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Division of Pulmonary and Critical Care Medicine, Department of Medicine, and Departments of Physiology and Pediatrics, University of Maryland School of Medicine, Baltimore, Maryland 21201; and Cardiovascular Institute, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100037 China
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
ACKNOWLEDGEMENTS
FOOTNOTES
REFERENCES
ABSTRACT 
Zhao, Yi-Ju, Jian Wang, Mary L. Tod, Lewis J. Rubin, and
Xiao-Jian Yuan. Pulmonary vasoconstrictor effects of prostacyclin in rats: potential role of thromboxane receptors. J. Appl. Physiol. 81(6): 2595-2603, 1996.
Endogenous
prostacyclin (PGI2; epoprostenol) is a potent endothelium-derived pulmonary vasodilator. However, the
effects of exogenous PGI2 on
isolated arteries could be either relaxant or contractile, depending on
the species and organ studied. The present study investigated the
distal pathways involved in the
PGI2-induced contraction in rat
intrapulmonary artery (PA) and relaxation in lamb PA. When vessels were
precontracted with 30 mM K+,
PGI2 (1 µM) induced relaxation
in lamb PA but caused contraction in rat PA. Use of 30 mM
K+, phenylephrine, serotonin,
angiotensin II, or hypoxia to precontract the vessels did not alter the
contractile effect of PGI2 in rat PA. Nevertheless, PGI2 produced a
mild relaxation in rat PA precontracted by U-46619, a thromboxane
A2
(TxA2)-receptor agonist, whereas the TxA2-receptor blocker SQ-29548
(0.1-0.5 µM) abolished the contractile response in rat PA. These
data suggest that PGI2-induced contraction is mediated by activation of
TxA2 receptors. The
PGI2-induced modest relaxation in
rat PA, which was only observed when
TxA2 receptors were blocked by
SQ-29548, suggests that the
PGI2-mediated vasorelaxant pathway
is diminished in these vessels. Simultaneous application of forskolin,
an adenylate cyclase activator, and rolipram, a phosphodiesterase
inhibitor, caused similar relaxation in both rat and lamb PA. This
suggests that the adenosine 3
,5-cyclic monophosphate-dependent relaxing pathway is intact in rat PA and is
comparable to that in lamb PA. On the basis of these data, we conclude
that the pathways responsible for the paradoxical effects of
PGI2 on rat and lamb PA are
located upstream of the adenosine 3,5-cyclic
monophosphate-dependent relaxing pathway and that a paucity of
PGI2 receptors in rat PA may be
responsible.
prostaglandin I2; epoprostenol; thromboxane A2; adenosine 3 INTRODUCTION PROSTACYCLIN
(PGI2; epoprostenol) is a
metabolite of arachidonic acid that is a potent endothelium-derived
pulmonary vasodilator (8, 11, 13). Infusion of
PGI2 decreases pulmonary vascular resistance and pulmonary arterial pressure and improves survival in
patients with primary pulmonary hypertension (1, 10) and adult
respiratory distress syndrome (25).
PGI2 also modulates hypoxia-induced increase of pulmonary vascular resistance in pigs (23),
dogs (7, 27, 30), and lambs (18) and decreases pulmonary arterial
pressure in fetal lambs (2, 17). Although PGI2 has been used effectively to
treat some patients with pulmonary hypertension, there are pulmonary
hypertensive patients in whom PGI2
does not improve hemodynamic parameters (1). Furthermore, the response
to PGI2 also varies considerably
in isolated perfused lungs and isolated pulmonary arteries (PAs)
obtained from different animals. For example,
PGI2 constricts rat PA (5) and
increases pulmonary arterial pressure in isolated rabbit lungs (12).
The mechanisms responsible for the divergent responses in animal PAs to
PGI2 and the diminished
vasodilator effects of PGI2 in
certain patients with pulmonary hypertension are still incompletely understood. Because PGI2 activates
both the PGI2 receptor and the
thromboxane A2
(TxA2) receptor (32), the
diminished vasodilator effects of
PGI2 on patients as well as the
paradoxical response to PGI2 in
different species may be related to
1) imbalanced distribution and
expression of contractile (TxA2)
or relaxant (PGI2) receptors in
PA smooth muscle cells and/or
2) different sensitivities of the
cellular signal transduction pathways to vasodilators (e.g., PGI2) and vasoconstrictors
(e.g., TxA2). By using the
intrapulmonary muscular arterial rings obtained from lamb (relaxed by
PGI2) and rat (constricted by
PGI2), we investigated potential
cellular mechanisms responsible for the divergent responses to
PGI2 between these two species.
