressed air and N2 to an incubator (Thermocare). O2 content was regulated at 10-11% O2 (PO2 66-74 Torr), and CO2 was maintained at 3-6 Torr by absorption with soda lime. The chamber was opened two times per day for cleaning and to weigh the piglets. The animals were fed ad libitum with an artificial sow milk replacer from a feeding device attached to the chamber. We have previously found no differences in vascular responses between piglets raised in a room-air environment for 3-5 days and piglets raised on a farm (10, 11). Therefore, for this study, most (n = 40) of the control piglets were studied on the day of arrival from the farm at 5-7 days of age.
Vessel preparation.
On the day of study, the piglets were preanesthetized with ketamine (30 mg/kg im) and acepromazine (1 mg/kg im) and then anesthetized with
pentobarbital sodium (10 mg/kg iv). All animals were given heparin (1,000 IU/kg iv) and then exsanguinated. The thorax was opened,
and the lungs were removed and placed in cold (4°C) physiological saline solution (PSS) until use. The PSS had the following composition (in mM): 141 Na+, 4.7 K+, 125 Cl
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2.5 Ca2+, 0.72 Mg2+, 1.7 H2PO
Protocols.
Each artery was allowed to equilibrate for 40-60 min to establish
basal tone. The arteries were equilibrated at transmural pressures
similar to those in vivo (11): 15 cmH2O for
control arteries and 25 cmH2O for hypoxic vessels. After
equilibration and establishment of basal tone, the arteries were tested
for viability by contraction to either KCl (102 M) or
U-46619 (107 M). The arteries were then washed with fresh
PSS and allowed to return to their precontracted diameter, i.e.,
allowed to reestablish basal tone.
8 to 105 M) were added to the reservoir
at 15-min intervals. Reproducibility of the ACh dose responses was
tested in some arteries. To do this, after the first set of responses,
the arteries were washed with fresh PSS and allowed to equilibrate for
15 min, and a second dose-response curve to ACh (108 to
105 M) was performed. Because the hypoxic arteries
constricted to ACh, the presence of a functional endothelium was
verified by assessing dilatory responses to cumulative doses
(108 to 105 M) of the calcium ionophore,
A-23187, administered at 15-min intervals. Responses to A-23187 were
also evaluated in control arteries.
In another series of studies, the influence of transmural pressure on
ACh responses was determined. Once the arteries had established basal
tone at their starting pressures, 15 cmH2O for control
arteries and 25 cmH2O for hypoxic arteries, the transmural pressure was increased to 25 cmH2O in the control arteries
and reduced to 15 cmH2O in the hypoxic arteries. After 15 min at these pressures, the ACh dose-response curves were performed.
The influence of elevated tone on ACh responses in control and hypoxic
arteries was assessed in another series of studies. Tests for viability
and a functional endothelium were done as described above, and then
either endothelin or the thromboxane mimetic, U-44619, was added in
increasing doses until the arterial diameter had decreased by
30-40%. After equilibration at the elevated tone, the
dose-response curves to ACh were performed.
To determine whether arteries from control and hypoxic piglets dilate
differently because of impaired smooth muscle dilation, responses to
the non-endothelium-dependent dilator, the nitric oxide (NO) donor
S-nitroso-N-acetylpenicillamine (SNAP), were determined. Because vessels at basal tone dilate minimally to SNAP,
tone was first elevated 30-40% by using either U-44619 or endothelin before the addition of SNAP (108 to
105 M).
The contribution from all COX metabolites and from the specific COX
metabolite thromboxane to ACh responses in control and hypoxic arteries
at basal tone was determined. These studies were performed with the
vessels at basal tone to avoid any confounding influence from use of
vasoconstrictors (4, 19). Cumulative doses of ACh were
added (108 to 105 M) before and then 20 min
after the addition of one of the following: the COX synthase inhibitor
indomethacin (105 M); the thromboxane synthase inhibitor
dazoxiben (105 M); the thromboxane synthase inhibitor
feregrelate (105 M); or the thromboxane-receptor
antagonist SQ-29548 (105 M). For the studies with
SQ-29548, at the completion of the ACh dose responses, the thromboxane
mimetic U-46619 was added to assess the effectiveness of receptor
blockade by SQ-29548.
