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Department of Physiology, National Taiwan University College of Medicine, Taipei, Taiwan, Republic of China
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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In this study we explored the hypothesis that
chronic activation of neurokinin-1 (NK-1) receptor induces pulmonary
hypertension in Wistar rats. First, the activation of NK-1 receptor on
the pulmonary circulation was investigated by use of a chronic
injection of NK-1 agonist
[Ser9,Met(O2)11]-substance
P (1 × 10
9 mol/kg)
for 2 wk at sea level (rats breathed room air) and during hypoxia (rats
were placed in a hypobaric 380-Torr chamber). Second, we studied the
effect of NK-1 antagonist (CP-96345) on developing and developed (after
4 wk of chronic hypoxia) pulmonary hypertension. Pulmonary arterial
pressure, the weight ratio of right ventricle to left ventricle + septum, hematocrit, and substance P (SP) were measured. We found that
NK-1 agonist significantly increased pulmonary arterial pressure in the
sea-level but not in the hypoxic group. However, NK-1 agonist induced
neither right heart hypertrophy nor polycythemia. CP-96345
significantly decreased pulmonary arterial pressure in the hypoxic
group but had no effect in the sea-level group. Furthermore, CP-96345
significantly attenuated the acute SP-induced increase in pulmonary
arterial pressure in the sea-level and hypoxic groups, with a larger
increase in the hypoxic group. These results suggest that chronic
activation of NK-1 receptor induces pulmonary hypertension and that
there is an increase in the sensitivity of pulmonary vessels in
response to SP in chronically hypoxic rats.
neurokinin-1 antagonist; tachykinins; pulmonary arterial pressure; right heart hypertrophy; cardiac output
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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PULMONARY HYPERTENSION is a common complication of chronic lung diseases, but its pathogenesis is not well understood. It is clear that one important factor in its development is chronic alveolar hypoxia, which by itself acutely produces pulmonary hypertension in humans and experimental animals (9). Recently, it was found that tachykinin depletion by chronic capsaicin pretreatment significantly attenuates chronic hypoxic pulmonary hypertension (CHPH) and right ventricular hypertrophy (16). Tachykinins in the lungs may play an important role in chronic hypoxia-induced vascular alterations.
Although tachykinin depletion suppresses CHPH, this depletion alone had no effect on pulmonary vascular parameters in control animals (16, 39). These data suggest that chronic hypoxia-induced pulmonary hypertension is closely related to tachykinins. This reasoning was supported by a significant correlation between substance P (SP) levels and pulmonary vascular parameters (16). Similar observations were found in fluid-percussion brain-injured rats. An acute pulmonary hypertension response was clearly evident in the control rats; pressure responses of the pulmonary artery and left atrium, but not a systemic response, were suppressed in capsaicin-treated animals (17).
We hypothesized that CHPH is closely related to SP (a tachykinin). Because SP acts on neurokinin-1 (NK-1) receptors, an NK-1 agonist, [Sar9,Met11(O2)]-SP, was used in this study. In addition, CP-96345, a nonpeptide antagonist of the NK-1 receptor, was employed for inhibition of the effects of SP.
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MATERIALS AND METHODS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Preparation of animals for chronic study.
Eighty-five female Wistar rats were used in the chronic study, which
was divided into three parts. In part
1, we tested whether chronic administration of an NK-1
agonist,
[Sar9,Met11(O2)]-SP
(catalog no. 7496, Peninsula Laboratory), induces pulmonary hypertension. Rats were divided into four groups: sea level
(n = 3), sea level + NK-1
agonist for 2 wk (n = 10), hypoxia for 2 wk (2-wk hypoxia, n = 6), and
hypoxia + NK-1 agonist for 2 wk (n = 7). Animals of the sea-level groups breathed room air. Hypoxic rats
were placed in an altitude chamber (380 Torr) from 5:00 PM to 8:00 AM
every day and were kept in the chamber for 2 wk at constant temperature
and light cycle (light from 7:00 AM to 7:00 PM). The level of 5,500 m
(380 Torr) was selected, because it represents the maximal altitude to
which most rats can successfully adapt. The body weight of the animals
was measured once a week. Food and water were provided ad libitum. Each
rat was injected intraperitoneally with
[Sar9,Met11(O2)]-SP
(109 mol/kg) or PBS every
day for 2 wk during room air or hypoxic exposure.
