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Departments of 1 Physiology and 2 Anesthesiology, Mie University School of Medicine, 514-8507 Mie, Japan
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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We determined the role of an endothelium-derived contracting factor in the impaired relaxation response to ACh of conduit pulmonary arteries (PAs) isolated from rats with hypoxic pulmonary hypertension (PH). A PGH2/thromboxane A2 (TxA2)-receptor antagonist (ONO-3708) partially restored the impairment of ACh-induced relaxation, whereas TxA2 synthase inhibitors (OKY-046 and CV-4151) did not affect the impaired relaxation in phenylephrine-precontracted hypertensive PAs. Endothelium-denuded hypertensive PA rings showed no difference in the response to ACh between preparations with and without ONO-3708. In both endothelium-denuded control and hypertensive PAs, exogenous PGH2 induced contractions, and the magnitude of the contractions was greater in the control than in hypoxic PH preparations. An endothelin A-receptor antagonist (BQ-485), an endothelin B-receptor antagonist (BQ-788), and a superoxide anion scavenger (superoxide dismutase) did not restore the impaired response to ACh in hypertensive PAs. These findings suggest that PGH2 produced from the conduit PAs of rats with chronic hypoxic PH may be the endothelium-derived contracting factor responsible for the impairment of ACh-mediated vasorelaxation.
chronic hypoxia; prostaglandin H2; thromboxane A2; nitric oxide
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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ENDOTHELIAL CELLS play a significant role in the regulation of vascular tone through the release of endothelium-derived vasorelaxing and vasoconstricting substances (8, 14, 16, 26, 32). Nitric oxide (NO) and prostacyclin are endothelium-derived relaxing factors (EDRFs) (16, 26). Endothelium also produces endothelium-derived contracting factors (EDCFs) such as PGH2/thromboxane A2 (TxA2) (6, 19, 32), endothelin (ET) (14, 28), and superoxide anion (8, 29) under certain conditions. ACh-mediated vasoconstriction is associated with an endothelial PGH2/TxA2 release in the aorta (7), intrarenal artery (6), and cerebral arteriole (18) of spontaneously hypertensive rats; the aorta (27) and pial arteriole (19) of diabetic rats; the aorta of diabetic New Zealand White rabbits (32); and the renal vessel in hypercholesterolemic rats (2). ACh also produces ET in human atherosclerotic coronary arteries (14). A superoxide anion-mediated inactivation of EDRF has been observed in the aorta of diabetic rats (8) and hyperlipidemic rabbits (29). Thus the EDCFs might differ among the species, vascular beds, and diseases examined.
ACh-induced relaxation is impaired in isolated conduit pulmonary arteries (PAs) (16), isolated perfused lungs of rats with chronic hypoxic pulmonary hypertension (PH) (1), and PAs isolated from patients with chronic obstructive pulmonary disease (5). The mechanism of impaired relaxation might be based on a reduced production and release of NO, a reduced sensitivity of pulmonary hypertensive smooth muscle cells to NO, or both. Another possible mechanism is the concomitant ACh-induced production of EDCFs from hypertensive pulmonary arterial endothelium. A previous study showed that indomethacin partly restored ACh-induced impaired relaxation toward the normal level (16). This result might suggest involvement of contracting metabolites of the cyclooxygenase pathway. Vasoconstriction and vasoproliferation have both been implicated as important features in chronic hypoxic PH (17, 23). It is possible that the imbalance between EDRFs and EDCFs is involved in the pathogenesis of chronic hypoxic PH. Therefore, we conducted the present study to investigate the possible involvement of EDCFs in isolated PAs of rats exposed to hypobaric hypoxia (380 mmHg for 10 days). We used ONO-3708 as a PGH2/TxA2-receptor antagonist (12) and OKY-046(34) and CV-4151(30) as TxA2 synthase inhibitors. We also used BQ-485, an ETA-receptor antagonist (11), and BQ-788, an ETB-receptor antagonist (10), to assess the involvement of ET. In addition, we used superoxide dismutase (SOD), a superoxide anion scavenger, to determine the role of superoxide anion in the altered responses of hypertensive PAs to ACh.
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MATERIALS AND METHODS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Induction of Hypoxic PH
Male Wistar rats (SLC, Shizuoka, Japan) weighing 170-220 g were randomly assigned to one of two groups: those exposed to chronic hypoxia in a hypobaric hypoxic chamber (air at 380 mmHg) for 10 days and age-matched control animals housed in room air at a normal atmospheric pressure. The pressure in the hypobaric chamber was reduced by using an electrically driven vacuum pump. Rats were housed under a 12:12-h light-dark cycle and were fed standard rat chow and water ad libitum. The chamber was opened for 15-30 min once a day so that the cage could be cleaned and food and water replenished. All rats were weighed at the start of the experiment and before they were killed for isolation of the PAs. Table 1 lists the number of rats and mean body weight of each group.
