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Department of Physiology, National Taiwan University College of Medicine, Taipei 100, Taiwan
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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We previously demonstrated that the
pulmonary vascular response to substance P (SP) increased in
chronically hypoxic rats. This study explored the temporal increase in
reactivity of the pulmonary vascular response to SP and its underlying
mechanisms. First, young female Wistar rats were exposed to sea level
(SL) or simulated high altitude (HA) for 15 h/day for 3 days, 1 wk, 2 wk, and 4 wk. Lungs were isolated and perfused with 4% bovine serum
albumin in Krebs-Henseleit buffer solution. SP (1.5 × 10
4 M) induced significant increases in pulmonary
arterial pressure (Ppa), venous pressure (Pv),
capillary pressure (Pc), arterial resistance
(Ra), and filtration coefficient
(Kfc) in SL lungs. Increases in Ppa
and Ra were significantly augmented in HA lungs, with a
temporal increase trend peaking at 2 wk of HA exposure. The selective
neurokinin (NK) type 1 (NK1) receptor antagonist SR-14033
significantly attenuated SP-induced increases in Ppa, Pv, Pc, Ra, and
Kfc in SL lungs. In lungs exposed to HA for 2 wk, SR-14033 suppressed the effect of SP on Ppa. Also,
chronic hypoxia induced significant increases in NK1
receptors and NK1 receptor mRNA, with a temporal trend. We
conclude that chronic hypoxia temporally augments SP-induced vascular
responses, which are closely associated with increases in
NK1 receptors and gene expression.
pulmonary hypertension; tachykinins; gene expression
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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WE PREVIOUSLY DEMONSTRATED in vivo that pulmonary hypertension in chronic hypoxia was closely associated with activation of neurokinin (NK) type 1 (NK1) receptors and that the pulmonary vascular response to substance P (SP) markedly increased in chronically hypoxic rats (2). SP is a member of the tachykinin family, and its action is mediated mainly via the NK1 receptor and much less via the NK type 2 (NK2) receptor (15). The time course and mechanism(s) of the enhanced pulmonary vascular reactivity to SP during chronic hypoxia are not clear.
Therefore, this study was carried out, first, to investigate, using isolated perfused lungs, the temporal trend of this increased pulmonary vascular reactivity to SP in chronically hypoxic rats. In addition, we tested whether the NK1 receptor antagonist SR-14033 (7) and the NK2 receptor antagonist SR-48968 (6) prevent the increased vascular reactivity. Finally, we explored whether the NK1 receptor and its gene expression are altered during the course of hypoxic exposure.
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MATERIALS AND METHODS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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This study was performed in three parts. Part 1 was carried out to explore temporal changes in pulmonary vascular reactivity to SP in chronically hypoxic rats. Part 2 was performed using the antagonist of SP. In part 3, we analyzed the NK1 receptor and NK1 receptor gene expression.
Animal preparation. In part 1, 29 young female Wistar rats weighing 219 ± 3 g were divided into five groups: sea level (SL; n = 6), hypoxia for 3 days (3D-HA; n = 5), hypoxia for 1 wk (1W-HA; n = 6), hypoxia for 2 wk (2W-HA; n = 6), and hypoxia for 4 wk (4W-HA; n = 6). Animals in the SL group breathed room air. HA rats were exposed to simulated high altitude (HA; 380 mmHg barometric pressure) in an hypobaric chamber for 15 h/day from 5 PM to 8 AM each day (intermittent exposure) and breathed room air the rest of the time (2). Temperature (23 ± 2°C) and light cycle (lights on from 7 AM to 7 PM) were kept constant in the hypobaric chamber.
For part 2, 36 young female Wistar rats weighing 234 ± 3 g were evenly divided into two groups: SL (n = 18) and 2W-HA (n = 18). The SL and 2W-HA animals were treated as described above. Each group was further evenly divided into three subgroups: SP, SR-14033 + SP, and SR-48968 + SP. For part 3, we analyzed the NK1 receptor and NK1 receptor gene expression in 20 young animals evenly divided into four groups: SL, 1W-HA, 2W-HA, and 4W-HA. For exposure to air (SL) or hypoxia, the animals were treated as described for part 1.Setup for the isolated perfused lungs.