1 · day1.
Each rat of the sea-level or 2-wk hypoxia group was also implanted with
a pump containing and delivering PBS. The osmotic pumps remained implanted in each rat's abdominal cavity for 2 wk, during the entire
period of room-air or hypoxic exposure.
In part 3, we studied whether CP-96345
can attenuate developed CHPH. Rats exposed to hypoxia for 4 wk were
used as animals that had developed CHPH. Each CHPH rat was treated with
PBS (n = 6), CP-96345
(n = 6), or CP-96344
(n = 6) via an osmotic pump, as
mentioned above, for an additional 2 wk of continuing hypoxic exposure.
Physiological measurement. After the treatments described above, each rat was anesthetized with pentobarbital sodium (35 mg/kg) and cannulated with a tracheal tube as well as with catheters in the femoral and cervical arteries. The systemic blood pressure was measured from the femoral artery by a pressure transducer (P23 Statham transducer, Grass) and recorded with a polygraph (model 79D, Grass). After the chest was opened and under artificial ventilation, a catheter was inserted into the pulmonary artery via the right ventricle for detection of the pulmonary arterial pressure. After measurement of pulmonary arterial pressure, 6 ml of blood were sampled from the carotid artery for determination of SP in plasma. Subsequently, the right ventricle and the left ventricle + septum were removed and weighed, and the weight ratio of the right ventricle to left ventricle + septum [RV/(LV + S)] was obtained.
Acute study.
An additional 32 female Wistar rats were used in this study. Sixteen
rats were kept at sea level, and the remaining rats were exposed to
chronic hypoxia for 4 wk. Each rat was anesthetized with pentobarbital
sodium (35 mg/kg) and then cannulated with a tracheal tube as well as
catheters in the femoral artery and vein. The systemic blood pressure
was measured from the femoral artery by a pressure transducer and
recorded with a polygraph. A catheter was inserted into the jugular
vein and advanced to the pulmonary artery for detecting pulmonary
arterial pressure in the chest-intact rat (34). Each rat was injected
with 0.1 ml of SP
(1014-1010
mol/ml; catalog no. 7451, Peninsula Laboratory). The interval between
any two doses was >10 min. After the dose-response study of SP,
sea-level rats were randomly separated into two groups. One group was
treated with a bolus injection of CP-96345 (0.05 mg in 0.1 ml) and then
continuously infused with CP-96345 (0.5 mg/h iv). After 30 min of
infusion the rat was again injected with 0.1 ml of SP
(1014-1010
mol/ml). The other group was treated with CP-96344 according to the
same experimental steps and doses described for the treatment with
CP-96345. In addition, chronically hypoxic rats were treated in the
same way as the sea-level rats.
Cardiac output measurement. An additional 19 rats were divided into two groups: sea level (control, n = 9) and sea level + NK-1 agonist (n = 10). In the second group, each rat was injected with the NK-1 agonist every day for 2 wk before the study. Anesthetization, cannulation, and systemic blood pressure recording were carried out according to the methods described above. Pulmonary arterial pressure was measured as described above for the chest-intact rat. A thermal-sensitive probe was inserted into the cervical artery and advanced into the aorta to measure cardiac output (Cardiomax-II model 85, Columbus Instruments) by injection of cold water from another catheter inserted into the vena cava.
Measurement of SP.
Plasma samples from rats were diluted with the same volume of
buffer A (RIK-BA-1, Peninsula
Laboratory). Then each sample was passed slowly through a
C18 Sep-Pak column (RIK-SEPCOL-1, Peninsula Laboratory). The column was washed with 9 ml of
buffer A and eluted with 3 ml of
buffer B (RIK-BB-1, Peninsula
Laboratory). The eluted samples were dried by vacuum centrifugation and
stored at 
70°C for later analysis. An SP enzyme immunoassay
kit (Cayman Chemical, Ann Arbor, MI) was used for detecting the SP
level. Each sample was dissolved in 1% hydrochloride, diluted to a
suitable concentration with enzyme immunoassay buffer, and assayed in
duplicate. The SP, which was linked to ACh esterase as a tracer, and
rabbit SP antiserum were added to the sample and incubated in the assay plate at 4°C for 18 h. Then the wells were rinsed five times with washing buffer. Ellman's reagent was added for development of the
plates in each well. After development, these plates were read at 410 nm, and SP levels were calculated.