To determine the influence of the endothelium on ACh responses, the
endothelium was disrupted by infusing air into control and hypoxic
arteries at basal tone (15). Functional disruption of the
endothelium was verified by loss of dilation to ACh and/or A-23817 in
the control arteries and to A-23187 in the hypoxic arteries. Reactivity
to either KCl or U-46619 was used to confirm viability of the arteries.
Then, the diameter of control and hypoxic arteries was continuously
monitored while cumulative doses of ACh were added before and 20 min
after the addition of either indomethacin (105 M) or
dazoxiben (105 M). In some of the hypoxic arteries,
responses to cumulative doses of ACh were measured before and after air infusion.
After all of the above studies, vessel viability was retested by using
KCl or U-46619. In addition, in some studies, vessel responses to the
vehicle used for solubilization of each agent were evaluated.
Materials. Concentrations for each drug listed in Protocols were expressed as final molar concentrations in the vessel bath. ACh, A-23187, and indomethacin were obtained from Sigma Chemical. Feregrelate was from Cayman Chemicals. SNAP and SQ-29548 were from Biomol. Dazoxiben was from Pfizer. ACh, SNAP, and dazoxiben were solubilized in distilled H2O. Indomethacin was solubilized in a mixture of equal parts saline and 8% NaHCO3. Feregrelate and A-23187 were solubilized in DMSO. SQ-29548 was solubilized in ethanol.
Statistics. Data are means ± SE. One-way ANOVA with post hoc multiple-comparison test was used to compared changes in vessel diameter between control and hypoxic arteries at the different transmural pressures for each dose of ACh. An unpaired t-test was used to compare changes in vessel diameter between control and hypoxic arteries for each dose of A-23187 or SNAP. A paired t-test was used to compare changes in vessels diameters before and after treatment with indomethacin, dazoxiben, feregrelate, or SQ-29548 for each dose of ACh for both control and hypoxic arteries. P < 0.05 was considered significant.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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After equilibration at basal tone, the mean diameter of all vessels used in these studies were 240 ± 6 µm for control arteries and 250 ± 6 µm for hypoxic arteries. None of the vehicles significantly changed arterial diameter in the concentrations used to solubilize any of the agents.
In control arteries at normal (15 cmH2O) and elevated (25 cmH2O) transmural pressures, vessel diameter increased to
all but the highest dose of ACh (Fig. 1).
In hypoxic arteries, the diameter decreased to all doses of ACh at both
normal (25 cmH2O) and reduced (15 cmH2O)
transmural pressure. When tone was elevated with either U-46619 or
endothelin, arteries from both hypoxic and control piglets dilated to
all doses of ACh (Fig. 2), although the
dilation to each dose of ACh was less in the hypoxic arteries. For both control and hypoxic arteries, results were similar for arteries with
tone elevated with either endothelin or U-46619 so that they were
combined (Fig. 2).
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Both control and hypoxic arteries dilated to the calcium ionophore,
A-23187 (Fig. 3), until the highest dose,
whereupon the diameters returned to control values. At
106 M, the hypoxic arteries had dilated significantly
more than the control arteries. Both artery types dilated similarly to
all doses of SNAP (Fig. 4). The dilations
to A-23187 (Fig. 3) and SNAP (Fig. 4) by the hypoxic arteries indicate
respectively that the endothelium can release dilators and that smooth
muscle cell dilation is unaltered.
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Table 1 summarizes the changes in
pulmonary arterial diameter by control and hypoxic vessels in which the
dose responses to ACh were repeated. In both control and hypoxic
arteries, the magnitude of the ACh dilation at each dilation was
similar in both trials. Therefore, differences in responses to ACh
measured before and after addition of inhibitors as described below
cannot be attributed to tachyphylaxis.
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Indomethacin reversed the ACh-induced response from dilation to
constriction in control arteries (Fig.
5), whereas indomethacin reversed the ACh
response from constriction to dilation in hypoxic arteries (Fig. 5). In
control arteries, the magnitude of ACh-induced dilation tended to be
blunted after the thromboxane synthase inhibitor, dazoxiben, or the
thromboxane-receptor antagonist SQ-29548 but was unaffected by the
thromboxane synthase inhibitor feregrelate (Fig.
6A). By comparison, the two
thromboxane synthesis inhibitors feregrelate or dazoxiben and the
thromboxane receptor antagonist SQ-29548 nearly abolished the
ACh-induced constriction of hypoxic arteries (Fig. 6B).