After a fixed period of air or hypoxic exposure, each animal was
anesthetized with pentobarbital sodium (40 mg/kg ip). Then the isolated
perfused lungs were prepared as described by Huang and Lin
(10), with some modifications. Briefly, after insertion of
a tracheal cannula, the chest was opened and the lungs were ventilated
with humidified 95% air-5% CO2 under an end-expiratory pressure of 2.5 cmH2O. After the right ventricle was
injected with heparin (150 IU), the pulmonary artery was cannulated and perfused with a perfusate. The perfusate was a mixture of bovine serum
albumin (4 mg/100 ml) and Krebs-Henseleit buffer solution containing
(in mM) 118 NaCl, 4.7 KCl, 2.5 CaCl · 2 H2O, 1.2 MgSO4 · 7 H2O, 1.2 KH2PO4, 25 NaHCO3, and 10 glucose.
A wide-bore cannula was placed in the left atrium through the left
ventricle to collect the effluent perfusate for recirculation. About 50 ml of initial perfusate were discarded to clear the blood before
initiation of recirculation. A perfusion rate of 3 ml · min1 · 100 g body wt1
was maintained by a roller pump through an air bubble trap. The heart
and lungs were removed en bloc and placed on a weighing pan, which was
mounted on a Grass force transducer for detecting the change in lung
weight and was suspended in a constant-temperature (37°C) humidified
chamber. The weighing system was calibrated by placing a 2-g weight on
the pan and adjusting the output to 5 cm of chart deflection. The
pulmonary arterial (Ppa) and venous pressures
(Pv) were continuously monitored with Statham pressure transducers, which were placed at the same height as the heart. Distances between the pressure transducers and the pulmonary artery and
vein were 29 and 50 cm, respectively. Resistances of the connecting catheters were measured, and then the above-measured Ppa
and Pv were corrected for these resistances of connecting
tubings. Changes in lung weight, Ppa, and
Pv were continuously recorded with a Grass recorder. In
addition, the isolated perfused lungs were continuously ventilated with
95% air-5% CO2.
Capillary pressure. With a constant-flow perfusion, venous outflow was momentarily stopped for 3-4 s at end expiration. There was a rapid rise in Pv followed by a slower but steady rise. Capillary pressure (Pc) was obtained by extrapolating the slow-rising component back to time 0 (3).
Filtration coefficient.
The filtration coefficient (Kfc) was determined
by the gravimetric method of Drake et al. (4). On
achieving an isogravimetric state, we raised the Pv rapidly
by 10 cmH2O for 10 min. This hydrostatic pressure caused
the lung to gain weight promptly. This was followed by a slow but
steady rise in lung weight. The rapid component represents the
expansion of pulmonary blood vessels, whereas the slow component is due
to fluid filtration into the interstitial space. The initial rate of
fluid filtration was estimated by extrapolating the slow component to
time 0 in a semilogarithmic plot. The value of the
y-intercept was divided by the hydrostatic pressure
challenge (
Pc) and normalized to 100 g of lung weight.
Experimental protocols.
In part 1, we studied the pulmonary vascular response to SP.
In a preliminary study, the dose-dependent increase of Ppa
in response to SP was analyzed. At the end of a 20-min equilibration (baseline) period, baseline values of vascular parameters were measured. Then SP (5 × 105, 1.5 × 104, or 2.5 × 104 M) was added to the
perfusate, and the vascular response to SP was recorded. At 10 min
after the first addition of SP or when pulmonary vascular parameters
returned to baseline, the perfusate was changed and a new SP solution
was added to the perfusate. Subsequently, with the same procedure,
SP-induced responses were tested again using another SP solution.
According to this preliminary study, 1.5 × 104 M SP
(unless otherwise noted) was chosen for vascular challenge in the
subsequent experiments.
4 M) challenge period. Ppa,
Pv, Pc, and change in lung weight were determined before (baseline period) and after the SP challenge. Then
arterial resistance (Ra), venous resistance
(Rv), and Kfc were calculated separately.