MATERIALS AND METHODS 
,5-cyclic monophosphate; lamb; pulmonary
artery
Resting passive tension was maintained at the levels that offered the maximal active tension when the rings were exposed to 30 mM K+-containing perfusate (~325 and ~625 mg for rat and lamb PA rings, respectively). The rings were equilibrated for 60-90 min at resting tension and then were challenged three times with 30 mM K+-containing perfusate to obtain a stable contractile response. Reagents and solutions. The modified Krebs solution (MKS) consisted of (in mM) 138 NaCl, 4.7 KCl, 1.2 MgSO4, 1.2 NaH2PO4, 5 N-2-hydroxyethylpiperazine-N
-2-ethanesulfonic acid, 1.8 CaCl2, and 10 glucose,
buffered to pH 7.4 with 2 M tris(hydroxymethyl)aminomethane. In
K+-rich solutions, NaCl in MKS was
replaced, mole for mole, by KCl. In hypoxic experiments, the perfusate
was bubbled with pure nitrogen gas to establish a hypoxic condition
with an oxygen tension
(PO2) of 15-30
Torr. To maintain low PO2 in these
experiments, perfusion tubing was replaced with an
air-impermeable tubing and the tissue chamber was covered with a
plastic lid.
PGI2 (a gift from Burroughs
Wellcome, Research Triangle Park, NC) was dissolved into glycine buffer
containing glycine, mannitol, and NaCl (pH 10 with NaOH) to make a
stock solution of 1 mM. Aliquots of the stock solutions were then
diluted with MKS to make corresponding concentrations from
10
12 to
105 M. The
diluted PGI2 solution was then
infused with the inflowing perfusate to make a corresponding final
concentration by adjusting the flow rate of the PGI2
solution.
In most of the experiments, PGI2
(Burroughs Wellcome) dissolved in glycine buffer was used. To test
whether the glycine buffer affected vessel tension,
PGI2 (purchased from Biomol
Research Laboratories, Plymouth Meeting, PA) was also used.
PGI2 (Biomol) was dissolved into
water to make a stock solution of 1 mM. Aliquots of the stock solution
were then diluted with MKS to make a final concentration of 1 µM.
L-Phenylephrine (PE; Sigma
Chemical, St. Louis, MO) and angiotensin II (ANG II; Sigma Chemical)
were dissolved in water to make a stock solution of 0.2 mM. Serotonin
[5-hydroxytryptamine (5-HT), Sigma] and meclofenamate
(Sigma Chemical) were directly dissolved in MKS. U-46619
(9,11-dideoxy-9
,11-methanoepoxyprostaglandin F2
, Biomol), SQ-29548
([1S-[1,2(5Z),3,4]]-7-[3-[[2-[(phenylamino)carbonyl]hydrazino]methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid, Biomol), rolipram (Biomol), acetylsalicylic acid (aspirin, Sigma
Chemical), and indomethacin (Sigma Chemical) were dissolved in ethanol
to make a stock solution; aliquots of the stock solution were then
diluted with MKS. Forskolin (Biomol) was
dissolved in dimethyl sulfoxide (DMSO) to make a stock solution of 5 mM; aliquots of the stock solution were then diluted with MKS. Neither
DMSO nor ethanol alone had any effect on basal tension and evoked
tension in either lamb or rat PA.
Endo)
from 1 ring while endothelium was intact (+Endo) in the other.
B and
C: summarized data showing effects of
BK and PGI2 on lamb PA rings with
(Endo +; n = 10) and without (Endo
; n = 6) endothelium.
Data are means ± SE. *** P < 0.001 vs. 30K.
Endo)
from 1 ring while the other had an intact endothelium (+Endo).
B and
C: summarized data showing effects of
ACh and PGI2 on rat PA rings with
(Endo +) and without (Endo ) endothelium. Data are means ± SE (n = 6).