Data analysis. Because there were no significant differences between them, the data for the sea-level rats of parts 1 and 2 were combined, and data for the rats exposed to 2 wk of hypoxia in parts 1 and 2 were averaged. Values are means ± SE. Differences in pulmonary arterial pressure, RV/(LV + S), hematocrit, and SP levels among various groups were analyzed with ANOVA. 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 acute injection of SP were analyzed by paired t-test.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Chronic Study
Part 1: effects of chronic NK-1 agonist administration.
Sea-level rats chronically injected with NK-1 agonist showed a
significant increase in pulmonary arterial pressure: from 15.5 ± 1.6 to 26.2 ± 2.7 mmHg. The NK-1 agonist-induced pulmonary
hypertension was similar to that induced by chronic hypoxia (Fig.
1). The administration of NK-1 agonist
could not further increase pulmonary arterial pressure in chronically
hypoxic rats. In addition, neither RV/(LV + S) (Fig.
2) nor the hematocrit (Fig.
3) was affected by the NK-1 agonist. The
rats chronically injected with NK-1 agonist showed significant
increases in their plasma SP levels compared with the rats exposed to 2 wk of hypoxia (Table 1).
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Part 2: effect of NK-1 antagonist on the development of CHPH.
The rats exposed to hypoxia for 2 wk showed significant increases in
pulmonary arterial pressure (Fig. 4),
RV/(LV + S) (Fig. 5), and hematocrit (Fig.
6). These chronic hypoxia-induced
alterations were reduced significantly by CP-96345 or CP-96344. On the
other hand, neither CP-96345 nor CP-96344 had any significant effects on pulmonary arterial pressure or hematocrit in sea-level rats. In rats
exposed to 2 wk of hypoxia and treated with CP-96345 or CP-96344,
RV/(LV + S) and hematocrit were significantly higher than in sea-level
rats (Figs. 5 and 6).
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Part 3: effects of SP antagonist on pulmonary hypertension developed
on hypoxia.
Two weeks of treatment with CP-96345 or CP-96344 had no significant
effect on pulmonary arterial pressure in CHPH rats (Fig. 7). However, CP-96344 induced an increase
in right heart hypertrophy in CHPH rats (Fig.
8). NK-1 antagonist did not significantly
change the increased hematocrit of CHPH rats (Fig.
9).
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Acute Study
Acute effect of SP on pulmonary arterial pressure.
The mean hemodynamic responses of the 32 animals to three doses of SP
are shown in Tables
3-6.
There were no significant differences in pulmonary arterial pressure
before and after PBS injection (Table 3). In the absence of NK-1
antagonist, all three doses of SP induced a significant increase in
pulmonary arterial pressure in sea-level rats and rats exposed to 4 wk
of hypoxia. CP-96345 or CP-96344 prevented significantly the increases
in pulmonary arterial pressure caused by the lowest dose of SP
(1015 mol) in sea-level
rats (Table 3). The percent pulmonary arterial pressure changes of
the six groups are shown in Table 4. Without NK-1 antagonist infusion,
the pulmonary arterial pressure of sea-level rats was increased ~36%
by 1013 or
1011 mol SP. This was
significantly different from the percent increase in pulmonary arterial
pressure brought about by
1015 mol SP. After CP-96345
infusion, there were no significant differences in pulmonary arterial
pressure among 1015,
1013, and
1011 mol SP. The
dose-dependent increase in pulmonary arterial pressure caused by SP was
not, however, eliminated in rats treated with CP-96344 (Table 4).
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15 mol SP
into hypoxic rats induced a 39% increase in pulmonary arterial
pressure, similar to the increase caused by
1013 mol SP in sea-level
rats, indicating a hyperreactive response to SP in pulmonary vessels of
chronically hypoxic rats. CP-96345 and CP-96344 attenuated the acute
SP-induced rises in pulmonary arterial pressure at
1015 and
1011 mol in rats exposed to
hypoxia. There was no significant difference in attenuating ability
between CP-96345 and CP-96344 (Table 4). CP-96345 alone decreased the
systemic blood pressure but increased pulmonary arterial pressure,
whereas CP-96344 affected only the systemic blood pressure (Tables 5
and 6).