For part 2, the general protocol for SP challenge was a
20-min equilibration (baseline) period, a 10-min antagonist
(107 M SR-14033 or 107 M SR-68968) period,
and the SP (104 M) challenge period. Ppa,
Pv, Pc, and Kfc were
determined before (baseline period) and after the SP challenge. Then
Ra, Rv, and Kfc were
calculated separately.
Immunoblotting of NK1 receptors in the lung tissue.
For part 3, lung and ileac tissues were removed from
anesthetized animals to prepare membrane fraction protein. All
procedures were performed at 4°C or on ice. The tissues were rinsed
with saline and homogenized in 50 mM Tris, pH 7.4, containing protease inhibitors (Sigma, St. Louis, MO), 10 mM phenylmethylsulfonyl fluoride,
10 µM benzamidine, 10 µM leupeptin, and 1 µg/ml trypsin inhibitor. The homogenate was centrifuged (3,000 rpm for 20 min) to
remove the cellular debris, and the supernatant was ultracentrifuged (45,000 rpm for 60 min). The pellet was suspended in 0.32 M PBS-sucrose containing protease inhibitors, as described above, and stored at
70°C for later analysis. Total protein in the membrane preparation was determined by Bradford's dye-binding assay method (Bio-Rad, Hercules, CA). The same amount of membrane protein from each
preparation, except the ileac tissue, was separated on a 10%
polyacrylamide gel under denaturing conditions and electrophoretically
transferred to nitrocellulose (Amersham, Buckingham, UK). Membranes
were incubated with NK1 receptor antiserum (1:1,000 titer;
Novus Biologicals, Littleton, CO) overnight at 4°C, washed, and then
incubated with goat biotinylated anti-rabbit IgG conjugated to
horseradish peroxidase (Vector, Burlingame, CA) for 1 h at room
temperature. The membrane samples were washed, and the bound antibody
was visualized using a commercial 3,3'-diaminobenzidine substrate kit
(Vector) for peroxidase following the manufacturer's protocol. The
same procedures were used for treatment of membrane protein
preparations from the ileac tissue [with an abundance of
NK1 receptors (17)]. The density of the major
band at ~79 kDa in each lane was semiquantitatively determined
densitometrically with an image analytic system (Alpha Innotech, San
Leandro, CA).
Quantitative real-time RT-PCR analyzing NK1 receptor mRNA. The theoretical basis and methodology of the ABI PRISM 7700 Sequence Detection System (TaqMan) for real-time quantitative PCR (Perkin-Elmer Applied Biosystem, Foster City, CA) have been described by Johnson et al. (13). Briefly, samples with a high starting copy number of interested genes show an increase in fluorescence early in the RT-PCR process, resulting in a low threshold cycle (CT) number.
The NK1 receptor cDNA sequence was evaluated using TaqMan Primer Express software (Perkin-Elmer). Oligonucleotides designed by the software were purified by HPLC after synthesis. The forward and reverse primers were designed to lie in adjacent exons to prevent amplification of genomic DNA that may be contained in the sample. The sequence-specific probe is designed to hybridize to a region between the PCR primers and was labeled with the reporter dye 6-carboxyfluorescein (FAM) at the 5'-end and the quencher dye 6-carboxytetramethylrhodamine (TAMRA) at the 3'-end. The NK1 receptor forward primer was 5'-GGC CAG AGG ACC AGA ACT TTT-3', the reverse primer was 5'-GCT AGC AAC TCC CAC TAA CAT ACG T-3', and its probe was 5'-FAM-CAA GCA ACA CTG CAC TGC GAG CA-TAMRA-3'. We also quantitated transcripts of the glyceraldehyde-3-phosphate dehydrogenase (GAPDH) gene as the endogenous control, with each unknown sample normalized to GAPDH content. The GAPDH gene forward primer was 5'-TTT CTC GTG GTT CAC ACC CA-3', the reverse primer was 5'-GTC ATC ATC TCC GCC CCT T-3', and its probe was 5'-FAM-CGC TGA TGC CCC CAT GTT TGT G-TAMRA-3'. The total NK1 receptor RNA preparation from the lung tissues of the SL and HA rats was extracted using TRIzol reagent (GIBCO BRL, Grand Island, NY) following the manufacturer's instructions. The exact amount of