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Vol. 301, Issue 3, 1060-1066, June 2002
Asthma Research Group, Father Sean O'Sullivan Research Centre, Firestone Institute for Respiratory Health, St. Joseph's Hospital, Department of Medicine, McMaster University, Hamilton, Ontario, Canada
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Abstract |
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 Top
 Abstract
 Introduction
Materials and Methods
Results
Discussion
References
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Although isoprostanes generally act on smooth muscle via
TXA2-selective prostanoid receptors (TPs), some suggest
other prostanoid receptors or possibly even a novel
isoprostane-selective receptor might be involved. We studied
contractions to several isoprostanes in porcine pulmonary vasculature
using organ bath techniques. 8-iso-prostaglandin E2
(PGE2) was the most potent and efficacious of the
isoprostanes, with a log EC50 of 
7.0 ± 0.2 in the
pulmonary artery and 6.8 ± 0.2 in the pulmonary vein. The
responses to all the isoprostanes were essentially completely blocked
by the TP receptor antagonist ICI 192605 [4(Z)-6-[(2,4,5-cis)2-(2-chlorophenyl)-4-(2-hydroxyphenyl)1,3-dioxan-5-yl]hexenoic acid], and the equilibrium dissociation constants for ICI 192605 competing with U46619 or 8-iso-PGE2 were both 
2
nM, indicating that isoprostane-evoked responses involve primarily TP
receptors. Only 8-iso-PGE2 was able to evoke substantial
contractions in the presence of ICI 192605 and only in the pulmonary
vein. The EC50 of these ICI 192605-insensitive responses
was 6.1 ± 0.2. Using a variety of prostanoid agonists, we found
the pulmonary vein lacked excitatory
PGF2
-selective prostanoid receptor (FP) or
PGD2-selective prostanoid receptor (DP) but expressed excitatory EP3 receptors. The ICI 192605-insensitive
responses to 8-iso-PGE2 were unaffected by the
EP1 antagonist SC-19220
[8-chloro-debenz[b,f][1,4]oxazepine-10(11H)-carboxy-(2-acetyl) hydrazine;
10
5 M] but were antagonized by the less selective
DP/EP1/EP2 antagonist AH6809
(6-isopropoxy-9-oxoxanthene-2-carboxylic acid; 105 M) or
by cyclopiazonic acid (105 M; depletes the internal
Ca2+ store). Our data indicate that, whereas
8-iso-PGE2 constricts pulmonary vasculature primarily
through TP receptors, a substantial portion of this response is also
directed through EP3 receptors or possibly a novel
isoprostane receptor.
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Introduction |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Isoprostanes
are metabolites of polyunsaturated fatty acids, such as arachidonic
acid, and are produced by peroxidative attack of lipid membranes. They
accumulate to substantial levels in a wide variety of clinical and
experimental settings associated with oxidative stress, including
systemic (Romero and Reckelhoff, 2000
) and pulmonary (Jankov et al.,
2000) hypertension, and during exposure to agents that are associated
with hypertension, such as subpressor doses of angiotensin II (Haas et
al., 1999; Reckelhoff et al., 2000), inflammatory mediators (Jourdan et
al., 1997b, 1999), and growth factors (Natarajan et al., 1996). For
this reason, they are used extensively as markers of oxidative stress
in general and membrane lipid peroxidation in particular. However, they
are much more than inert markers; there is a growing body of literature describing powerful biological effects of these autacoids on smooth muscle (Fukunaga et al., 1993a,b), platelets (Longmire et al., 1994;
Yin et al., 1994), and endothelial cells (Yura et al., 1999). We have
previously characterized the effects of several different isoprostanes
on pulmonary vascular smooth muscle, finding them to exert
vasoconstriction via activation of tyrosine and Rho kinases (Janssen et
al., 2001).