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Preparation of PAs
After the 10-day hypoxia period, all of the control and experimental animals were anesthetized with intraperitoneal pentobarbital sodium (50 mg/kg). The lung and heart were removed en bloc and placed in modified Krebs-Henseleit solution at room temperature. The composition of this solution was the following (in mM): 115.0 NaCl, 4.7 KCl, 2.5 CaCl2, 1.2 MgCl2, 25.0 NaHCO3, 1.2 KH2PO4, and 10.0 dextrose. The right ventricle (RV) of the heart was dissected from the left ventricle plus septum (LV+S), and these cardiac portions were weighed separately. The value of RV/(LV+S) was then calculated to determine whether right ventricular hypertrophy had developed. Two pulmonary artery segments, a left extrapulmonary artery (EPA; 1.4-1.6 mm OD) and an intrapulmonary artery (IPA; 0.7-1.1 mm OD), were isolated and carefully cleaned of fat and connective tissue. Ring segments (2 mm) were cut (1-2 rings from the EPA and 2-4 rings from the IPA) and suspended vertically between hooks in an organ bath (20 ml) containing modified Krebs-Henseleit solution, maintained at 37°C, and bubbled with a mixture of 95% air-5% CO2. The optimal resting tension for the vasorelaxation studies was adjusted to 0.75 g for EPA rings and 0.5 g for IPA rings from the control rats, and 1.0 g and 0.75 g, respectively, for the experimental rat preparations, as previously described (16). At these resting tensions, the peak contraction was obtained in response to 70 mM KCl. In all experiments, changes in isometric force were measured with a force-displacement transducer (model TB-651T, Nihon Kohden, Tokyo, Japan) connected to a carrier amplifier (model EF601G, Nihon Kohden) and were recorded on a pen recorder (model WT-645G, Nihon Kohden). In some strips, the endothelium was removed by gently rubbing the luminal surface with a small roughened stainless steel needle. Successful removal of the endothelium from the PAs was verified with the absence of relaxation response to ACh (10
6 M) and
the use of a scanning-electron microscope.
Endothelium-Intact PAs
Blockade of
PGH2/TxA2
receptor.
EPA and IPA rings under the optimal resting tension were washed every
15-20 min and allowed to equilibrate for 120 min. After the
equilibration period, 70 mM KCl contraction curves were recorded routinely twice as a measure of maximal contractility with the contraction shown by the second curve considered as the maximal response. A cumulative concentration-response curve to phenylephrine (108-105
M) was obtained, and the approximate concentration of phenylephrine needed to produce 50% of the maximal contraction induced by 70 mM KCl
was determined. The PA rings were then washed every 15-20 min and
allowed to equilibrate for 60 min.
5 M) was
added to the organ bath 20 min before the precontraction with
phenylephrine (105 M) to
obtain 40-70% of the maximal contraction induced by 70 mM KCl.
After precontraction with phenylephrine, cumulative dose-tension curves
were obtained for ACh
(108-104
M). Finally, papaverine
(104 M) was added to
produce maximal relaxation. Rings without ONO-3708 were tested at the
same time.
In another set of rings from the other group of experimental rats, in
the presence of an NO synthase inhibitor,
N
-nitro-L-arginine
methyl ester (L-NAME;
104 M), a cumulative
concentration-response curve for ACh was obtained in the presence and
absence of ONO-3708.
Blockade of TxA2 synthase,
ETA receptor, ETB
receptor, and superoxide.
Similarly, the relaxation response to ACh in the
phenylephrine-precontracted rings was also recorded in the presence of
OKY-046 (a TxA2 synthase
inhibitor; 105 M or
104 M), CV-4151 (a
TxA2 synthase inhibitor;
106 M), BQ-485 (an
ETA-receptor antagonist;
106 M), BQ-788 (an
ETB-receptor antagonist;
106 M), or SOD (a
superoxide anion scavenger; 50 U/ml). Each of these drugs was examined
in preparations of different rings from different experimental rats. In
all experiments, rings from chronic hypoxic rats were examined in
parallel with preparations from age-matched control rats.
