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CARDIOVASCULAR
Firestone Institute for Respiratory Health, Father Sean O'Sullivan Research Centre, and Department of Medicine, McMaster University, St. Joseph's Hospital, Hamilton, Ontario, Canada
Received for publication
January 23, 2003
Accepted
February 27, 2003.
 |
Abstract |
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 Top Abstract Materials and MethodsResultsDiscussionReferences |
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also evoked
relaxations (albeit with lower potency), whereas the other F-ring isoprostanes
(8-iso-PGF1
,
8-iso-PGF1, and
8-iso-PGF2) were largely ineffective in this
respect. The potency and efficacy of 8-iso-PGE2 in reversing tone
were not dependent upon the concentration of U46619
[GenBank]
used to preconstrict the
tissues (10-8 to 10-6 M),
indicating a lack of U46619
[GenBank]
-induced functional antagonism of these responses.
8-iso-PGE2 was able to completely relax tissues that had been
denuded of endothelium (as indicated by loss of responsiveness to bradykinin).
8-iso-PGE2-evoked relaxations were markedly reduced by elevating
the K+ equilibrium potential using 30 mM KCl and abolished by 60 mM
KCl; they were also sensitive to charybdotoxin (10-7 M)
but not to 4-aminopyridine (1 mM). 8-iso-PGE2 also caused membrane
hyperpolarization and augmentation of outward K+ current. We
conclude that 8-iso-prostaglandin E2 acts directly on the smooth
muscle to increase K+ conductance, leading to membrane
hyperpolarization and vasodilation.
). As such, they
have been used clinically and experimentally as markers for many disease
states in which oxidative stress is a prominent feature, including myocardial
and renal ischemia-reperfusion injury
(Takahashi et al., 1992;
Mobert and Becker, 1998),
atherosclerosis (Pratico et al.,
1997), pulmonary hypertension
(Christman et al., 1998), and
hypercholesterolemia (Oguogho et al.,
1999).
They are now recognized to also have powerful effects on mechanical
activity in vascular smooth muscle. Many have described contractile responses
to isoprostanes in a wide variety of arterial beds, generally via stimulation
of thromboxane A2 receptors (TP receptors), which then enhance the
Ca2+-sensitivity of the contractile apparatus through
some mechanism that is largely dependent on tyrosine kinase activation
(Janssen, 2001). They may also
cause vasoconstriction through an action on PGE2-selective (EP)
receptors coupled to release of internally sequestered
Ca2+ (Janssen and
Tazzeo, 2002). More recently, some have identified important
vasodilatory actions of isoprostanes
(Jourdan et al., 1997;
Janssen et al., 2000;
Janssen et al., 2001);
however, the signaling mechanisms underlying those inhibitory responses have
not been investigated. Likewise, the vascular electrophysiological actions of
isoprostanes, both excitatory and inhibitory, have also been unexplored.
In general, many vasodilators act indirectly via the endothelium, causing
the latter to release prostacyclin, nitric oxide, and/or one or more
endothelium-derived hyperpolarizing factors (EDHFs). Much is known about the
properties and actions of EDHF, but there is still considerable debate
regarding its identity (McGuire et al.,
2001; Busse et al.,
2002). In the porcine coronary artery, vasodilators such as
bradykinin stimulate production of reactive oxygen species by cytochrome P450
enzymes in the endothelium (Fleming et
al., 2001) and trigger a series of events that results in
activation of large-conductance Ca2+-dependent
K+ currents and vasodilation
(Barlow and White, 1998;
Hayabuchi et al., 1998b;
Pomposiello et al., 1999). One
of these events appears to include release of a cyclooxygenase-independent
metabolite of arachidonic acid (Cowan and Cohen,
1991,
1992;
Hecker et al., 1994;
Weintraub et al., 1995;
Chataigneau et al., 1998;
Hayabuchi et al., 1998a), one
which is not a cannabinoid (Chataigneau et
al., 1998; Pomposiello et al.,
1999; Grainger and
Boachie-Ansah, 2001). Although many acknowledge that cytochrome
P450 plays a key role in the production of EDHF(s) in this tissue
(Bauersachs et al., 1994;
Fleming et al., 2001;
Busse et al., 2002), it is not
clear whether the vasoactive metabolite is an epoxyeicosatrienoic acid or some
oxygen free radical, which could, in turn, lead to generation of isoprostanes.