After treatment with SQ-29548, U-46619 elicited no change in either
control or hypoxic arterial diameter. For purposes of illustration and
because of their similarity, the responses to ACh measured before the
addition of either of the thromboxane inhibitors or the receptor
antagonist were combined for all control arteries in Fig. 6A
and for all hypoxic arteries in Fig. 6B.
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After air infusion, both control (Fig.
7A) and hypoxic (Fig.
7B) arteries constricted to all doses of ACh. In hypoxic
arteries, the magnitude of constriction to ACh was similar to that
before air infusion (Table 2). In both
artery types, dazoxiben and indomethacin diminished, but did not
abolish, the constriction (Fig. 7, A and B).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The findings of diminished dilation to ACh but preserved dilation to the non-endothelium-dependent dilator SNAP by small, 100- to 400-µm-diameter, pulmonary arteries from newborn piglets exposed to short hypoxia are consistent with our previous findings in isolated lungs showing blunted pulmonary vascular responses to ACh but unaltered responses to the non-endothelium-dependent dilators, sodium nitroprusside and papaverine (10, 11). Thus impaired smooth muscle dilation does not appear to contribute to altered ACh responses in the pulmonary vasculature of piglets exposed to short hypoxia.
The major new finding of this study is that a COX-dependent, vascular wall-derived contracting factor, most likely thromboxane, appears to be at least partly responsible for the abnormal pulmonary vascular responses to ACh that develop when newborn piglets are exposed to short hypoxia. In addition, these impaired responses may involve receptors and/or G proteins (3, 9).
Besides our studies, there are only a few others in which pulmonary vascular responses to ACh have been evaluated in newborn animals with chronic hypoxia-induced pulmonary hypertension. Similar to our results, dilation to ACh was blunted in rings of 2- to 3-mm-diameter pulmonary arteries from piglets raised in hypobaric hypoxia for 3 days (30), and ACh responses were reduced in lobar pulmonary arteries isolated from calves exposed to high-altitude (hypobaric hypoxia) for 14 days (23). Of note, the latter group of investigators found greater pulmonary vascular responses to ACh in high-altitude calves in vivo than in comparably aged control calves (23). The discrepancy between the in vivo results and those in lobar pulmonary arteries from high- altitude calves could be due to inherent differences in the two preparations or to a difference in the influence of hypobaric hypoxia on conduit-level (as reflected by results of lobar pulmonary arteries) vs. resistance-level (as reflected by in vivo results with whole lungs) pulmonary arteries (23). Nonetheless, the combined results from studies with newborn piglets and newborn calves suggest that exposure to chronic hypoxia impairs ACh responses in some, if not all, segments of the newborn pulmonary circulation.
ACh responses are mediated by muscarinic receptors coupled to G proteins (9). Because dilation to the non-receptor-dependent, non-G-protein-dependent agent A-23187 was preserved (Fig. 3), our findings indicate that impaired ACh responses might involve either muscarinic receptors or G proteins. In particular, it is possible that chronic in vivo hypoxia alters the density and/or the subtypes of muscarinic receptors on either endothelial or smooth muscle cells. Consistent with our findings, ACh dilation was blunted but responses to A-23187 were unaltered in 2- to 3-mm-diameter pulmonary artery rings of piglets raised in hypobaric hypoxia from birth to 2.5 days of age (30). However, the same group of investigators found diminished responses to both ACh and A-23187 in pulmonary artery rings of piglets raised in hypoxia from 3 to 6 days of age (30). Thus the involvement of receptors and/or G proteins with altered ACh responses might vary with length of hypoxia, the age at which the animal is exposed to hypoxia, and the size of the pulmonary artery studied. Moreover, it is possible, as suggested by studies with adult rats, that other receptor G protein-coupled pathways are also affected with chronic hypoxia (28). All these issues will require future clarification.