*** P < 0.001;
** P < 0.01 vs.
30K.
Statistics. The composite data are expressed as means ± SE. Statistical analysis was performed by using paired and unpaired Student's t-test and one-way analysis of variance as indicated. Differences were considered to be significant when P < 0.05.
RESULTS
12 to
105 M) was introduced, with
10-fold increment of previous concentration, to vessels when evoked
contraction reached a plateau (A and
B) or after vessels were stabilized
in modified Krebs solution (MKS) for ~60 min at resting passive tone
(C).
D: normalized dose-response curves to
PGI2
(1012 to
105 M) when rings were
pretreated with PE (n = 6), 30K
(n = 6), or MKS
(n = 6). Each data point was
normalized to maximal tension (as 100%) induced by
PGI2
(105 M). Data are means ± SE.
Effects of endothelium removal on PGI2-induced relaxation in lamb PA and contraction in rat PA. Bradykinin (BK) and acetylcholine (ACh) are both endothelium-dependent pulmonary vasodilators, whereas PGI2 causes vascular relaxation by an endothelium-independent mechanism (3). Consistently, in lamb (Fig. 2, A and B) and rat (Fig. 3, A and B) PA rings with intact endothelium (+Endo), BK (0.5 µM) and ACh (5 µM) relaxed the vessels by 59 and 48%, respectively, whereas PGI2 (1 µM) relaxed lamb PA by 59% (Fig. 2, A and C) but constricted rat PA by 32% (Fig. 3, A and C). Removal of endothelium (
Endo) abolished BK- and ACh-mediated relaxation in lamb (Fig.
2, A and B) and rat (Fig. 3, A and
B) PA rings. However, PGI2-induced relaxation
in lamb PA (Fig. 2, A and
C) and contraction in rat PA (Fig.
3, A and
C) were not affected by functional
impairment of the endothelium. These data suggest that relaxant and
contractile effects of PGI2 (1 µM) on lamb and rat PA rings are independent of endothelium. Although
endothelium-dependent relaxations were not evaluated in every vessel,
there was no effort made to intentionally damage the endothelium, and,
indeed, great care was used to minimize any endothelial injury.
Effects of PGI2 on PA contraction induced
by distinct agonists.
Tseng et al. (28) reported that
PGI2-induced relaxation in canine
PA is dependent on the agonist used to precontract the vessels. In our study,
PGI2 (1 µM) caused further
contraction in rat PA precontracted by 0.2 µM PE (55 ± 6%;
n = 11), 5 µM 5-HT (68 ± 6%;
n = 7), 1 µM ANG II (73 ± 6%; n = 6), and hypoxia (65 ± 7%; n = 5) (Fig.
4, A-C,
E, and
F). In contrast,
PGI2 slightly relaxed the rat PA
rings (5 ± 3%, n = 6)
precontracted by 1 nM U-46619 (Fig. 4,
D and
F), a selective
TxA2-receptor agonist (4, 6).
Dose response of rat PA to PGI2.
In systemic (e.g., aortic, cerebral, and mesenteric) arteries, the
contractile or relaxant effects of
PGI2 are concentration dependent
(32). In rat PA rings precontracted by PE (Fig. 5, A and
D) or 30K (Fig. 5,
B and
D),
PGI2
(1012 to
105 M) caused further
contraction in a dose-dependent manner. Furthermore, in rat PA rings
maintained at the resting passive tension,
PGI2 (1012 to
105 M) also caused similar
dose-dependent contractile effects (Fig. 5,
C and
D). The normalized dose-response
curves, shown in Fig. 5D, demonstrate
that PGI2 caused significant
contraction in rings precontracted with PE
(P < 0.001, at
1011 M) or 30K
(P < 0.05; at
1010 M) and in the rat PA
rings maintained at the resting passive tone
(P < 0.05; at
109 M). These results
demonstrate that PGI2, at both low
and high concentrations, causes contraction in rat
PA.
, Pretreatment; +, no
pretreatment.