In fact, it is possible that epoxyeicosatrienoic acids, isoprostanes, and
reactive oxygen species could all collectively play the role of EDHF in this
tissue.
In this study, we explored the mechanisms by which isoprostanes exert
inhibitory effects on porcine coronary artery (outer diameter 0.5–1.0
mm). We examined the effects of two E-ring isoprostanes (8-iso-PGE1
and 8-iso-PGE2) and four F-ring isoprostanes
(8-iso-PGF1,
8-iso-PGF1,
8-iso-PGF2, and
8-iso-PGF2) using standard organ bath,
intracellular microelectrode, and patch-clamp electrophysiological
techniques.
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Materials and Methods |
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TopAbstractMaterials and MethodsResultsDiscussionReferences |
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Muscle Baths. Intact tissues were mounted as ring segments
(3–4 mm long) in standard organ baths for recording of mechanical
activity, as described elsewhere (Janssen et al.,
2000,
2001), and bathed at 37°C
in Krebs buffer (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) supplemented with 0.01 mM
indomethacin and bubbled to maintain pH at 7.4. Where indicated, the
endothelium was intentionally damaged by gently rubbing the lumen of the
tissue using a wood splinter. Although the endothelium was clearly affected by
this procedure (as indicated by the reduction in bradykinin-evoked responses;
see Fig. 2), the smooth muscle
per se appeared not to be seriously damaged, since the magnitude of
contractions evoked by 10-6 M U46619
[GenBank]
were 0.92 ±
0.21 g and 0.74 ± 0.16 g in endothelium-intact and -denuded tissues,
respectively (n = 6 for both). After a 60- to 90-min equilibration
period, tissue viability was assessed using 60 mM KCl, after which tissues
were washed and preload-adjusted to 0.4 to 0.5 g, and L-NNA was
added; experiments commenced 30 min later. Isometric changes in tension were
digitized (2 samples/s) and recorded on-line (DigiMed System Integrator;
Micro-Med Inc., Louisville, KY) for subsequent analysis using Origin 6.0
software (OriginLab Corp., Northampton, MA).
|
Intracellular Microelectrode Recordings. Porcine coronary arterial
segments were slipped over a cannula with adventitia outward, or were cut open
and pinned out with adventitia upward. These were superfused with Krebs buffer
(composition above; supplemented with 0.01 mM indomethacin) at 37°C at a
rate of 3 ml/min. Cells were impaled with microelectrodes having tip
resistance of 30–100 M
when filled with 3 M KCl. Membrane
potentials were amplified (Duo 773; World Precision Instruments, New Haven,
CT) and digitized at 5 Hz using SigmaPlot 2000 software (SPSS Inc., Chicago,
IL).