Effect of NK-1 Agonist on Cardiac Output
Effects of NK-1 agonist on cardiac output, heart rate, systemic resistance, and pulmonary resistance are shown in Table 7, and their changes (percentage of the pretreatment value) are presented in Fig. 10. The chronic injection of NK-1 agonist caused a significant decrease in cardiac output: from 73.1 ± 2.5 to 38.0 ± 4.4 ml/min. On the contrary, systemic and pulmonary resistance increased significantly in the NK-1 agonist-treated groups.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Chronic Effect of NK-1 Agonist on Pulmonary Arterial Pressure
Pulmonary arterial pressure increased nearly twofold (similar to that of rats exposed to 2 wk of hypoxia) in the sea-level rats chronically injected with [Ser9,Met(O2)11]-SP. Lai and colleagues (16) found that chronic hypoxia-induced pulmonary vascular changes were significantly lessened by capsaicin pretreatment. Capsaicin pretreatment alone, however, did not induce any significant alterations in the vascular function of sea-level animals. These results suggest that chronic hypoxia causes an increase in lung tachykinin levels, which, in turn, enhance the development of pulmonary hypertension (16). Our study provided evidence that indicates the involvement of NK-1 agonist in the development of pulmonary hypertension. SP may have induced pulmonary hypertension, whereas NK-1 antagonist in combination with chronic hypoxia attenuated CHPH.There were no differences in pulmonary arterial pressure between the hypoxic rats and the hypoxic rats treated with [Ser9,Met(O2)11]-SP. Moreover, there were no significant differences in pulmonary arterial pressure between the rats exposed to hypoxia for 2 and 4 wk. It is possible that chronic hypoxia or NK-1 agonist may induce a maximal increase in pulmonary arterial pressure. This could mean that the additional factor cannot produce an additional rise in pulmonary arterial pressure. Another possibility is that the hypoxic treatment induced a release of SP sufficient to increase pulmonary arterial pressure. Therefore, additional NK-1 agonist cannot induce a greater increase in pulmonary arterial pressure during hypoxic treatment.
We also provided evidence that SP induces pulmonary hypertension through NK-1 receptors. During 2 wk of hypoxia, continuous administration of CP-96345 significantly reduced CHPH. We suggest that SP acts through NK-1 receptors to augment the increase in pulmonary arterial pressure during chronic hypoxia. The SP antagonist reduced pulmonary arterial pressure only in the hypoxic group, and not in the sea-level group. This can perhaps be interpreted to mean that SP does not play a main role in modulating pulmonary vascular tone in control rats but augments remodeling of pulmonary vessels in the chronic hypoxic state. The regulation of NK-1 receptors might be important in chronic hypoxia; it is possible that NK-1 receptors are altered during chronic hypoxia.
Furthermore, we tested the curative effect of SP antagonist on well-developed pulmonary hypertension. When rats were exposed to hypoxia for 4 wk, their pulmonary hypertension was in a stable and well-developed state. After 4 wk of hypoxia, rats were treated with CP-96345 or CP-96344 during an additional 2 wk in hypoxia, but this did not attenuate the CHPH that had developed (Figs. 7 and 8). We hypothesized that SP plays an important role in development of hypertension but not in maintenance of that hypertension. Accordingly, the SP antagonist had no attenuating effect on the well-developed pulmonary hypertension. This result was similar to that of an experiment with cHyp (32), a collagen synthesis inhibitor. It was shown that vascular collagen content is increased during established pulmonary hypertension and that cHyp treatment is effective in partially preventing the hemodynamic, structural, and biochemical changes if the treatment is started before the development of pulmonary hypertension. However, this treatment, if it was provided after pulmonary hypertension, did not modify the established pulmonary hypertension (32). A possible explanation is that the vascular remodeling has progressed for some time and causes narrowing of the pulmonary arterial diameter during established pulmonary hypertension. SP antagonist and cHyp may not alter the vessel structure, and thus they cannot decrease pulmonary hypertension. It is also possible that the treatment time for the SP antagonist may be too short to reduce the pulmonary hypertension. Pulmonary arterial pressure decreases maximally within the 1st mo of recovery after 1 mo of chronic hypoxia but remains higher than in age-matched controls (33).