Because ACh stimulates the endothelium to release NO, it has been suggested that altered production of, or responsiveness to, NO might contribute to abnormal pulmonary vascular dilation to ACh (7, 18). Indeed, our laboratory (11, 12) and others (2) have provided consistent evidence that pulmonary vascular NO production is decreased in newborn piglets exposed to long hypoxia. By comparison, evidence for decreased pulmonary vascular NO production with short hypoxia is less certain (11, 16, 30) and may depend on the age at which the animal is first exposed to hypoxia (16). Furthermore, whereas we have found that pulmonary vascular responsiveness to the NO donors SNAP and sodium nitroprusside remains unaltered in small pulmonary arteries (Fig. 4) and whole lungs (11), respectively, other investigators using either exogenous NO (30) or the NO donor 3-morpholinosydnonimine-N-ethylcarbamide (2) reported that responses to NO were diminished in whole lungs (2) or rings of conduit-level pulmonary arteries (30) of piglets exposed to short hypoxia. Thus the role of NO in the abnormal ACh responses that develop when newborn piglets are exposed to short hypoxia is not certain.
In addition to NO, ACh can stimulate the release of a variety of other vasoactive agents. For example, it has been shown that vasoconstrictor COX products are released by stimulation with ACh or its stable analog, methacholine, in cerebral arteries of spontaneously hypertensive rats (22); in aortas of rabbits exposed to high glucose levels (29); in renal arteries from cholesterol-fed rats (1); in rings of intrapulmonary arteries from adult rabbits (5); and in 700- to 1,600-µm-diameter, conduit-level, pulmonary arteries from adult rats with pulmonary hypertension after 10 days of chronic hypoxia (21). To our knowledge, this is the first report that COX-dependent contracting factors contribute to abnormal ACh responses in a newborn model of pulmonary hypertension. Moreover, our study with newborns is the first to show that the COX-dependent contracting factors are involved with altered ACh responses in small, resistance-level, pulmonary arteries and that the contribution from the contracting factor occurs within a time period as short as 3 days of hypoxia.
Because of its known potent vasoconstrictive effects in the neonatal pulmonary circulation (6, 25), we pursued the possibility that thromboxane might be the COX-dependent contracting factor underlying altered pulmonary vascular ACh responses in short-hypoxic piglets. We found that ACh-induced constriction of small pulmonary arteries from piglets exposed to short hypoxia was nearly abolished by two different thromboxane synthesis inhibitors and by a thromboxane-PGH2-receptor antagonist. However, on the basis of the observation that nonspecific COX inhibition with indomethacin appears to have a greater inhibitory effect on ACh induced constriction (Fig. 5) than does either selective thromboxane synthesis inhibition or thromboxane-PGH2-receptor antagonism (Fig. 6B), an additional COX-dependent contracting factor might also be involved. Also, COX inhibition does not completely restore ACh-induced dilation in short hypoxic piglets; i.e., there is less ACh-induced dilation in arteries of piglets exposed to short hypoxia after nonspecific COX inhibition than in untreated arteries from control piglets (Fig. 5). The concomitant inhibition of COX-dependent dilators along with the constrictors might explain why ACh-induced dilation was not restored by indomethacin. However, there is also the possibility that, in addition to COX products, a yet-to-be-identified, non-COX-dependent contracting factor contributes to the blunted ACh responses in pulmonary arteries of piglets exposed to short hypoxia.
Because our conclusions are based on results using pharmacological inhibition, we must consider that there could also be non-COX- or non-thromboxane-mediated effects. Precursor arachidonate might be shunted to non-COX-mediated pathways. COX is only one of a number of enzyme pathways in the pulmonary circulation known to synthesize vasoactive agents from the precursor arachidonate. Indeed, the constrictor response to ACh in control arteries after COX inhibition with indomethacin could be explained by the shunting of arachidonate to the lipoxygenase pathway. Another possibility is that inhibiting COX dilators and constrictors might unmask the effects from some nonarachidonate vasoconstrictors, such as endothelin. However, such an effect from COX inhibition in the hypoxic arteries would lead to an enhanced, not lessened, constriction to ACh.
Evidence that the thromboxane synthesis inhibitors and the receptor antagonist might have some non-thromboxane-mediated effects, including a possible effect on COX-dependent dilators, is suggested by findings with control arteries. Dazoxiben and SQ-29548 tended to blunt ACh-induced dilation in control arteries (Fig. 6A). Yet, a similar effect by these agents in hypoxic arteries would be expected to augment, not diminish, the ACh-induced constriction. Moreover, the marked and similar ability of more than one thromboxane synthesis inhibitor as well as the PGH2-thromboxane-receptor antagonist to blunt the ACh-induced constriction in hypoxic arteries adds strength to the argument that thromboxane mediates the constrictor response.