Patch-Clamp Electrophysiology. Intact tissues were minced and
incubated for 30 to 60 min with collagenase (Sigma-Aldrich, St. Louis, MO;
blend F, 0.9 U/ml) and elastase (Sigma-Aldrich type IV, 12.5 U/ml) and
incubated at 37°C for 1 h, then gently triturated to liberate individual
myocytes. The single cells were allowed to settle and adhere to the bottom of
a recording chamber (1-ml volume), superfused at room temperature with
standard Ringer's solution (130 mM NaCl, 5 mM KCl, 1 mM CaCl2, 1 mM
MgCl2, 20 mM HEPES, 10 mM D-glucose, pH 7.4) containing
the thromboxane receptor antagonist ICI 192605, and studied within 8 h after
dissociation. Patch-clamp recordings were made in cells that were phase-dense
and appeared relaxed. The majority of recordings were made using the
nystatin-perforated configuration of the whole-cell patch-clamp technique
(Hamill et al., 1981) and
pipettes with tip resistance of 3 to 5 M when filled with standard
electrode solution (140 mM KCl, 1 mM MgCl2, 0.4 mM
CaCl2, 20 mM HEPES, 1 mM EGTA, and 150 U/ml nystatin, pH 7.2). The
current-voltage relationship of the membrane currents was examined using a
series of incrementing step depolarizations (10-mV increments from holding
potential of -70 mV; 1-s duration). Membrane currents were amplified, filtered
at 1 kHz, and sampled at 2 kHz using an Axopatch 200B amplifier and pCLAMP8
software (Axon Instruments, Union City, CA). The current-voltage relationships
of outward currents were compared before and after application of
8-iso-PGE2; the time course of the changes exerted by
8-iso-PGE2 was followed using depolarizing pulses to +30 mV (from
the holding potential of -70 mV) delivered at 15-s intervals. In a variation
of this approach, an excised vesicle (total capacitance of >3 pF) was
formed by gently removing the electrode while maintaining a tight seal
(electrode solution as described above), after which unitary outward currents
were recorded as described above.
Chemicals and Solvents. Isoprostanes were purchased from Cayman Chemical (Ann Arbor, MI); all other chemicals were obtained from Sigma-Aldrich. The 10 mM stock solutions were prepared in absolute EtOH (isoprostanes, U46619 [GenBank] ) or distilled water (bradykinin, L-NNA). Dilutions of these were made in physiological medium; the maximal bath concentration of EtOH did not exceed 0.1%, which we have found elsewhere to have little or no effect on mechanical activity.
Statistics. The half-maximum effective concentration
(EC50) for the isoprostanes was interpolated from individual
concentration-effect curves as described previously (Janssen et al.,
2000,
2001). Mechanical responses to
isoprostanes were standardized relative to responses to either 60 mM KCl or
10-6 M U46619
[GenBank]
, as indicated, and are reported as mean
± S.E.M. ANOVA (with Newman-Keuls post hoc test) analyses were
performed using SigmaStat software (SPSS Inc.). p < 0.05 was
considered statistically significant; n refers to the number of
animals.
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Results |
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TopAbstractMaterials and MethodsResultsDiscussionReferences |
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were the most potent, with
negative log EC50 (half-maximally effective concentrations) of 6.9
± 0.1, 6.6 ± 0.1, and 6.3 ± 0.1, respectively. These
excitatory effects of isoprostanes have been examined in detail in numerous
vascular beds (Janssen, 2001)
including the coronary artery (Mobert et
al., 1997; Kromer and Tippins,
1999) and have been shown to involve TP receptors: we did not
characterize these effects any further in this study.
|
After preconstriction of the tissues with the thromboxane mimetic U46619
[GenBank]
(10-6 M; sufficient to saturate the TP receptors), three
of the isoprostane molecules studied reversed U46619
[GenBank]
-induced tone in a
concentration-dependent fashion (Figs.
2 and
3A); 8-iso-PGE2 was
the most potent (negative log EC50 of 6.0 ± 0.1; n
= 5), whereas 8-iso-PGE1 and 8-iso-PGF2
were somewhat less so (negative log EC50 values of 5.5 ±
0.1; n = 5). The other F-ring isoprostanes, on the other hand, were
largely ineffective in this respect, evoking less than 10% reversal of tone at
the highest concentration tested (Fig.
3A).
|
In a separate set of experiments, we reexamined 8-iso-PGE2 relaxations under conditions in which the TP receptors were not already maximally stimulated (10-8 and 10-7 M U46619 [GenBank] elicited an increase in tone of 0.69 ± 0.17 and 0.85 ± 0.19 g, respectively, compared with the 1.21 ± 0.14 g response evoked by 10-6 U46619 [GenBank] ). Following submaximal stimulation, addition of 8-iso-PGE2 led to further contraction at submicromolar concentrations, followed by complete reversal of tone at higher concentrations (Fig. 3B); there were no significant differences with respect to potency (EC50) or efficacy (percentage reversal of tone) of 8-iso-PGE2 in producing these relaxations at any of the [U46619] used to preconstrict the tissues (Table 1).