total extracted RNA was determined by optical density for each sample, and its quality was confirmed by electrophoresis on a 1.2% agarose gel stained with ethidium bromide. The PCR procedure for amplification reactions was performed in a 50-µl final volume containing 5× TaqMan buffer, 3.0 mM Mn(OAc)2, dNTP (0.3 mM each), 0.5 U of AmpErase uracil N-glycosylase (1 U/µl), and 5.0 U of rTth DNA polymerase (2.5 U/µl) from the TaqMan EZ RT-PCR kit (Perkin-Elmer). The final concentration of NK1 receptor and GAPDH gene forward and reverse primers was 4.1 µM. The final concentration of NK1 receptor and GAPDH gene fluorogenic probes was 2.05 µM. To reduce variability between replicates, PCR premixes, which contained all reagents except total RNA, were prepared and aliquoted into 1.5-ml microtubes. Forty microliters of the reaction mixture were added to the PCR optical tube (MicroAmp, Perkin-Elmer) containing 10 µl of 200 ng of unknown sample RNA or ileac RNA, termed the calibrator sample. Thermal cycling conditions were 2 min at 50°C and 30 min at 60°C followed by 5 min at 95°C and 50 cycles of 15 s at 94°C and 1 min at 60°C.Statistical analysis. Values are means ± SE. Differences in parameters among groups were analyzed with analysis of variance. If significant differences existed among groups, statistical differences between any two groups were analyzed by the Newman-Keuls test. Differences were considered significant if P < 0.05. Differences between values before and after the SP challenge were analyzed by paired t-test.
The comparative CT (CT) method was used
to quantify NK1 receptor mRNA levels (13, 24).
The advantage of this method is that it eliminates the need for
standard curves. The CT method uses a single sample,
termed the calibrator sample, for comparison of every unknown sample's
gene expression level. The calibrator sample is analyzed on every assay
plate with unknown samples of interest. We used the mRNA expression of
the rat ileum as the calibrator sample to represent onefold expression
of the gene of interest. The calculation is as follows:
CT = [CT NK1 (unknown sample) CT GAPDH (unknown sample)] [CT NK1 (calibrator sample) CT GAPDH (calibrator sample)]. The formula that can be
used is as follows: fold induction = 2[
CT] (24).
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Part 1.
Compared with the baseline value, two doses of SP (1.5 × 104 and 2.5 × 104 M) caused a
significant increase in Ppa (Fig.
1). Because 1.5 × 104
M SP caused a prominent increase in Ppa, we used this dose
for the subsequent SP challenges.
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4 M SP caused a marked
increase in Ppa in all groups. Compared with SL lungs, the
SP challenge induced significant increases in Ppa (Fig.
2) and Ra (Fig.
3) in all hypoxic lungs. In addition,
hypoxia-augmented, SP-induced increases in Ppa and
Ra showed a temporal increasing trend, with a peak response at 2 wk of hypoxia (2W-HA). Also, a hypoxia-augmented, SP-induced increase in Pc was found in 3D-HA and 1W-HA lungs (Fig. 2).
On the other hand, chronic hypoxia did not significantly augment the
SP-induced increase in Pv (Fig. 2).
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Part 2.
In SL lungs, SR-14033 significantly attenuated SP-induced increases in
Ppa (Fig. 5), Pc
(Fig. 5), and Kfc (Fig.
6). However, SR-48968 did not induce any
significant effect on SP-induced alterations in pulmonary
vascular parameters, except Pc. For HA lungs, SR-14033 significantly attenuated the SP-induced increase in Ppa
(Fig. 7). On the other hand, SR-48968 did
not cause any significant alteration in SP-induced increases in
vascular parameters.
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Part 3.
The NK1 receptor antiserum recognized broad protein bands
of 70 to >120 kDa in membranes prepared from the rat ileum (Fig. 8A, lane 1). The pattern of
the protein bands in membranes prepared from lung tissue in the SL rats
was the same as that in membranes prepared from the ileum (Fig.