Blockade of TxA2 receptor inhibits PGI2-induced contraction in rat PA. Pretreatment with the selective TxA2-receptor antagonist SQ-29548 (0.1, 0.2, and 0.5 µM) (6, 21, 22) reversibly and dose-dependently inhibited PGI2 (1 µM)-induced contraction (by 59 ± 3, 73 ± 3, and 98 ± 3%, respectively; n = 6) in rat PA rings maintained at the resting passive tension (Fig. 6, A and B). SQ-29548 (0.5 µM) completely blocked the PGI2-induced contraction in rat PA rings precontracted with 30K (Fig. 6, C and D). In addition, SQ-29548 (0.5 µM) also completely blocked 1 nM U-46619-induced contraction in rat PA rings (data not shown). These results suggest that the PGI2-induced contraction may be related to activation of TxA2 receptor. Effects of cyclooxygenase inhibitors on PGI2-induced contraction in rat PA. It has been suggested that exogenous PGI2-mediated PA contraction is due to a release of endogenous TxA2 from endothelium (12). In this study, the cyclooxygenase inhibitors aspirin, indomethacin, and meclofenamate were employed to determine whether endogenous TxA2 is involved in the epoprostenol-induced contraction in rat PA. If PGI2 causes contraction by enhancing the production of endogenous TxA2, the three cyclooxygenase inhibitors should block the PGI2-induced contractile response. The data shown in Fig. 7 demonstrate that neither indomethacin (15 µM) nor aspirin (15 µM) (Fig. 7, A and B) significantly affected PGI2-mediated effects on rat PA rings. These results suggest that PGI2-induced PA contraction in rats is not due to increased TxA2 production. However, pretreatment of the vessels with 15 µM meclofenamate decreased the PGI2-induced contraction by 28% (n = 6; P < 0.01; Fig. 7C) in the rat PA rings maintained at resting tone and inhibited the U-46619-induced contraction by 32% (from 229 ± 28 to 156 ± 20 mg; P < 0.01; n = 6). These effects are consistent with other investigators' reports that meclofenamate, in addition to inhibiting cyclooxygenase, also directly blocks TxA2 receptors (9, 31). Effects of adenylate cyclase activator and phosphodiesterase inhibitor on contraction in lamb and rat PAs. PGI2 relaxes blood vessels by increasing the intracellular adenosine 3
,5-cyclic
monophosphate (cAMP) levels via activation of the
PGI2 receptor (16, 20). Whether a
cAMP-dependent relaxing mechanism is responsible for the divergent
effects of PGI2 on lamb and rat PA
rings was determined by using the phosphodiesterase inhibitor rolipram
and the adenylate cyclase activator forskolin. In both lamb and rat PA
rings precontracted with 30K, rolipram (10 µM), which increases cAMP
content by decreasing its degradation, relaxed the vessels by 18 ± 2 and 6 ± 1%, respectively (Fig.
8A). The relaxant
effect of rolipram on lamb PA rings was slightly, but significantly,
greater than that on rat PA rings (P < 0.01), suggesting that the basal production of cAMP and/or
phosphodiesterase activity may be different between lamb and rat PAs.
In addition, forskolin (5 µM), which increases cAMP content by
activating its production, produced significant relaxation in both lamb
(n = 6) and rat
(n = 6) PA rings (79 ± 3 vs. 88 ± 3%; P < 0.05; Fig. 8B), suggesting a different basal
activity of adenylate cyclase in lamb and rat PAs. Total relaxation
induced by simultaneous application of rolipram and forskolin was not
significantly different in lamb (n = 6) and rat (n = 6) PAs (97 ± 2 vs.
94 ± 3%; P = 0.18; Fig.
8C), suggesting that the
cAMP-dependent relaxing pathway is intact in rat PA and comparable to
that in lamb PA.
DISCUSSION
In isolated arterial rings, PGI2 has been reported to produce either relaxation (3, 11, 13) or constriction (12, 26). The present study investigated the dual effects of PGI2 on lamb and rat PA. The results demonstrated that 1) PGI2 relaxes lamb PA but constricts rat PA, 2) activation of TxA2 receptors by U-46619 abolishes PGI2-mediated rat PA contraction, 3) blockade of TxA2 receptors by SQ-29548 uncovers a modest PGI2-induced relaxation in rat PA, and 4) the cAMP-dependent relaxing pathway in rat PA is intact and is comparable to that in lamb PA. Our data are consistent with other investigators' observations that PGI2 relaxes PAs of cats (11), sheep (2), dogs (7, 13, 19), pigs (24), and humans (1, 8, 29) but constricts PAs of rats (5) and rabbits (12, 26).