|
Endothelial Dependence of 8-iso-PGE2-Evoked Relaxations. Many vasodilators (e.g., bradykinin) mediate their effects via an action on the endothelium, causing the latter to release EDHF. To test whether isoprostanes also act here in such an endothelium-dependent fashion, we examined the responses to 8-iso-PGE2 in indomethacin/L-NNA-treated tissues that had been intentionally denuded of endothelium; bradykinin (10-7 M) was used as a functional assay for endothelial integrity. 8-iso-PGE2 was able to completely reverse U46619 [GenBank] tone (10-6 M) even in tissues that had lost all responsiveness to bradykinin (Fig. 2). On average, relaxations evoked by bradykinin (10-7 M) were 18 ± 10% (n = 6) in intentionally denuded tissues, but 106 ± 8% (n = 5) in tissues that were intended to be left intact. The corresponding responses to 8-iso-PGE2 (10-5 M) in the very same tissues, however, were 73 ± 22% and 115 ± 14%, respectively, indicating that the latter are not dependent on the functional integrity of the endothelium. Thus, we conclude that 8-iso-PGE2 does not act via the endothelium (i.e., to stimulate EDHF release) but, rather, through a receptor found on the vascular smooth muscle cells.
Role of Membrane Hyperpolarization in 8-iso-PGE2-Evoked Responses. To test whether isoprostane-evoked relaxations were dependent on membrane hyperpolarization and K+ channels, we first investigated the sensitivity of the 8-iso-PGE2-evoked relaxations to high millimolar concentrations of potassium chloride: under this experimental condition, the potassium equilibrium potential is elevated such that membrane hyperpolarization does not occur even if potassium channels do open. Tissues were maximally stimulated with U46619 [GenBank] (10-6 M) in the presence or absence of KCl (the latter did not evoke further tone above that elicited by U46619 [GenBank] ). Relaxations evoked by 8-iso-PGE2 (10-6 and 10-5 M) were markedly and significantly reduced in the presence of 30 mM KCl, and were abolished in the presence of 60 mM KCl (p < 0.05; Fig. 4). Thus, the relaxant response to 8-iso-PGE2 requires hyperpolarization of the membrane.
|
Intracellular microelectrodes were used to record the hyperpolarization that accompanies this relaxant response. In the presence of indomethacin and L-NNA (10-5 and 10-4 M, respectively), resting membrane potential was -60.0 ± 1.9 mV (n = 11). Upon addition of a single bolus of 8-iso-PGE2 (3 x 10-5 M), the membrane potential was briefly depolarized by 5.5 ± 1.0 mV and then exhibited a larger and sustained hyperpolarization of 16.6 ± 1.9 mV (to -71.9 ± 1.9 mV; n = 3; p < 0.05).
Finally, pharmacological blockers were employed to test the pharmacological sensitivities of the 8-iso-PGE2-evoked responses. Tissues were pretreated with 4-aminopyridine (1 mM) or with charybdotoxin (10-7 M) 20 min before evaluating the response to 10-6 M 8-iso-PGE2; in the presence of 4-aminopyridine, there was a nonsignificant trend for reduced relaxations, whereas charybdotoxin completely abolished them (Fig. 5).
|
8-iso-PGE2 Augments Outward K+
Conductances. Patch-clamp electrophysiological techniques were employed
to examine more unequivocally whether or not 8-iso-PGE2 activated
outward potassium conductances. Step depolarizations (10-mV increments) from a
holding potential of -70 mV were used to examine the current-voltage
relationship of outward K+ conductances before and after
application of 8-iso-PGE2, while test pulses to +30 mV (from the
holding potential of -70 mV; 1-s duration, delivered at 15-s intervals) were
used to monitor the time course of any 8-iso-PGE2-evoked changes.