Our studies in hypoxic arteries provide evidence regarding possible cellular source(s) of thromboxane. The ability to reduce ACh-induced constriction by treatment with either a COX inhibitor or a thromboxane synthesis inhibitor was similar in both endothelium intact arteries and those in which the endothelium had been disrupted by air infusion (Figs. 6B and 7B). In addition, the magnitude of ACh-induced constriction was similar before and after endothelial disruption (Table 2). If the endothelium were the major source of the contracting factor(s), then endothelial disruption and/or removal should have diminished both the magnitude of ACh-induced constriction and the effectiveness of contracting factor inhibitors in reducing ACh-induced contraction. Thus our findings with air-infused hypoxic arteries suggest that, rather than the endothelium, cells in the vascular wall are the major source of the contracting factor(s), including thromboxane.
It is of interest that our findings suggest that, when the endothelium of small pulmonary arteries from control piglets is disrupted, ACh stimulates the release of COX-dependent contracting factor(s) from cells in the vascular wall and that thromboxane is one of these contracting factors. Consistent with this finding, recent studies have shown that thromboxane synthase is found in cells in the vascular wall, including smooth muscle cells, but not in the endothelium, of pulmonary vessels from normal rats (8). Moreover, members of our group have provided evidence that, rather than endothelial or smooth muscle cells, platelets adherent to endothelial cells are the cellular source of thromboxane synthase in intrapulmonary arteries of adult rabbits and that thromboxane production requires an interaction between platelets and endothelial cells (5, 24). The precise cellular source(s) of thromboxane production in the vascular wall of resistance-level pulmonary arteries from newborn piglets remains to be determined.
Unlike our findings in newborn piglets, when adult rats are exposed to 10 days of hypoxia, the endothelium, not the vascular wall, is the source of the COX-dependent constrictor PGH2 that underlies the development of ACh-induced constriction in conduit-level pulmonary arteries (21). Differences between species, size of arteries studied, and length of hypoxia could contribute to the variability between studies with adult rats and newborn piglets.
Altogether, our findings with newborn piglets show that COX-dependent agents are involved in ACh responses in small pulmonary arteries from both control and hypoxic animals. However, it is important to note that the COX metabolites that play the most important roles in mediating ACh responses appear to differ between arteries from control and hypoxic piglets. Specifically, our findings indicate that the influence from COX-dependent dilators predominates in control arteries, whereas the influence from COX-dependent contracting factors predominates in hypoxic arteries. In other words, one possible explanation for our findings is that both dilators and contracting factors are produced by control arteries but that the influence from dilators produced by the endothelium overrides the constrictors produced by the smooth muscle. During hypoxia, it is possible that the influence of dilators from the endothelium is lost, thereby unmasking the contractile response. Another explanation for the change with hypoxia could be that COX-dependent contracting factor production increases with short hypoxia. Yet another possibility is that sensitivity to the COX-dependent dilators and/or contracting factors is altered by exposure to short hypoxia. These possibilities merit further investigation.
To summarize, our findings indicate that a COX-dependent, vascular wall-derived contracting factor, most likely thromboxane, is at least partly responsible for the abnormal pulmonary vascular responses to ACh that develop when newborn piglets are exposed to short hypoxia. These findings have important implications for the pathogenesis of hypoxia-induced pulmonary hypertension in newborns. In addition to its vasoconstrictive effect, thromboxane is a smooth muscle cell mitogen (26). Thus intervening with thromboxane at an early time point may not only diminish the early elevation in pulmonary arterial pressure but also may inhibit progressive smooth muscle hypertrophy and thereby ameliorate the progression of hypoxia-induced pulmonary hypertension. Future studies are needed to evaluate these possibilities.
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ACKNOWLEDGEMENTS |
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This work was supported by a March of Dimes Research Grant (to C. D. Fike).
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FOOTNOTES |
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Address for reprint requests and other correspondence: C. D. Fike, Dept. of Pediatrics, Wake Forest Univ. School of Medicine, Medical Center Blvd., Winston-Salem, NC 27157 (E-mail: cfike{at}wfubmc.edu).
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.
Received 7 June 2001; accepted in final form 23 August 2001.
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TOP
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METHODS
RESULTS
DISCUSSION
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different from hypoxic arteries
before SQ-29548, P < 0.05 (paired
t-test).