The excitatory effects of 8-iso-PGE2 and
8-iso-PGF2 are sensitive to a wide variety of
agents, which are structurally distinct but all exhibit TP-receptor
blocking activity, including ICI 192605 [4(Z)-6-[(2,4,5-cis)2-(2-chlorophenyl)-4-(2-hydroxyphenyl)1,3-dioxan-5-yl]hexenoic acid] (Jourdan et al., 1997a; Janssen et al., 2000, 2001), SQ 29548 (Banerjee et al., 1992; Fukunaga et al., 1993b; Mohler et al., 1996; Elmhurst et al., 1997; John and Valentin, 1997; Wagner et
al., 1997; Sametz et al., 2000), L 657925 (Wagner et al., 1997), L 670596 (Elmhurst et al., 1997; Wagner et al., 1997), GR
32191 (Elmhurst et al., 1997; Oliveira et al., 2000), and BMS
180291 (Mohler et al., 1996). Thus, the bulk of the data would strongly suggest that TP receptors are involved.
However, certain findings have prompted some to suggest that
isoprostanes act through some other receptor, perhaps even a novel
isoprostane-selective receptor. For example, in aortic smooth muscle,
8-iso-PGF2 displaces the binding of TP
receptor-acting ligands with much less potency (two to three orders of
magnitude less) than the homoligands but stimulates
IP3 production and
[3H]thymidine incorporation with a higher
potency than TP agonists (Fukunaga et al., 1993a,b). Binding
experiments have indicated the presence of both low-affinity and
high-affinity binding sites for 8-iso-PGF2
(Fukunaga et al., 1993a, 1995, 1997; Yura et al., 1999), which could
represent the TP receptor and a unique isoprostane receptor,
respectively. Finally, astroglia, endothelial cells, and microvessel
smooth muscle cells are all able to respond to the TP agonist U46619,
whereas 8-iso-PGF2 stimulates only the former
two but not the smooth muscle cells (Hou et al., 2000); in platelets,
8-iso-PGF2 is only a partial agonist on TP
receptors (Morrow et al., 1992; Longmire et al., 1994; Yin et al.,
1994). Collectively, these data point toward another receptor for the
isoprostanes distinct from the TP receptor. There are limited data that
isoprostanes can act on other prostanoid receptors. 12-iso-PGF2 is a powerful agonist for FP
receptors (Kunapuli et al., 1997), and there is evidence that some
isoprostane responses may involve EP receptors (Elmhurst et al., 1997;
Sametz et al., 2000; Unmack et al., 2001). In this study, we examined
the actions of isoprostanes on pulmonary vascular smooth muscle using a
variety of agonists and antagonists of prostanoid receptors.
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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 Isolated Tissues and Single Cells.
Lobes of
lung were obtained from pigs (20-90 kg) euthanized at a local abattoir
and immediately put in ice-cold physiological solution for transport to
the laboratory. After removing the overlying parenchyma and connective
tissue, the pulmonary artery and vein were excised and cut into ring
segments 4- to 5-mm long (o.d. 2-10 mm); no attempt was made to
remove the endothelium.
Muscle Bath Technique.
Ring segments were mounted into 3-ml
muscle baths using stainless steel hooks inserted into the lumen. One
hook was fastened to a Grass FT .03 force transducer using silk thread
(Ethicon 4-0); the other was attached to a Plexiglas rod, which served as an anchor. Tissues were bathed in Krebs-Ringer buffer (see below for
composition) containing indomethacin (10 µM), bubbled with 95%
O2/5% CO2, and maintained
at 37°C; tissues were passively stretched to impose a preload tension
of 1 g (determined to allow maximal responses). Isometric changes in
tension were amplified, digitized (two samples per second), and
recorded on-line (DigiMed System Integrator; MicroMed, Louisville, KY)
for plotting on the computer. Tissues were equilibrated for 1 h
before commencing the experiments, during which time the tissues were
challenged with 60 mM KCl at least once to assess the functional state
of each tissue. Tissues were then washed, and the preload was
readjusted just prior to onset of the actual study (i.e., at the end of
the equilibrium period).
Solutions and Chemicals. Tissues were studied using Krebs-Ringer buffer containing 116 mM NaCl, 4.2 mM KCl, 2.5 mM CaCl2, 1.6 mM NaH2PO4, 1.2 mM MgSO4, 22 mM NaHCO3, 11 mM D-glucose, bubbled to maintain pH at 7.4. Indomethacin (10 µM) was also added to the latter to prevent generation of cyclooxygenase metabolites of arachidonic acid.