Step depolarizations evoked large outwardly rectifying potassium currents
(Fig. 6); these have been
characterized in detail elsewhere
(Balwierczak et al., 1995;
Barlow and White, 1998) and
were found to represent primarily large-conductance
Ca2+-dependent potassium currents. 8-iso-PGE2
(10-5 M) caused a marked augmentation of these currents
at all potentials tested (i.e., the current-voltage relationship was displaced
to more negative potentials; Fig.
6B). This augmentation was maximal after 2 to 3 min of application
(Fig. 6C). On average, the
magnitude of currents evoked using depolarizing pulses to +30 mV were
significantly increased to 122 ± 8% of control (n = 5;
p < 0.05) by 8-iso-PGE2. When large-conductance
Ca2+-dependent K+ conductances were blocked
using charybdotoxin (10-7 M), however,
8-iso-PGE2 did not cause an increase in depolarization-evoked
K+ currents (n = 3). There was no evidence of activation
of any inward current by 8-iso-PGE2.
|
Finally, Fig. 7 shows
discontinuous recordings of membrane current obtained from an excised vesicle
using the nystatin-perforated patch configuration, including activation of
unitary conductances of approximately 14 pA during application of
8-iso-PGE2 (10-5 M) from a puffer pipette.
The driving force on potassium under these conditions is 
115 mV, given
that the K+ equilibrium potential is -85 mV and the membrane
potential is held at +30 mV. As such, unitary currents of this magnitude arise
from opening of channels with a conductance of 122 pS. Others have found that,
in the porcine coronary artery, peroxide stimulates
Ca2+-dependent K+ channels with a unitary
conductance of 119 pS (Barlow and White,
1998).
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Discussion |
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TopAbstractMaterials and MethodsResultsDiscussionReferences |
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;
Mobert et al., 1997;
Kromer and Tippins, 1999;
Janssen et al., 2000,
2001). However, their
inhibitory effects on smooth muscle have been largely unexplored: only two
groups have described their relaxant effects in pulmonary vasculature
(Jourdan et al., 1997;
Janssen et al., 2001) and
airway smooth muscle (Janssen et al.,
2000), and none have examined the signaling pathways involved.
Moreover, there have been no studies of the electrophysiological actions
(neither excitatory nor inhibitory) of any isoprostane.
Here, we describe in detail the relaxations and electrophysiological
effects that are evoked by E-ring isoprostanes, but not their F-ring
counterparts, in porcine coronary artery; in fact, 8-iso-PGE2
achieves this effect with a similar potency and greater efficacy than that of
anandamide, another compound that has recently received a great deal of
attention with respect to the regulation of vascular smooth muscle function
(White and Hiley, 1997;
Zygmunt et al., 1997;
Chataigneau et al., 1998;
Grainger and Boachie-Ansah,
2001; Harris et al.,
2002). We have also observed similar relaxations in mesenteric and
bronchial arteries, but found cerebral arteries to only constrict in response
to any of the isoprostanes tested (data not shown). Clearly, then, this
vasodilatory response to isoprostanes is both compound- and
tissue-specific.
The inhibitory response in the coronary artery is completely independent of
a functional endothelium, indicating that isoprostanes do not act by releasing
some other EDHF. Instead, they appear to act directly on the smooth muscle.
Furthermore, this direct action is clearly receptor-mediated, since certain
isoprostanes were highly effective, whereas others were completely
ineffective. In particular, the E-ring compounds were generally far better
vasodilators than the F-ring molecules: these two different subgroups of
isoprostanes differ solely with respect to whether the second carbon of the
central cyclopentane ring features a ketone or a hydroxyl group, respectively.
Also, 8-iso-PGF2 could evoke large relaxations
(albeit at relatively high concentrations), whereas
8-iso-PGF2 did not; these two compounds differ
only in the orientation of a hydroxyl group on the cyclopentane ring. As such,
the marked compound-related specificity in the responsiveness of this tissue
speaks toward a receptor-mediated mechanism, rather than nonspecific changes
such as altered membrane fluidity, redox state, or effects of vehicle. We did
not characterize the receptor(s) involved in mediating this response. However,
many believe that isoprostanes act through prostanoid receptors
(Janssen, 2001); thus, it is
possible that these actions are exerted through the same inhibitory receptors
that are activated by PGE2 or PGI2.