Acute Effect of SP on Pulmonary Arterial Pressure
There was a higher sensitivity of the pulmonary artery in response to SP in chronically hypoxic than in sea-level rats (Table 4). In the sea-level group, a 100-fold higher concentration of SP was required to induce an increase in pulmonary arterial pressure equal to that observed in the hypoxic group. CP-96345 attenuated the acute effect of SP in sea-level and hypoxic rats. However, CP-96344 attenuated the acute effect of SP on pulmonary arterial pressure only in the hypoxic group and not in the sea-level group. This result indicated that CP-96344 is a weaker antagonist for NK-1 receptors, because it attenuated only the acute SP-induced large increase in pulmonary arterial pressure. This could also explain why CP-96344 significantly reduced chronic hypoxia-induced large increases in pulmonary arterial pressure. Usually, CP-96344 acts as the allotrope and an enantiomer to CP-96345, because it had no inhibitory effect on SP in control animals.Our data indicate that SP has opposite effects on systemic blood pressure and pulmonary arterial pressure. There are also many published studies of SP on isolated lung and pulmonary arterial segments, but the results are inconsistent. In rabbit isolated pulmonary arteries, SP increased isometric tension in a dose-dependent manner (37). However, there are conflicting reports that SP acts as a vasodilator in guinea pig isolated pulmonary arteries (20). In the isolated lung, SP increases pulmonary arterial pressure in guinea pigs but acts as a vasodilator in cats (21). In addition, a report shows that SP causes a marked fall in systemic vascular resistance but minimal pulmonary vasodilation (3). This is similar to the finding that SP has no effect on pulmonary arterial pressure, total pulmonary vascular resistance, or cardiac output (38). These diverse data may be due to different vessel tones in various experiments.
Hemodynamic Changes in NK-1 Agonist-Induced Pulmonary Hypertension
Chronic NK-1 agonist treatment increased the vascular resistance in the systemic and pulmonary circuits. In the systemic circulation, this increase was mainly due to a decrease in cardiac output, because the systemic blood pressure was not significantly altered. By contrast, in the pulmonary circulation, this increase in resistance was due to a decrease in cardiac output and an increase in pulmonary pressure. In comparison to control rats, the cardiac output of NK-1 agonist-treated rats was reduced 48%, whereas their pulmonary arterial pressure rose fourfold. In CHPH, it was reported that cardiac output decreased while pulmonary arterial pressure and resistance increased (9), a condition similar to our chronic NK-1 agonist-treated rats. Our data suggest that NK-1 agonist-induced pulmonary hypertension may change pulmonary vascular tone and/or arterial structure.It is well known that chronic hypoxia induces an increase in pulmonary arterial pressure and right heart hypertrophy. In this study, NK-1 agonist increased pulmonary arterial pressure but did not induce right heart hypertrophy. There are several possible explanations: 1) NK-1 agonist may cause an increase in cardiac output, which induces an increase in pulmonary arterial pressure but not right heart hypertrophy. However, our finding of decreased cardiac output after chronic treatment of NK-1 agonist has to rule out this possibility. 2) The time of NK-1 agonist treatment is just long enough to increase pulmonary arterial pressure but not long enough to induce right ventricular hypertrophy. It is also possible that the NK-1 agonist causes only an increase in pulmonary resistance, whereas other factors induce the right heart hypertrophy during chronic hypoxia. Differential effects of an agent on pulmonary arterial pressure and right ventricular hypertrophy were also observed by other investigators. Enalapril, an angiotensin-converting enzyme (ACE) inhibitor, significantly decreased the right ventricular weights but did not significantly change pulmonary arterial pressure in hypoxia-exposed or monocrotaline-treated rats. Enalapril reduced cardiac hypertrophy and improved the prognosis in pulmonary hypertension (14, 30). Therefore, further studies are needed to investigate the mechanism for right heart hypertrophy.