Isoprostanes and SC-19220 [8-chloro-dibenz[b,f][1,4]oxazepine-10(11H)-carboxy-(2-acetyl)hydrazide] were purchased from Cayman Chemical (Ann Arbor, MI), and ICI 192605 was a gift from Zeneca Pharmaceuticals plc (Alderley Park, UK); all other chemicals were obtained from Sigma-Aldrich (St. Louis, MO). Stock solutions (10 mM) were prepared in absolute ethanol (isoprostanes, U46619; prostanoids, AH6809) or dimethyl sulfoxide (ICI 192605, SC-19220, cyclopiazonic acid); the final bath concentration of dimethyl sulfoxide and ethanol did not exceed 0.1%, which we have found elsewhere to have little or no effect on mechanical activity.Data Analysis.
The maximal contraction
(Emax) produced with the highest
concentration and the half-maximum effective concentration
(EC50) for the isoprostanes were interpolated
from the individual concentration-effect curves. The equilibrium
dissociation constant (KB) for ICI
192605 was calculated using the equation:
KB = [B]/(DR 1), where [B] is the concentration of the antagonist and DR (dose ratio) is the ratio
of EC50 in the presence and absence of antagonist.
6 M U46619, as indicated and are
reported as mean ± S.E.M; n refers to the number of
animals. Statistical comparisons were made using analysis of variance
(with Newman-Keuls post hoc test), as appropriate; P < 0.05 was considered statistically significant.
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Results |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Excitatory Effects of Isoprostanes in Porcine Pulmonary Vein.
We first examined the ability of various isoprostanes to elevate tone
in porcine pulmonary vasculature; isoprostanes tested included
8-iso-PGE1, 8-iso-PGE2,
8-iso-PGF1,
8-iso-PGF2, and
8-iso-PGF2
.
7.0 ± 0.2 and 6.8 ± 0.2, respectively. Supramaximal concentrations of
8-iso-PGE2 consistently reversed tone in the arterial segments but not the vein segments (Fig. 1).
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50% KCl response at
105 M (Fig. 1).
Involvement of Both TP and Non-TP Receptors in Mediating
Isoprostane Contractions.
In many other smooth muscle
preparations, the excitatory effects of isoprostanes are sensitive to
antagonists of TP receptors (see Introduction). Therefore we examined
the effect of the TP receptor antagonist ICI 192605 on
isoprostane-evoked contractions in porcine pulmonary vein. Tissues were
first preconstricted with the TP receptor agonist U46619 to standardize
responses (106 M) and treated with ICI 192605 (106 M) for 20 min, after which the
dose-response relationships for the different isoprostanes were
reexamined (Fig. 2).
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and
8-iso-PGF2 in the pulmonary vein. However,
8-iso-PGE2 was still able to evoke a response of
25% that of the U46619 response (which is comparable with the
response to 60 mM KCl) in the pulmonary vein pretreated with ICI
192605; likewise, 8-iso-PGF2 could still evoke
a response of 8% that of the U46619 response (Fig. 2). It was not
clear if these responses were maximal at 105 M
(the highest concentration tested) but, assuming that to be the case,
the log EC50 value for
8-iso-PGE2 in the presence of ICI 192605 was
6.1 ± 0.2.
Derivation of Inhibitory Constant for ICI 192605.
To test the
possibility that the isoprostane-evoked contractions in the presence of
106 M ICI 192605 are due to incomplete block of
the TP receptors, we ascertained the
KB value for ICI 192605 in this
preparation. Tissues were pretreated with vehicle or ICI 192605 (109, 108, or
107 M) for 20 min and challenged with
increasing concentrations of U46619 or 8-iso-PGE2
in cumulative fashion (both
109-105 M;
n = 5).
9, 108, or
107 M ICI 192605 were 1.4 × 109 M, 2.9 × 109
M, and 2.5 × 109 M, respectively.
Likewise, ICI 192605 displaced the 8-iso-PGE2 dose-response relationship in similar fashion (Fig. 3B).
KB values of 2.1 × 109 and 1.9 × 109
M were obtained in the presence of 109 and
108 M ICI 192605, respectively. In fact,
107 M ICI 192605 inhibited
8-iso-PGE2 responses to such an extent that a
distinct Emax was not obtained;
however, assuming an Emax of 115% KCl
(comparable with that for the other data),
KB was 5.9 × 109 M. The potency of ICI 192605 against
8-iso-PGE2 responses (log KB of 2-5 nM) argues strongly
against the possibility that 8-iso-PGE2 evokes
constriction in the presence of 106 M ICI
192605 by merely displacing the latter receptor blocker.