Endothelium-Denuded PAs
Contractions to cumulative concentrations of ACh (108-104
M) were determined in hypertensive PA rings in the presence and absence of ONO-3708(105 M). To
examine the smooth muscle sensitivity to
PGH2, contractions to cumulative
concentrations of PGH2
(108-106
M) in another set of rings of control rats and rats exposed to hypoxia
for 10 days were determined in the presence and absence of ONO-3708.
Reagents
The following drugs were used: ACh hydrochloride, papaverine hydrochloride (Nacalai Tesque, Kyoto, Japan); phenylephrine (Kowa, Nagoya, Japan); ONO-3708, OKY-046 (Ono Pharmaceutical, Osaka, Japan); CV-4151 (Takeda Chemical Industries, Tokyo, Japan); PGH2, BQ-485, BQ-788 (Calbiochem, La Jolla, CA); SOD, and L-NAME (Sigma Chemical, St. Louis, MO). The concentrations of the drugs are expressed as the final molar concentrations in the organ bath. PGH2 was stored at
80°C
and diluted with distilled water just before each experiment.
Data Analysis
Results are expressed as means ± SE. The significance of differences between control and experimental rats was determined by Student's t-test. When more than two means were compared, a one-way analysis of variance was used. If a significant difference was found, Fisher's least significant difference test was used to identify which groups were different. A P value of < 0.05 was considered to indicate statistical significance.| |
RESULTS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Body Weight and Right Ventricular Hypertrophy
The control rats gained weight throughout the experiment (Table 1). The hypoxic rats lost weight compared with the controls. The RV/(LV+S) ratios were increased in the experimental group after 10 days of hypoxia compared with control group, indicating the occurrence of right ventricular hypertrophy.PA Ring Responses to 70 mM KCl and Phenylephrine
The endothelium-intact EPA rings from control rats and those from rats exposed to 10 days of hypoxia showed similar contractions in response to 70 mM KCl (Table 2). Phenylephrine induced greater contractions in endothelium-intact EPA and IPA rings from the hypoxic rats compared with those from control rats at 108,
106, 3 × 106, and
105 M in EPA and 3 × 108-106
M in IPA (Fig. 1). ONO-3708 attenuated
phenylephrine-induced contraction in endothelium-intact rings from
hypertensive rats at 3 × 108-3 × 106 M in EPA and at
108,
107, 3 × 107,
106, and 3 × 106 M in IPA (Fig.
2). Both endothelium-denuded EPA and IPA
rings from hypoxic rats showed less contractility to phenylephrine
compared with control rat preparations at 3 × 108-3 × 106 M in EPA and at all
concentrations in IPA (Fig. 3).
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Effects of ONO-3708 on ACh-Induced Relaxation in Endothelium-Intact PA Rings
In EPA and IPA rings from control rats precontracted with phenylephrine (105 M), ACh
(108-104
M) caused relaxation in a concentration-dependent manner (Fig. 4). The relaxation induced by ACh was
markedly reduced in both EPA and IPA rings from rats exposed to 10 days
of hypoxia compared with the control rat rings (Fig. 4). There was an
increase in tension at
106-104
M of ACh. ONO-3708 (105 M)
did not affect the resting tone of endothelium-intact rings from either
control or hypoxic rats. In control rat preparations, ONO-3708 did not
significantly affect the relaxation caused by ACh (Fig. 4). In rings
from rats exposed to 10 days of hypoxia, ONO-3708 did not affect the
impaired relaxation at lower concentration of ACh
(108-106
M), whereas it restored the impaired relaxation response at higher concentrations of ACh
(105-104
M) toward those observed in the control rat preparations (Fig. 4). When
EPA and IPA rings from experimental rats were precontracted with
phenylephrine in the presence of
L-NAME, ACh induced no
relaxation but actually induced contraction at higher concentrations
(Fig. 5). ONO-3708 attenuated this
contraction at higher concentrations of ACh in both EPA and IPA (Fig.
5).
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Effects of OKY-046 and CV-4151 on ACh-Induced Relaxation in Endothelium-Intact PA Rings
OKY-046 (105 and
104 M) and
CV-4151(106 M) did not
affect the resting tone of rings from either control or hypoxic rats.
Both of these drugs did not restore the impaired relaxation of the endothelium-intact EPA and IPA rings in response to ACh (Figs. 6 and 7).