Additive effect of PGI2 on agonist-induced contraction in rat PA. Daffonchio et al. (5) reported that PGI2 contracted rat PA. The mechanism involved in the contractile response remains unclear. In PA rings isolated from dog, PGI2 caused relaxation when the vessels were contracted by PE or 5-HT, whereas it had little effect on vessels precontracted with 25 mM K+ (28). This suggests that the response of PAs to PGI2 depends on the agonist used to constrict the vessels. In the present study, PGI2 not only constricts rat PA rings maintained at the resting passive tone but also causes further contraction in the PA rings precontracted by 30K, PE, 5-HT, ANG II, or hypoxia. PGI2, at all concentrations studied (1012 to
105 M), elicited only
contractile responses in rat PA, although
PGI2 causes relaxation at low
doses but constriction at high doses in systemic arteries (30, 32). In
rat PA rings, application of
1012 to
105 M
PGI2 caused contraction in a
concentration-dependent manner in the presence or absence of agonists.
These results suggest that PGI2
not only directly induces contraction but also has an additive effect
with certain agonists, e.g., 30K or PE, in rat PA.
PGI2-induced contraction in rat PA is
mediated by TxA2 receptors.
Receptor-binding studies have demonstrated that
PGI2 not only binds with the
PGI2 receptor but also may bind
with other contractile prostaglandin receptors such as
TxA2, prostaglandin F (PGF), and prostaglandin E (PGE) receptors (15, 32). Although
PGI2 is much less potent than is
prostaglandin F2
(PGF2) at the PGF receptor,
prostaglandin E2 at the PGE
receptor, or TxA2 at the
TxA2 receptor, it is possible that
PGI2 activates these contractile
prostaglandin receptors, leading to vessel contraction. Thus the
vascular response to PGI2 is
largely determined by the balance between its relaxing effect, mediated
by activation of PGI2 receptor,
and its contracting effect, mediated by activation of contractile
receptors such as the TxA2
receptor.
By activating the TxA2 receptor
(4, 6), U-46619 induced a significant contractile response in rat PA;
this contractile effect was completely abolished by SQ-29548, a
selective TxA2-receptor antagonist
(6, 21, 22). Pretreatment of rat PA rings with SQ-29548 also completely
blocked PGI2-induced contraction.
These results suggest that 1) the
TxA2 receptor is present in rat PA and 2) the contractile effect of
PGI2 is probably due to activation of the TxA2 receptor.
Consistently, U-46619, which has a much higher affinity than does
PGI2 for the
TxA2 receptor, completely eliminated PGI2-mediated
contraction in rat PA. Interestingly, PGI2 even produced a mild
relaxation when the vessels were pretreated with a very low dose of
U-46619, suggesting that activation of the
TxA2 receptor by
PGI2, to produce contraction, is
partially inhibited by competitive occupancy of the receptors by
U-46619. Accordingly, PGI2 causes
mild relaxation by activating PGI2
receptors in rat PA.
The results obtained from the present study cannot completely rule out
the possibility that PGI2-induced
contraction in rat PA may also involve other contractile prostanoid
receptors, such as the PGF2
receptor. Indeed, in rat aorta and guinea pig trachea, SQ-29548, in
addition to significantly inhibiting
11,9-epoxymethano-PGH2-mediated contraction, also partially inhibits
PGF2-mediated
contraction. In these experiments, 0.1 µM SQ-29548
caused a 70-fold inhibition of
11,9-epoxymethano-PGH2-mediated
contraction [increasing the effective concentration producing
50% of maximum response (EC50) from 10 to ~700 nM] but only induced a 2.2-fold inhibition of PGF2-mediated contraction
(increasing the EC50 from 226 to ~500 nM) (22). Thus it is possible that activation of
the PGF receptor may also be involved in the
PGI2-induced rat PA contraction, but the TxA2 receptor may be the
predominant contributor in this contractile response. In addition,
PGF2 may interact with the
TxA2 receptor as well to produce
contraction; whether this mechanisms is involved in the
PGI2-mediated contraction in rat PA is unclear.