Despite the great number of studies addressing the biological actions of
EDHF, there is still debate as to its identity
(McGuire et al., 2001;
Busse et al., 2002). Candidate
molecular species have been proposed, each being met simultaneously with
support and dispute. Several lines of evidence have prompted us to suggest
that isoprostanes might be an EDHF
(Janssen, 2002). However, two
critical pieces of evidence were lacking at that time.
First, the electrophysiological actions of isoprostanes had been completely unexplored prior to that earlier study. Here we show that the relaxant response evoked by 8-iso-PGE2 is accompanied by and dependent upon membrane hyperpolarization and augmentation of outward K+ currents. Our observations that 8-iso-PGE2 activates outward unitary currents of approximately 120 pS and that the isoprostane relaxations are sensitive to charybdotoxin both suggest that the K+ channel involved is of a large-conductance Ca2+-dependent variety; a full pharmacological and electrophysiological characterization of this current is beyond the scope of the present study. Nonetheless, these findings are consistent with our hypothesis that isoprostanes might mediate EDHF effects.
Second, it will be necessary to show that the endothelium synthesizes and
releases one or more of the vasodilatory isoprostanes upon stimulation with an
appropriate agonist (e.g., substance P or bradykinin), an endeavor that is
also beyond the scope of the present study. Others have shown that the
endothelium can release isoprostanes
(Watkins et al., 1999).
Although this has generally been viewed as a result of membrane damage, it is
entirely possible that the endothelium might do so in a carefully controlled,
enzymatically driven fashion. For example, free radicals and reactive oxygen
species are produced by cyclooxygenase, cytochrome P450, lipoxygenase,
nitric-oxide synthase, and NADPH oxidase
(Fulton et al., 1997;
Matoba et al., 2000;
Thannickal and Fanburg, 2000;
Fleming et al., 2001), which
in turn are under direct regulation by the endothelial cell. This could
explain some of the reports that EDHF is sensitive to inhibitors of cytochrome
P450 (Bauersachs et al., 1994;
Hecker et al., 1994;
Adeagbo, 1997), or EDCF to COX
inhibitors (Yang et al.,
1991), as well as the apparent insensitivity of EDHF/EDCF to free
radical scavengers when they are applied extracellularly
(Rodriguez-Martinez et al.,
1998).
In theory, dozens (if not hundreds) of isoprostane species and their
metabolites may exist (Janssen,
2001), but only a handful of these have been tested to date; in
fact, most studies of isoprostane pharmacology and pathophysiology focus
solely on 8-iso-PGF2. It may be that the
physiologically relevant isoprostane(s) may be one(s) that are not yet
commercially available. In the present study, we found 8-iso-PGE2
to be the best vasodilator molecule among the six that were tested, but this
relaxant effect was masked by its excitatory actions at TP receptors; an
isoprostane that would be a better candidate for EDHF would be one that does
not stimulate TP receptors [we have previously identified several of these
(Janssen et al., 2000,
2001)] and/or is much more
potent at inhibitory receptors.
Thus, isoprostanes are capable of exerting both excitatory and inhibitory
actions on smooth muscle, depending on the particular isoprostane and tissue
being tested. In this study, 8-iso-PGE2 in particular caused
excitation at submicromolar concentrations, likely via activation of TP
receptors (Janssen, 2001), but
relaxation at slightly higher concentrations. Isoprostanes have been the
subject of investigation for only a little over one decade, and for most of
that time they have been viewed primarily as breakdown products of lipid
peroxidation. Recently, however, there has been a growing interest in their
biological actions, particularly in the context of oxidative pathophysiology;
as such, they have been elevated from being merely markers of oxidative stress
to being a novel class of inflammatory mediator
(Janssen, 2001). Now it may
even be possible that isoprostanes serve a physiological role in the
regulation of vascular smooth muscle tone by the endothelium.