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Effects of ONO-3708 on ACh-Induced Response and on Contraction to PGH2 in Endothelium-Denuded PA Rings
Phenylephrine-precontracted EPA and IPA rings from experimental rats showed similar response to ACh in the presence and absence of ONO-3708 (data not shown). In EPA and IPA rings from control rats and hypoxic rats, PGH2 caused contractions in a concentration-dependent manner (Fig. 8). ONO-3708 remarkably attenuated contractile responses to PGH2 at all concentrations in EPA and IPA from control rats and rats exposed to 10 days of hypoxia. The contraction induced by PGH2 was reduced in EPA rings from the hypoxic rats compared with the control rats at higher concentrations (107-106
M) (Fig. 8). In IPA, PGH2 induced
greater contractions at 3 × 108 and
107 M in rings from the
experimental rats compared with those from the control rats, whereas it
induced similar contractions in rings from control and experimental
rats at 3 × 107 and
106 M (Fig. 8).
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Effects of BQ-485 and BQ-788 on ACh-Induced Relaxation of Endothelium-Intact PA Rings
BQ-485 (106 M) and BQ-788
(106 M) did not affect the
resting tone of the rings from both control and experimental rats.
BQ-485 (106 M) partially
reduced the response at concentrations of
107 and
106 M ACh in EPA rings of
rats exposed to 10 days of hypoxia but not in those of control rats
(Fig. 9). BQ-485 did not affect the impaired ACh-induced response in IPA from control and experimental rats. BQ-788 (106 M) did
not affect the impaired relaxation to ACh in
phenylephrine-precontracted EPA and IPA rings from either control or
experimental rats (Fig. 10).
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Effects of SOD on ACh-Induced Relaxation of Endothelium-Intact PA Rings
SOD (50 U/ml) did not affect the resting tone of the rings from both control and experimental rats. SOD (50 U/ml) did not affect the impaired relaxation to ACh in phenylephrine-precontracted EPA and IPA rings from either control or experimental rats (Fig. 11).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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ACh-induced relaxation was impaired in isolated conduit PAs from hypoxic PH in rats. Blockade of PGH2/TxA2 receptors restored the impaired relaxation at higher concentrations of ACh but not inhibition of TxA2 synthesis in both EPA and IPA. Contractions to PGH2 were reduced in endothelium-denuded rings in chronic hypoxic rats compared with those of normal rats. Blockade of ET and superoxide anion did not restore the impairment of ACh-induced relaxation. These results showed functional abnormalities in both endothelial cells and smooth muscle cells that might have modulated vascular tone in the hypertensive PAs.
ACh-Induced Responses in Hypertensive Conduit PAs
We previously described that ACh-induced relaxation was impaired in isolated conduit PAs of rats with chronic hypoxic PH (16). The impairment of ACh-induced relaxation in isolated perfused rat lung with chronic PH (1) and in isolated PA rings from human lung with cor pulmonale (5) has been reported, consistent with the present results. However, recently there are contradictory reports concerning about the NO/cGMP mechanism of relaxation in chronic PH. Preserved or enhanced relaxation to endothelium-dependent relaxing substances was demonstrated in isolated perfused rat lung with chronic PH (9, 21). These findings might suggest that conduit PAs behave very differently from resistance PAs. Orton and co-workers (21) showed the difference in response to ACh between isolated conduit PAs and in vivo resistance PAs in calves with chronic PH.Indomethacin, a cyclooxygenase inhibitor, partially restored the impairment of ACh-induced relaxation in hypertensive PAs (16). Blockade of the cyclooxygenase pathway may enhance the production of lipoxygenase metabolites. In fact, Vanderhoek and Bailey (33) demonstrated that cyclooxygenase blockade induced the release of lipoxygenase metabolites, leukotrienes, which are potent vasoconstrictors. If so, indomethacin would reduce ACh-induced relaxation. However, in a previous study, we reported that indomethacin enhanced ACh-induced relaxation in chronic hypoxic rats (16). We could not exclude the possibility that leukotrienes were increased in the impaired relaxation in hypoxic PH. However, we would suggest that constriction of the cyclooxygenase pathway is responsible at least in part. It is possible that one of main causes of the difference in response to ACh between conduit PAs and resistance PAs is the production and/or release of cyclooxygenase-derived EDCFs in conduit PAs.
PGH2/TxA2
In the present study, the impairment of endothelium-dependent ACh-induced relaxation was significantly attenuated by ONO-3708, a PGH2/TxA2-receptor antagonist (12), whereas OKY-046 (34) and CV-4151 (30), TxA2 synthase inhibitors, failed to restore the ACh-induced response. Because ONO-3708 had no effect on the ACh-induced response in phenylephrine-precontracted endothelium-denuded rings from rats exposed to 10 days of hypoxia, the effects of ONO-3708 on ACh-induced responses in rings with endothelium seemed to take place through its effect on endothelial cells. These results suggested that the constricting substance was derived from endothelial cells in the PAs of hypoxic rats and that it might be a vasoconstrictor PG, most likely PGH2, not TxA2. Another candidate vasoconstrictor PG is PGF2
(4).