Endogenous TxA2 is not involved in
PGI2-induced contraction in rat PA.
Endogenous PGI2 and
TxA2 are predominantly synthesized
from arachidonic acid in endothelial cells, although PA smooth muscle can also make TxA2 (26). Kaapa et
al. (12) reported that in isolated blood-perfused rabbit lungs,
PGI2 induced pulmonary
vasoconstriction. This contractile effect was age and dose dependent;
pretreatment with indomethacin completely abolished the response. They
thus suggested that the
PGI2-induced contractile effect is
mediated by enhanced release of endogenous
TxA2 from endothelium (12). Other
investigators, however, demonstrated that the contraction induced by
isocarbacyclin, a stable PGI2
analogue, in isolated cerebral and mesenteric arteries is not affected
by removal of endothelium (14). The data obtained from the present
study also demonstrated that neither indomethacin nor aspirin inhibited
PGI2-induced contraction in rat
PA. Taken together with the data that
PGI2-mediated effects on lamb and
rat PAs do not depend on intact endothelium, our results do not support
the idea that an endogenous contractile cyclooxygenase product is
involved in PGI2-induced rat PA
contraction.
cAMP-dependent relaxing pathway is intact in rat PA.
The PGI2 receptor is coupled with
adenylate cyclase. When PGI2 binds
with the PGI2 receptor, the
activated adenylate cyclase would facilitate production of
intracellular cAMP and thereby cause smooth muscle relaxation (16, 20).
Thus, in the presence of the
TxA2-receptor blocker SQ-29548,
PGI2 produced a mild relaxation in
rat PA. The blockade effect of SQ-29548 on
PGI2-induced contraction in rat PA
suggests that the contractile response is due to activation of
TxA2 receptors existing in the PA
smooth muscle. When the TxA2 receptors were blocked by SQ-29548, the weaker relaxant effect of
PGI2 on rat PA, in comparison with
lamb PA, suggests that 1) rat PA has
fewer PGI2 receptors,
2) the linkage between
PGI2 receptor and adenylate
cyclase or G protein is defective in rat PA, and/or 3) the cAMP-dependent relaxing
pathway differs between lamb and rat PAs. This last explanation was
further assessed by the studies showing that the cAMP-dependent
relaxing mechanism is indistinguishable between rat and lamb PAs.
Rolipram, a phosphodiesterase inhibitor, and forskolin, an adenylate
cyclase activator, both relaxed lamb and rat PA rings. Rolipram caused
a greater degree of relaxation in lamb PA than in rat PA, suggesting
that the basal production of cAMP and/or activities of
phosphodiesterase (or adenylate cyclase) may be different between lamb
and rat PAs. However, the relaxant effects induced by simultaneous
application of both rolipram and forskolin are not significantly
different between lamb and rat PA rings, suggesting an intact and
comparable cAMP-dependent relaxing mechanism in these two types of
vessels.
Conclusion.
In summary, the results from the present study demonstrated that
PGI2 relaxed lamb PA but
contracted rat PA. The contractile effect of
PGI2 in rat PA was probably due to
activation of TxA2 receptors,
whereas the cAMP-dependent relaxing mechanisms appear to be intact and
comparable in both lamb and rat PAs. The divergent effects of
PGI2 on lamb and rat PAs suggest a
lack of or underexpressed PGI2
receptors in rat PA. Accordingly,
PGI2-mediated relaxation, by
activating PGI2 receptors, can be
easily masked by contraction, via activating
TxA2 receptors.
ACKNOWLEDGEMENTS
We gratefully acknowledge A. M. Aldinger for excellent technical assistance and R. T. Bright for the review of the manuscript.
FOOTNOTES
Address for reprint requests: X.-J. Yuan, Div. of Pulmonary and Critical Care Medicine, Univ. of Maryland School of Medicine, 10 S. Pine St., Suite 800, Baltimore, MD 21201 (E-mail: xyuan{at}umabnet.ab.umd.edu).
Received 6 February 1996; accepted in final form 10 July 1996.
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