|
Footnotes |
|---|
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
ABBREVIATIONS: TP, thromboxane A2-selective prostanoid
receptor; 8-iso-PG, 8-iso-prostaglandin; EDHF, endothelium-derived
hyperpolarizing factor; EC50, half-maximally effective
concentration; U46619
[GenBank]
,
9,11-dideoxy-11,9-epoxymethanoprostaglandin
F2; L-NNA,
N-
-nitro-L-arginine; ICI 192605,
4(Z)-6-[(2,4,5-cis)2-(2-chlorophenyl)-4-(2-hydroxyphenyl)1,3-dioxan-5-yl]
hexenoic acid; EDCF, endothelium-derived contracting factor.
Address correspondence to: Dr. L. J. Janssen, Department of Medicine, McMaster University St. Joseph's Healthcare, 50 Charlton Avenue, East Hamilton, Ontario, L8N 4A6, Canada. E-mail: janssenl{at}mcmaster.ca
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References |
|---|
|
TopAbstractMaterials and MethodsResultsDiscussionReferences |
|---|
Adeagbo AS (1997) Endothelium-derived hyperpolarizing
factor: characterization as a cytochrome P450 1A-linked metabolite of
arachidonic acid in perfused rat mesenteric prearteriolar bed. Am J
Hypertens 10:
763–771.[CrossRef][Medline]
Balwierczak JL, Krulan CM, Kim HS, DelGrande D, Weiss GB, and Hu S
(1995) Evidence that BKCa channel activation contributes to K+
channel opener induced relaxation of the porcine coronary artery.
Naunyn Schmiedebergs Arch Pharmacol
352:
213–221.[Medline]
Barlow RS and White RE (1998) Hydrogen peroxide
relaxes porcine coronary arteries by stimulating BKCa channel activity.
Am J Physiol 275:
H1283–H1289.
Bauersachs J, Hecker M, and Busse R (1994) Display of
the characteristics of endothelium-derived hyperpolarizing factor by a
cytochrome P450-derived arachidonic acid metabolite in the coronary
microcirculation. Br J Pharmacol
113:
1548–1553.[Medline]
Busse R, Edwards G, Feletou M, Fleming I, Vanhoutte P, and Weston A
(2002) EDHF: bringing the concepts together. Trends
Pharmacol Sci 23:
374–380.[CrossRef][Medline]
Chataigneau T, Feletou M, Thollon C, Villeneuve N, Vilaine JP,
Duhault J, and Vanhoutte PM (1998) Cannabinoid CB1 receptor and
endothelium-dependent hyperpolarization in guinea-pig carotid, rat mesenteric
and porcine coronary arteries. Br J Pharmacol
123:
968–974.[CrossRef][Medline]
Christman BW, Robbins JM, Gaine S, Loyd JD, Rubin LJ, Price P, and
Barst BJ (1998) Oxidant stress correlates with impairment of
tissue oxygenation in patients with pulmonary hypertension. Am J
Respir Crit Care Med 157:
A593.
Cowan CL and Cohen RA (1991) Two mechanisms mediate
relaxation by bradykinin of pig coronary artery: NO-dependent and -independent
responses. Am J Physiol
261:
H830–H835.
Cowan CL and Cohen RA (1992) Different mechanisms of
relaxation of pig coronary artery to bradykinin and cromakalim are
distinguished by potassium channel blockers. J Pharmacol Exp
Ther 260:
248–253.
Fleming I, Michaelis UR, Bredenkotter D, Fisslthaler B, Dehghani F,
Brandes RP, and Busse R (2001) Endothelium-derived
hyperpolarizing factor synthase (Cytochrome P450 2C9) is a functionally
significant source of reactive oxygen species in coronary arteries.
Circ Res 88:
44–51.
Fulton D, McGiff JC, Wolin MS, Kaminski P, and Quilley J
(1997) Evidence against a cytochrome P450-derived reactive oxygen
species as the mediator of the nitric oxide-independent vasodilator effect of
bradykinin in the perfused heart of the rat. J Pharmacol Exp
Ther 280:
702–709.