However, PGF2 is unlikely
because it has a low affinity to
PGH2/TxA2
receptors (4).
In this study, the response to ACh in hypertensive rings was biphasic: impaired relaxation at lower concentrations of ACh and increased tension at higher concentrations. These results showed that the ACh-induced response might be dependent on its concentration in hypertensive PAs. ONO-3708 blocked the tension increase and caused relaxation at higher concentrations of ACh (toward those observed in the control rat preparations). L-NAME completely abolished relaxation at lower concentrations of ACh and caused contraction at higher concentrations. In the presence of both L-NAME and ONO-3708, ACh did not induce any relaxation or contraction. These results suggested the biphasic responses to ACh in the experimental groups were mainly associated with release of endothelium-derived NO at all concentrations of ACh and release of endothelium-derived constricting factor, likely PGH2, at higher concentrations of ACh.
To investigate whether there was an augumented sensitivity to PGH2 in smooth muscle cells of chronic hypertensive PAs, we studied the contraction to exogenous PGH2 in control and chronic hypertensive PAs without endothelium. PGH2 did induce contractions, and ONO-3708 abolished these contractions in control and hypertensive PA rings, which confirmed the PGH2-receptor blocking effect of ONO-3708 in both of these conditions. The magnitude of responses to PGH2 was depressed in EPA rings from hypertensive PAs compared with control EPA rings at higher concentrations, whereas it was similar in control and hypoxic IPA rings. These findings suggested that the existence of endothelium-dependent contractions to ACh was not associated with a supersensitivity of the smooth muscle cells in hypertensive PA to PGH2.
ACh-mediated vasoconstriction is associated with an endothelial PGH2/TxA2 release in the aorta (7), intrarenal artery (6), and cerebral arteriole (18) of spontaneously hypertensive rats (SHR). Ge et al. (7) described a greater expression of PGH synthase-1 and an increased release of PGH2 in SHR aorta. In PH, indirect evidence of an increased production of TxA2 has been described, although the origin of this vasoconstrictor has not been determined. The plasma TxB2 (stable metabolite of TxA2) concentration was found to be increased in patients with primary and secondary PH such as congenital heart disease with high pulmonary blood flow (3). Vasodilator PGs might also be produced. Shaul et al. (26) described that locally produced prostacyclin is increased in the rat main PAs after chronic hypoxia. The metabolism of prostanoids might thus be accelerated in PH. We suggested a relative increased production of PGH2, not TxA2, in rat chronic hypertensive PAs, which was consistent with the results in systemic hypertensive arteries.
We could not determine from our present results whether the existence of EDCF is a cause or a result of chronic PH. Chronic hypoxic PH is characterized by vascular changes, including the new muscularization of normally nonmuscular peripheral PAs and the medial hypertrophy of muscular arteries (17, 23). An elevation of pulmonary arterial pressure due to hypoxic pulmonary vasoconstriction (24) precedes the development of these vascular changes. Because prostacyclin and PGH2/TxA2 have opposite roles in the regulation of vasomotor tone and vascular smooth muscle cell differentiation and growth in the pulmonary circulation (20, 22), the imbalance between the release of these mediators may be involved in the pathogenesis of the chronic PH. A previous study showed that indomethacin did not prevent the development of chronic hypoxic PH in rats (25). Indomethacin prevents the production of both vasodilator and vasoconstrictor PGs. Increased prostacyclin production might ameliorate chronic hypoxic PH. Rabinovitch et al. (25) have shown that continuous angiotensin II administration prevents chronic hypoxic PH and the associated structural vascular remodeling, most likely by inducing prostacyclin production. Further experiments are required to determine whether a chronic blockade of the production of PGH2 can prevent chronic hypoxic PH.