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Involvement of Other Prostanoid Receptors in Mediating Non-TP
Contractions.
It may be that 8-iso-PGE2 is
able to evoke constriction in the presence of ICI 192605 through an
action on some prostanoid receptor other than TP receptors. We
therefore characterized the sensitivity of this preparation to various
prostanoid receptor agonists to determine which other excitatory
prostanoid receptors might be present. Agonists included prostaglandin
D2, prostaglandin E2,
prostaglandin F2, BW245C
(DP-selective), sulprostone (EP3-selective), and
fluprostenol (FP-selective). Tissues were pretreated with ICI 192605 (106 M) to rule out confounding effects of
these prostanoids on TP receptors.
were both able to markedly elevate tone, although the former autacoid
was considerably more potent than the latter (Fig.
4). PGE2 responses
increased in magnitude over the concentration range
108 to 106 M, with a
log EC50 value of 7.1 ± 0.2, comparable
with the published pD2 value for
PGE2 acting at an EP receptor; at
105 M, however, PGE2
responses decreased in magnitude (i.e., PGE2 seemed to cause relaxation). PGF2 responses,
on the other hand, increased in magnitude over the concentration range
107 to 105 M; since a
plateau was not attained, we could not calculate an EC50 value (but it is clearly greater than 1 µM). Sulprostone was even more potent (EC50
value of 7.2 ± 0.2) and effective than both these
prostaglandins, eliciting contractions nearly twice as large as those
evoked by PGE2 or PGF2.
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Do Non-TP Contractions Involve EP Receptors?
It may be, then,
that 8-iso-PGE2 is also acting through excitatory EP
receptors, in addition to the TP receptors characterized above.
EP1 receptors couple to Gq and phospholipase C
and mediate excitation via IP3-induced Ca2+
release, whereas EP3 receptors couple to Gi and
thereby inhibit adenylate cyclase (Coleman et al., 1994; Narumiya et
al., 1999). We therefore examined the effect of the
DP/EP1/EP2 receptor antagonist AH6809 and the
EP1-selective antagonist SC-19220, as well as the effect of
depleting the internal Ca2+ pool using cyclopiazonic acid.
Tissues were pretreated with ICI 192605 (106 M), and then
with either AH6809 (105 M), SC-19220 (105
M), or with cyclopiazonic acid (105 M) for 20 min, after
which the 8-iso-PGE2 dose-response relationship was reexamined.
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Discussion |
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|
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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For over a decade, isoprostanes have been recognized as being
useful as markers of oxidative stress in clinical and experimental settings. Now it is also known that these autacoids exert powerful biological effects. Some have described the vasoconstrictor effects of
8-iso-PGF2 on pulmonary vasculature (Hill et
al., 1997; John and Valentin, 1997) and on other vascular beds (Mohler
et al., 1996; Wagner et al., 1997; Oliveira et al., 2000). However, very few have compared the effects of a wide range of isoprostanes, as
we have done in this study. We found several E- and F-ring isoprostanes
to increase tone in pulmonary vasculature to varying degrees. In
particular, the most potent and efficacious of these was
8-iso-PGE2, much more so than
8-iso-PGF2, the isoprostane upon which most
previous studies of isoprostane effects have focused solely. In fact,
others have described vasodilatory responses to
8-iso-PGF2 in the rat pulmonary artery
(Jourdan et al., 1997a). We were again struck by the very high degree
of specificity in these actions of the isoprostanes;
8-iso-PGE2 differs only very slightly from
8-iso-PGF2 (a ketone versus a hydroxyl group,
respectively, on the central cyclopentane ring) or from 8-iso-PGE1 (two versus one unsaturated bonds,
respectively) but differs tremendously with respect to biological
activity. This argues strongly for a receptor-mediated mechanism,
rather than some nonspecific mechanism such as altered membrane fluidity.