8A, lane 2). These protein bands were detected strongly in
the membranes prepared from HA rats (Fig. 8A, lanes
3-5). Figure 8B shows the semiquantitative density of the major 79-kDa band in both groups. The integrated digital values
per counting area were significantly higher in 1W-HA, 2W-HA, and 4W-HA
groups (107.7 ± 8.5, 121.3 ± 8.5, and 123.2 ± 5.8, respectively) than in the SL group (91.7 ± 7.1; Fig. 8). Hypoxia
induced a significant increase in NK1 receptor mRNA (Fig.
9); the increase reached a maximal value
in the 4W-HA group.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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We demonstrated SP-induced increases in Ppa, Pv, Pc, Ra, and Kfc in isolated perfused SL lungs. Prolonged exposure to hypoxia augmented the SP-induced increases in Ppa, Pc, and Ra, with a temporal increase trend peaking at 2 wk. On the other hand, chronic hypoxia significantly attenuated the SP-induced increase in Kfc. SP-induced increases in vascular responses were significantly attenuated by SR-14033 in SL lungs. Also, SR-14033 significantly attenuated the SP-induced increase in Ppa of HA lungs. In addition, chronic hypoxia induced significant increases in NK1 receptors and NK1 receptor mRNA. Several features of the relationship between prolonged hypoxia and SP-induced pulmonary vascular alterations are discussed below.
Vascular alterations caused by SP in isolated perfused rat lungs. SP increased Ppa, Pv, Pc, Ra, and Kfc in the isolated perfused SL lungs. These pulmonary vascular alterations were similar to those observed in the isolated perfused guinea pig lung (20) and the isolated rabbit pulmonary arterial strip (23). However, the dose of SP needed to produce a marked increase in Ppa was much larger than that required in the isolated guinea pig lung (20) or the isolated rabbit pulmonary arterial strip (23). This difference might be due mainly to fewer NK1 receptors in the rat lung than in the guinea pig lung (8). In addition, there might be a difference in NK1 receptors between the rat and the guinea pig lungs (8).
A much higher dose of SP was also required to cause vascular constriction in the isolated perfused lungs than in the in vivo preparation (2, 22). This may be due to a difference caused by different preparations. The doses of agonists required to induce pharmacological responses in the in vitro isolated perfused lung are often larger than those in the in vivo preparation (12). Because the in vitro lung was perfused with the physiological salt solution without blood, the higher vascular reactivity to SP in vivo might relate, partly at least, to a component(s) of blood. In SL and HA lungs, SP induced a large increase in Ppa and a small elevation in Pv (Fig. 2). Therefore, it is tempting to reason that SP causes mainly a constriction in the arterial segment of the pulmonary vasculature.Temporal increases in SP-induced vascular reactivity of HA rats. After prolonged exposure to hypoxia, SP-induced increases in Ppa and Ra were augmented (Fig. 2). In addition, this augmentation increased gradually with exposure time until 2 wk of hypoxia. No significantly temporal augmentation of SP-induced increase in Pv, Pc, or Kfc was found, however. We reasoned that several factors may cause this temporal augmentation during chronic hypoxia. 1) There is a temporal increase in NK1 receptors during the process of hypoxia (Fig. 8). 2) Prolonged hypoxia may induce a change in neutral endopeptidase (NEP; the major degradation enzyme of SP) activity. It is known that oxygen radical production increases during hypoxic exposure (16) and that NEP activity is inhibited by oxygen radicals. Therefore, the same dose of SP could become more potent because of a decrease in NEP activity followed by prolonged hypoxia. 3) SP may induce releases of more constrictors in the lungs after chronic hypoxia. Previous studies have shown that SP may release thromboxane (20) and leukotrienes (5). These releasing mechanisms may be enhanced, since oxygen radical production increases during prolonged hypoxia. 4) There is a controversy over whether endothelium-derived nitric oxide activity is increased or decreased in the hypertensive pulmonary vasculature of chronically hypoxic rats (1, 19, 21, 25). It is possible that prolonged hypoxia induces an impaired endothelium-dependent relaxant activity (1) and a decrease in nitric oxide production in the pulmonary vasculature (21). Then the impaired endothelial function should augment SP-induced vasoconstriction. 5) The wall thickness of pulmonary vessel increased after prolonged hypoxia (18). The same dose of SP should induce a larger response in the vessel with more smooth muscle mass and, thus, an increase in SP reactivity.