CHPH was aggravated by accompanying polycythemia and was characterized by elevated pulmonary vascular smooth muscle tone, augmented reactivity to many vasoconstrictor stimuli, connective tissue proliferation, medial hypertrophy of small muscularized pulmonary arteries, and the appearance of new smooth muscle in previously nonmuscular arteries (13, 22, 23, 35, 36). However, Hill et al. (11) and Petit et al. (31) demonstrated that the chronic hypoxia-induced increase in hematocrit does not play an important role in the development of CHPH. We also found in this study that there was no close relationship between hematocrit and hypertension. Consequently, vascular remodeling (34) is expected to be the major mechanism for the development of CHPH.
Possible Mechanism of Pulmonary Hypertension
Several mechanisms may account for the observed vascular effect of tachykinins in the lungs. 1) Hypoxia enhances the release of tachykinins (18). In addition, prolonged hypoxia augments the production of oxygen radicals (6), which inactivate neutral endopeptidase, the main degradation enzyme for tachykinins (2). The inactivation of neutral endopeptidase could result in elevated tachykinin levels due to decreased degradation of tachykinins. 2) Tachykinins closely interact with several other mediators such as leukotrienes (1) and thromboxane (19), which promote the development of vascular abnormalities (24). 3) Tachykinins augment the proliferation of smooth muscle cells and connective tissues (26, 29). In pulmonary hypertension, it is known that structural changes of increased muscle and connective tissue occur in the media of pulmonary arteries. Thickening of the muscular coat of small pulmonary arteries begins a few days after exposure to hypoxia in rats (4, 12, 23). There are reports indicating that SP stimulates DNA synthesis in cultured arterial smooth muscle cells and augments human lung fibroblast proliferation in a dose-dependent manner in vitro (10, 29). It is suggested that SP stimulates pulmonary arterial smooth muscle and fibroblast proliferation during chronic hypoxia. Therefore, vascular remodeling is the principal pathological feature of CHPH.There were many studies investigating the mechanism of CHPH. Chronic administration of NK-1 antagonists, similar to the chronic treatment with endothelin-A receptor antagonists (4, 8), serotonin synthesis inhibitor (15), ACE inhibitors (25), or collagen synthesis inhibitor (32), decreased pulmonary arterial pressure and RV/(LV + S) in chronically hypoxic rats. However, the exact interaction among SP, endothelin-A, serotonin, and angiotensin is not clear. On the other hand, an endothelin antagonist, CI-1020 (4), and an ACE inhibitor, quinapril (27), reduced pulmonary arterial pressure in well-developed pulmonary hypertension, but NK-1 antagonists and a collagen synthesis inhibitor, cHyp (32), did not have this curative effect. SP may play an important role in the initial but not the following stages of pulmonary hypertension. Calcium channel blocker and potassium channel activator were effective in acutely reversing chronic pulmonary hypertension and even decreasing the pulmonary arterial pressure and blood pressure of normal animals (5, 7, 28). However, CP-96345 induced a rise in pulmonary arterial pressure in normal rats.
In summary, in this study we found that 1) NK-1 agonist increased pulmonary arterial pressure in sea-level but not in hypoxic rats, 2) NK-1 antagonist attenuated pulmonary arterial pressure in hypoxic but not in sea-level rats, and 3) pulmonary arterial vessels were more sensitive to SP in hypoxic than in sea-level rats. However, NK-1 antagonist could not attenuate the developed pulmonary hypertension. Also, NK-1 agonist increased pulmonary arterial pressure to a level similar to that induced by chronic hypoxia, but it did not induce right heart hypertrophy or polycythemia. These results suggest that SP may induce pulmonary hypertension through NK-1 receptors.
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ACKNOWLEDGEMENTS |
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We thank Si Lai for careful reading of the manuscript and correcting the English and Yu-Jean Su for excellent technical assistance. We are grateful to Pfizer for providing CP-96345 and CP-96344.
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FOOTNOTES |
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This investigation was supported by National Science Council Grant NSC 87-2314-B002-121M41.
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. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: Y.-L. Lai, Department of Physiology, College of Medicine, National Taiwan University, No. 1, Jen Ai Road, 1st Section, Taipei, Taiwan, ROC (E-mail: tiger{at}ha.mc.ntu.edu.tw).
Received 24 April 1998; accepted in final form 11 January 1999.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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