ET
Recent studies of hypertensive renal vessels of rats have shown the increased release of ET-1 (13) in addition to PGH2/TxA2 (6). Moreover, ACh increased the local production of ET in coronary arteries of patients with atherosclerosis (14). It is possible that increases in several EDCFs coexist in diseases characterized by an endothelial dysfunction, and ACh might augment the production and/or release of several EDCFs at the same time. Therefore, we also investigated the effect of ET and superoxide anion in the impaired relaxation response to ACh.ET levels in lung tissue and plasma are increased in chronic hypoxic PH
(15). ACh produces ET in certain diseases (14). In this study, BQ-485
and BQ-788 did not restore the impaired relaxation to ACh in EPA and
IPA of rats with hypoxic PH. BQ-485 partially reduced the relaxation
response at concentrations of 107 and
106 M ACh in EPA rings of
rats exposed to 10 days of hypoxia. The reason for these results is
unclear. If contracting substances coupled with ET receptors were
released in hypertensive PAs, blockade of ET receptors would enhance
ACh-induced relaxation. Therefore, these results at least suggested
that one of main EDCFs associated with the impaired relaxation in
response to ACh was not ET.
Superoxide Anion
In this study, pretreatment with SOD, an agent that scavenges superoxide anion, did not alter the relaxation of the EPA and IPA rings to ACh in both the control and hypoxic rats. The highly reactive free radical of oxygen has been proposed as an EDCF and is known as an inactivator of NO (8, 29). The EDCF(s) associated with the impaired relaxation to ACh in chronic hypoxic PH probably does not include a superoxide anion. In contrast, ACh produces superoxide anion in diabetic rat (8) and hyperlipidemic rabbit (29) aorta. A previous report described that PGH2 not only directly induced contractions but also caused the formation of superoxide anions in isolated normal rabbit aortic rings, thereby supressing EDRF/NO (31). The latter possibility is unlikely in chronic hypoxic PA, because SOD had no effect on the impaired ACh-induced responses.In conclusion, the relaxation effect of ACh might be counteracted by the concomitant release of an EDCF, likely PGH2 in PA isolated from rats with chronic hypoxic PH. ACh-induced ET or superoxide production was not detected in isolated hypertensive PAs. This study suggested that the impaired ACh-induced relaxation was due at least in part to the accelerated formation of PGH2 in the PAs of rats with chronic hypoxia.
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ACKNOWLEDGEMENTS |
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This work was supported in part by Grants-In-Aid for Scientific Research 08770045 and 09770038 from the Japanese Ministry of Education, Science and Culture.
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FOOTNOTES |
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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: J. Maruyama, Dept. of Physiology, Mie Univ. School of Medicine, 2-174, Edobashi, Tsu, 514-8507 Mie, Japan (E-mail: j-maru{at}doc.medic.mie-u.ac.jp).
Received 13 July 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
|
|---|
1.
Adnot, S.,
B. Raffestin,
S. Eddahibi,
P. Braquet,
and
P. E. Chabrier.
Loss of endothelium-dependent relaxant activity in the pulmonary circulation of rats exposed to chronic hypoxia.
J. Clin. Invest.
87:
155-162,
1991.
2.
Bank, N.,
and
H. S. Aynedjian.
Role of thromboxane impaired renal vasodilation response to acetylcholine in hypercholesterolemic rats.
J. Clin. Invest.
89:
1636-1642,
1992.
3.
Christman, B. W.,
C. D. McPherson,
J. H. Newman,
G. A. King,
G. R. Bernard,
B. M. Groves,
and
J. E. Loyd.
An imbalance between the excretion of thromboxane and prostacyclin metabolites in pulmonary hypertension.
N. Engl. J. Med.
327:
70-75,
1992[Abstract].
4.
Coleman, R. A.,
W. L. Smith,
and
S. Narumiya.
International union of pharmacology classification of prostanoid receptors: properties, distribution, and structure of the receptors and their subtypes.
Pharmacol. Rev.
46:
205-229,
1994[Medline].
5.
Dinh-Xuan, A. T.,
T. W. Higenbottam,
C. A. Clelland,
J. Pepke-Zaba,
G. Cremona,
A. Y. Butt,
S. R. Large,
F. C. Wells,
and
J. Wallwork.
Impairment of endothelium-dependent pulmonary-artery relaxation in chronic obstructive lung disease.
N. Engl. J. Med.
324:
1539-1547,
1991[Abstract].
6.
Fu-Xiang, D.,
J. Skopec,
A. Diederich,
and
D. Diederich.
Prostaglandin H2 and thromboxane A2 are contractile factors in intrarenal arteries of spontaneously hypertensive rats.
Hypertension
19:
795-798,
1992
7.
Ge, T.,
H. Hughes,
D. C. Junquero,
K. K. Wu,
P. M. Vanhoutte,
and
C. M. Boulanger.
Endothelium-dependent contractions are associated with both augmented expression of prostaglandin H synthase-1 and hypersensitivity to prostaglandin H2 in the SHR aorta.