In general, isoprostanes seem to mediate their effects on vascular
smooth muscle via TP receptors. Consistent with this, we found that
nearly all the excitatory responses of the isoprostanes in the
pulmonary vasculature were prevented by pre-exposure to the TP receptor
blocker ICI 192605. Moreover, we obtained similar values of
KB for ICI 192605 acting against
U46619 (pKB 1-2 nM) and against
8-iso-PGE2 (2-5 nM), and both of these values compare favorably with published literature values for this antagonist (Narumiya et al., 1999). These data indicate that, in the porcine pulmonary vein, ICI 192605, U46619, and
8-iso-PGE2 compete at a common receptor.
Although the actions of the other isoprostanes were essentially
completely prevented by TP receptor blockade, this was not true of
8-iso-PGE2 in the porcine pulmonary vein; only
this isoprostane was able to evoke substantial contraction in the
maintained presence of ICI 192605 (at concentrations three orders of
magnitude above the KB value we
obtained for this blocker in this preparation). Once again, this high
degree of compound-related specificity speaks toward a
receptor-mediated mechanism. Others have provided limited evidence that
isoprostanes can activate other prostanoid receptors, including EP
(Elmhurst et al., 1997; Sametz et al., 2000; Ungrin et al., 2001) and
FP (Kunapuli et al., 1997) receptors.
8-iso-PGE2 has been shown elsewhere to be only a
partial agonist at TP receptors in the coronary artery (Kromer and
Tippins, 1996) and in platelets (Morrow et al., 1992; Longmire et al., 1994; Yin et al., 1994). If this were true also of the pulmonary vein,
this might complicate interpretation of the effects of ICI 192605 on
8-iso-PGE2-evoked responses. We found, however,
that in tissues studied concurrently with either the full TP agonist U46619 or with 8-iso-PGE2, the former evoked a
peak response of 120% KCl, whereas the response to the latter was
already 110% KCl before it reached a peak (we were
unable to use sufficiently high concentrations to reach a peak). This
observation is not consistent with partial agonism. Furthermore,
partial agonism would not explain the different sensitivity of these
responses to CPA; the responses that persist in the presence of ICI
192605 were completely eliminated by CPA (Fig. 6), whereas the ICI
192605-sensitive responses are unaffected (Janssen et al., 2001). Thus,
8-iso-PGE2 appears to be a full agonist at TP
receptors in this tissue, and the ICI 192605-resistant component
appears to be mediated through a non-TP receptor.
The non-TP-mediated effects of 8-iso-PGE2 would
not involve FP receptors; the FP-selective agonist fluprostenol was
devoid of activity, indicating the absence of any functionally coupled FP receptors in the porcine pulmonary vein. Although
PGF2 did evoke contractions, the
concentrations required to do so were considerably in excess of the
literature pD2 value for this prostanoid; instead, PGF2 may be acting nonselectively
through some other prostanoid receptor. The non-TP-mediated effects of
8-iso-PGE2 also would not involve DP receptors,
since the DP-selective agonists PGD2 and BW245C
evoked only relaxations. PGE2, however, was able to evoke substantial contractions with an EC50
value of 100 nM, comparable with the published literature value for
its action at EP receptors (Coleman et al., 1994; Ungrin et al., 2001).
Thus, in addition to its actions at the TP receptor,
8-iso-PGE2 may also be acting at one of the four
subtypes of EP receptors. PGE2 and
8-iso-PGE2 shared similar concentration-response
characteristics; the threshold concentration for both is approximately
10 nM, and both evoke a response of approximately 20% U46619 response when applied at 1 µM. At concentrations above 1 µM, the
PGE2 responses reversed whereas those to
8-iso-PGE2 continued to increase in magnitude at
higher concentrations; as a result, the EC50
values for these two compounds differed somewhat (0.1 and 1.0
µM, respectively). One interpretation of this finding is that
PGE2 might be acting nonselectively at the
inhibitory DP receptors, whereas the isoprostane does not.
With respect to the subtype of EP receptor that might mediate the
non-TP responses to isoprostanes, only two subtypes are generally
associated with excitation in smooth muscle: EP1
and EP3 (Coleman et al., 1994). Our data indicate
that these tissues express excitatory EP3 but not
EP1 receptors since 1) the
EP3-selective agonist sulprostone was as potent
(EC50 value of 100 nM) and twice as effective
as PGE2; 2) the
EP1-selective antagonist SC-19220 had no
significant effect on PGE2- or
8-iso-PGE2-evoked responses; and 3)
PGE2 responses were also insensitive to the
DP/EP1/EP2 receptor
antagonist AH6809. Strangely, 8-iso-PGE2-evoked
contractions were significantly inhibited by AH6809. One interpretation
of this paradoxical finding is that the isoprostane is acting through a
novel isoprostane-selective receptor that is also sensitive to the
relatively poorly selective blocker AH6809.