Contrary to the changes in vascular pressures, SP caused a large increase in Kfc in SL lungs but only a small increase in HA lungs (Fig. 4). In other words, the SP-induced marked elevation in Kfc in SL lungs was significantly reduced in all HA lungs. Accordingly, these data may imply that there should be a marked decrease in vascular leakage after prolonged exposure to hypoxia. This is compatible with the fact that HA pulmonary edema during reascent is rare when the SL sojourn is short (<10-14 days) (11).NK1 receptors in the augmented vascular response to SP in HA rats. Because the action of SP is mediated mainly via NK1 and much less via NK2 receptors (15), we employed the NK1 receptor antagonist SR-14033 and the NK2 receptor antagonist SR-48968 to test their blocking action on SP-induced vascular reactivity. In SL lungs, SR-14033 significantly attenuated SP-induced increases in Ppa, Pv, Pc, Ra, and Kfc (Figs. 5 and 6), while SR-48968 significantly attenuated the increase in Kfc (Fig. 6). In HA lungs, SR-14033 significantly attenuated the SP-induced increase in Ppa (Fig. 7), while SR-48968 did not significantly attenuate any SP-induced response. Thus it is clear that the action of SP is mediated mainly via the NK1 receptor in SL lungs, while the same action is mediated almost exclusively via the NK1 receptor in HA lungs. Fewer SP-induced vascular alterations were significantly attenuated by SR-14033 in HA than in SL lungs. This difference between SL and HA lungs may be explained by the fact that HA lungs have more NK1 receptors and, thus, are less suppressed by SR-14033 than SL lungs.
Results from Western blotting (NK1 receptors) and real-time RT-PCR NK1 receptor gene expression experiments suggest that the increased density of NK1 receptors after prolonged hypoxia may be due to increased transcription of the NK1 receptor gene. Therefore, our data support the conclusion that the increase in the pulmonary vascular response to SP induced by chronic hypoxia can be attributed to an upregulation of NK1 receptors during the hypoxic exposure process. It is not clear why there is an upregulation of NK1 receptors in the lungs of chronically hypoxic rats. We speculate that this upregulation might relate to hypoxia-inducible factor, reactive oxygen species, leukotrienes, and endothelins. Further studies are needed to delineate the speculated effects of these possible factors.Perspectives
In 1995, using capsaicin to deplete tachykinins, we found that tachykinins play an important role in chronic hypoxic pulmonary hypertension (14). However, capsaicin depletes several neuropeptides in afferent C-fibers, including bombesin, calcitonin gene-related peptide, somatostatin, and tachykinins (9). Compared with other neuropeptides in the afferent C-fibers, tachykinins may induce different responses in the pulmonary circulation. To carry out more specific studies related to the role of tachykinins in chronic hypoxic pulmonary hypertension, we started to use specific tachykinin receptor agonists and antagonists to demonstrate that tachykinin NK1 and/or NK2 receptors are involved in chronic hypoxic pulmonary hypertension in vivo (2). This study is a continuation of this series of studies. Using in vitro experiments, we demonstrated that the temporal increase in pulmonary vascular reactivity to SP was closely related to an increase in NK1 receptor gene expression during exposure to chronic hypoxia.| |
ACKNOWLEDGEMENTS |
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We thank Dr. X. Emonds-Alt (Sanofi Recherche) for providing SR-48968 and SR-14033.
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FOOTNOTES |
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This investigation was supported by the National Science Council Grant 89-2320-B002-078.
Address for reprint requests and other correspondence: Y.-L. Lai, Dept. of Physiology, College of Medicine, National Taiwan Univ., No. 1, Sec. 1, Jen-Ai Rd., Taipei 100, Taiwan (E-mail: tiger{at}ha.mc.ntu.edu.tw).
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.
10.1152/ajpregu.00429.2001
Received 23 July 2001; accepted in final form 31 October 2001.
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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