Circ. Res.
76:
1003-1010,
1995
8.
Hattori, Y.,
H. Kawasaki,
K. Abe,
and
M. Kanno.
Superoxide dismutase recovers altered endothelium-dependent relaxation in diabetic rat aorta.
Am. J. Physiol.
261 (Heart Circ. Physiol. 30):
H1086-H1094,
1991
9.
Isaacson, T. C.,
V. Hampl,
E. K. Weir,
D. P. Nelson,
and
S. L. Archer.
Increased endothelium-derived NO in hypertensive pulmonary circulation of chronically hypoxic rats.
J. Appl. Physiol.
76:
933-940,
1994
10.
Ishikawa, K.,
M. Ihara,
K. Noguchi,
T. Mase,
N. Mino,
T. Saeki,
T. Fukuroda,
T. Fukami,
S. Ozaki,
T. Nagase,
M. Nishikibe,
and
M. Yano.
Biochemical and pharmacological profile of a potent and selective endothelin 
-receptor antagonist, BQ-788.
Proc. Natl. Acad. Sci. USA
91:
4892-4896,
1994
11.
Itou, S.,
T. Sasaki,
K. Ide,
K. Ishikawa,
M. Nishikibe,
and
M. Yano.
A novel endothelin ETA receptor antagonist, BQ-485, and its preventive effect on experimental cerebral vasospasm in dogs.
Biochem. Biophys. Res. Commun.
195:
969-975,
1993[Medline].
12.
Katsura, M.,
T. Miyamoto,
N. Hamanaka,
K. Kondo,
T. Terada,
Y. Ohgaki,
A. Kawasaki,
and
M. Tsuboshima.
In vitro and in vivo effects of new powerful thromboxane antagonists.
Adv. Prostaglandin Thromboxane Leukot. Res.
11:
351-357,
1983[Medline].
13.
Largo, R.,
D. Gomez-Garre,
X. H. Liu,
J. Alonso,
J. Blanco,
J. J. Plaza,
and
J. Egido.
Endothelin-1 upregulation in the kidney of uninephrectomized spontaneously hypertensive rats and its modification by the angiotensin-converting enzyme inhibitor quinapril.
Hypertension
29:
1178-1185,
1997
14.
Lerman, A.,
D. R. Holmes,
M. R. Bell,
K. N. Garratt,
R. A. Nishimura,
and
J. C. Burnett.
Endothelin in coronary endothelial dysfunction and early atherosclerosis in humans.
Circulation
92:
2426-2431,
1995
15.
Li, H.,
S. Chen,
Y. Chen,
Q. C. Meng,
J. Durand,
S. Oparil,
and
T. S. Elton.
Enhanced endothelin-1 and endothelin receptor gene expression in chronic hypoxia.
J. Appl. Physiol.
77:
1451-1459,
1994
16.
Maruyama, J.,
and
K. Maruyama.
Impaired nitric oxide-dependent responses and their recovery in hypertensive pulmonary arteries of rats.
Am. J. Physiol.
266 (Heart Circ. Physiol. 35):
H2476-H2488,
1994
17.
Maruyama, K.,
C. Ye,
M. Woo,
H. Venkatacharya,
L. D. Lines,
M. M. Silver,
and
M. Rabinovitch.
Chronic hypoxic pulmonary hypertension in rats and increased elastolytic activity.
Am. J. Physiol.
261 (Heart Circ. Physiol. 30):
H1716-H1726,
1991
18.
Mayhan, W. G.
Role of prostaglandin H2-thromboxane A2 in responses of cerebral arterioles during chronic hypertension.
Am. J. Physiol.
262 (Heart Circ. Physiol. 31):
H539-H543,
1992
19.
Mayhan, W. G.,
L. K. Simmons,
and
G. M. Sharpe.
Mechanism of impaired responses of cerebral arterioles during diabetes mellitus.
Am. J. Physiol.
260 (Heart Circ. Physiol. 29):
H319-H326,
1991
20.
Morinelli, T. A.,
L. M. Zhang,
W. H. Newman,
and
K. E. Meier.
Thromboxane A2/prostaglandin H2-stimulated mitogenesis of coronary artery smooth muscle cells involves activation of mitogen-activated protein kinase and S6 kinase.
J. Biol. Chem.
269:
5693-5698,
1994
21.
Orton, E. C.,
J. T. Reeves,
and
K. R. Stenmark.
Pulmonary vasodilation with structually altered pulmonary vessels and pulmonary hypertension.