Whatever the type/subtype of non-TP receptor that mediates these ICI
192605-insensitive responses, it appears to trigger mobilization of
intracellular Ca2+; we found these contractions
to be eliminated by pretreatment of the tissues with CPA, which
effectively depletes the internal Ca2+ pool. In a
previous study of the effects of isoprostanes in human and canine
pulmonary vasculature (Janssen et al., 2001), CPA was largely
ineffective against the TP receptor-mediated effects of 8-iso-PGE2.
In conclusion, we find that 8-iso-PGE2 evokes
vasoconstriction in the pulmonary vasculature via an action on TP
receptors. In the pulmonary vein, 8-iso-PGE2 can
also act upon another type of excitatory receptor, likely
EP3 receptors or possibly a unique isoprostane
receptor. This may represent an important mechanism during
hypertension, which is characterized in part by production of large
amounts of isoprostanes (Jankov et al., 2000; Romero and Reckelhoff,
2000).
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Footnotes |
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Accepted for publication February 11, 2002.
Received for publication October 31, 2001.
These studies were supported by operating funds from the Canadian Institutes of Health Research and the Ontario Thoracic Society, and a Scientist Award from the Medical Research Council of Canada.
Address correspondence to: Dr. Luke J. Janssen, Department of Medicine, McMaster University, St. Joseph's Hospital, 50 Charlton Avenue East, Hamilton, Ontario, L8N 4A6, Canada. E-mail: janssenl{at}mcmaster.ca
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Abbreviations |
|---|
ICI 192605, 4(Z)-6-[(2,4,5-cis)2-(2-chlorophenyl)-4-(2-hydroxyphenyl)1,3-dioxan-5-yl]hexenoic
acid;
SC-19220, 8-chloro-dibenz[b,f][1,4]oxazepine-10(11H)-carboxy-(2-acetyl)hydrazide;
AH6809, 6-isopropoxy-9-oxoxanthene-2-carboxylic acid;
PG, prostaglandin;
CPA, cyclopiazonic acid;
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;
L 670596, ()6,8-difluoro-9-p-methylsulfonyl
benzyl-1,2,3,4-tetrahydrocarbazol-1-yl-acetic acid;
L 657925, 9,11-dimethyl-methano-11,12-methano-16-(3-iodo-4-hydroxyl)-13-aza-15,-
-tetranorthromboxane
A2;
GR 32191, [1R-
[1(Z)-2,3,5-(+)-7-[[1,1'-biphenyl)-4-yl]methoxy]-3-hydroxy-2-(1-piperidinyl)cyclopentyl]-4-4-heptanoic
acid] hydrochloride;
BMS 180291, [1S-(exo,exo)]-2-[[3-[4-[(pentylamino)carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]-benzenepropanoic
acid;
BW245C, (4S)-(3-[(3R,S)-3-cyclohexyl-3-hydroxypropyl]-2,5-dioxo)-4-imidazolidine
heptanoic acid.
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References |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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.
Br J Pharmacol
119:
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 P. MONTUSCHI, P. J. BARNES, and L. J. ROBERTS II Isoprostanes: markers and mediators of oxidative stress FASEB J, December 1, 2004; 18(15): 1791 - 1800. [Abstract] [Full Text] [PDF]
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T. J. Weber and L. M. Markillie Regulation of Activator Protein-1 by 8-iso-Prostaglandin E2 in a Thromboxane A2 Receptor-Dependent and -Independent Manner Mol. Pharmacol., May 1, 2003; 63(5): 1075 - 1081. [Abstract] [Full Text] [PDF]
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),
8-iso-PGE2 (
), 8-iso-PGF1
),
8-iso-PGF2
), and 8-iso-PGF2
).
Responses are expressed as a percentage of the response to 60 mM KCl
evoked in each tissue at the beginning of the study
(n = 4-7).