J. Appl. Physiol.
65:
2459-2467,
1988
22.
Owen, N. E.
Prostaglandin can inhibit DNA synthesis in vascular smooth muscle cells.
In: Prostaglandins, Leukotrienes and Lipoxins, edited by J. M. Bailey. New York: Plenum, 1985, p. 193-204.
23.
Rabinovitch, M.,
W. Gamble,
A. S. Nadas,
O. S. Miettinen,
and
L. Reid.
Rat pulmonary circulation after chronic hypoxia: hemodynamic and structural features.
Am. J. Physiol.
236 (Heart Circ. Physiol. 5):
H818-H827,
1979
24.
Rabinovitch, M.,
M. A. Konstam,
W. J. Gamble,
N. Papanicolaou,
M. J. Aronovitz,
S. Treves,
and
L. Reid.
Changes in pulmonary blood flow affect vascular response to chronic hypoxia in rats.
Circ. Res.
52:
432-441,
1983
25.
Rabinovitch, M.,
M. Mullen,
H. C. Rosenberg,
K. Maruyama,
H. O'Brodovich,
and
P. M. Olley.
Angiotensin II prevents hypoxic pulmonary hypertension and vascular changes in rat.
Am. J. Physiol.
254 (Heart Circ. Physiol. 23):
H500-H508,
1988
26.
Shaul, P. W.,
B. Kinane,
M. A. Farrar,
L. M. Buja,
and
R. R. Magness.
Prostacyclin production and mediation of adenylate cyclase activity in the pulmonary artery.
J. Clin. Invest.
88:
447-455,
1991.
27.
Shimizu, K.,
M. Muramatsu,
Y. Kakegawa,
H. Asano,
Y. Toki,
Y. Miyazaki,
K. Okumura,
H. Hashimoto,
and
T. Ito.
Role of prostaglandin H2 as an endothelium-derived contracting factor in diabetic state.
Diabetes
42:
1246-1252,
1993[Abstract].
28.
Stelzner, T. J.,
R. F. O'Brien,
M. Yanagisawa,
T. Sakurai,
K. Sato,
S. Webb,
M. Zamora,
I. F. McMurtry,
and
J. H. Fisher.
Increased lung endothelin-1 production in rats with idiopathic pulmonary hypertension.
Am. J. Physiol.
262 (Lung Cell. Mol. Physiol. 6):
L614-L620,
1992
29.
Tagawa, H.,
H. Tomoike,
and
M. Nakamura.
Putative mechanisms of the impairment of endothelium-dependent relaxation of the aorta with atheromatous plaque in heritable hyperlipidemic rabbits.
Circ. Res.
68:
330-337,
1991
30.
Terashita, Z.,
Y. Imura,
M. Tanabe,
K. Kawazoe,
K. Nishikawa,
K. Kato,
and
S. Terao.
CV-4151
a potent, selective thromboxane A2 synthase inhibitor.
Thromb. Res.
41:
223-237,
1986[Medline].
31.
Tesfamariam, B.,
and
R. A. Cohen.
Role of superoxide anion and endothelium in vasoconstrictor action of prostaglandin endoperoxide.
Am. J. Physiol.
262 (Heart Circ. Physiol. 31):
H1915-H1919,
1992
32.
Tesfamariam, B.,
J. A. Jakubowski,
and
R. A. Cohen.
Contraction of diabetic rabbit aorta caused by endotheliumderived PGH2-TxA2.
Am. J. Physiol.
257 (Heart Circ. Physiol. 26):
H1327-H1333,
1989
33.
Vanderhoek, J. Y.,
and
J. M. Bailey.
Activation of a 15-lipoxygenase/leukotriene pathway in human polymorphonuclear leukocytes by the anti-inflammatory agent ibuprofen.
J. Biol. Chem.
259:
6752-6756,
1984
34.
Vezza, R.,
G. G. Nenci,
and
P. Gresele.
Thromboxane synthase inhibitors supress more effectively the aggregation of thromboxane receptor-desensitized than that of normal platelets: role of adenylylcyclase up-regulation.
J. Pharmacol. Exp. Ther.
275:
1497-1505,
1995
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) and 32 experimental rats at 10 days
of hypoxia (
). * P < 0.05, ** P < 0.01 compared with
control rats.
, Experimental rats with
ONO-3708. * P < 0.05, ** P < 0.01 compared with
experimental rats without ONO-3708 (
P < 0.05, 
P < 0.05, 
).