Grainger J and Boachie-Ansah G (2001)
Anandamide-induced relaxation of sheep coronary arteries: the role of the
vascular endothelium, arachidonic acid metabolites and potassium channels.
Br J Pharmacol 134:
1003–1012.[CrossRef][Medline]
Hamill OP, Marty A, Neher E, Sakmann B, and Sigworth FJ
(1981) Improved patch-clamp techniques for high-resolution
current recording from cells and cell-free membrane patches.
Pflugers Arch 391:
85–100.[CrossRef][Medline]
Harris D, McCulloch AI, Kendall DA, and Randall MD
(2002) Characterization of vasorelaxant responses to anandamide
in the rat mesenteric arterial bed. J Physiol
539:
893–902.
Hayabuchi Y, Nakaya Y, Matsuoka S, and Kuroda Y
(1998a) Endothelium-derived hyperpolarizing factor activates
Ca2+-activated K+ channels in porcine coronary artery smooth muscle cells.
J Cardiovasc Pharmacol
32:
642–649.[CrossRef][Medline]
Hayabuchi Y, Nakaya Y, Matsuoka S, and Kuroda Y
(1998b) Hydrogen peroxide-induced vascular relaxation in porcine
coronary arteries is mediated by Ca2+-activated K+ channels. Heart
Vessels 13:
9–17.[Medline]
Hecker M, Bara AT, Bauersachs J, and Busse R (1994)
Characterization of endothelium-derived hyperpolarizing factor as a cytochrome
P450-derived arachidonic acid metabolite in mammals. J
Physiol 481 (Pt 2):
407–414.
Janssen LJ (2001) Isoprostanes: an overview and
putative roles in pulmonary pathophysiology. Am J Physiol Lung Cell
Mol Physiol 280:
L1067–L1082.
Janssen LJ (2002) Are endothelium-derived
hyperpolarizing and contracting factors isoprostanes? Trends
Pharmacol Sci 23:
59–62.[CrossRef][Medline]
Janssen LJ, Premji M, Netherton S, Catalli A, Cox G, Keshavjee S,
and Crankshaw DJ (2000) Excitatory and inhibitory actions of
isoprostanes in human and canine airway smooth muscle. J Pharmacol
Exp Ther 295:
506–511.
Janssen LJ, Premji M, Netherton S, Coruzzi J, Lu-Chao H, and Cox PG
(2001) Vasoconstrictor actions of isoprostanes via tyrosine
kinase and Rho kinase in human and canine pulmonary vascular smooth muscles.
Br J Pharmacol 132:
127–134.[CrossRef][Medline]
Janssen LJ and Tazzeo T (2002) Involvement of TP and
EP3 receptors in vasoconstrictor responses to isoprostanes in pulmonary
vasculature. J Pharmacol Exp Ther
301:
1060–1066.
Jourdan KB, Evans TW, Curzen NP, and Mitchell JA
(1997) Evidence for a dilator function of 8-iso-prostaglandin F2
alpha in rat pulmonary artery. Br J Pharmacol
120:
1280–1285.[CrossRef][Medline]
Kromer BM and Tippins JR (1999) The vasoconstrictor
effect of 8-epi prostaglandin F2alpha in the hypoxic rat heart. Br
J Pharmacol 126:
1171–1174.[CrossRef][Medline]
Matoba T, Shimokawa H, Nakashima M, Hirakawa Y, Mukai Y, Hirano K,
Kanaide H, and Takeshita A (2000) Hydrogen peroxide is an
endothelium-derived hyperpolarizing factor in mice. J Clin
Investig 106:
1521–1530.[Medline]
McGuire JJ, Ding H, and Triggle CR (2001)
Endothelium-derived relaxing factors: a focus on endothelium-derived
hyperpolarizing factor(s). Can J Physiol Pharmacol
79:
443–470.[CrossRef][Medline]
Mobert J and Becker BF (1998) Cyclooxygenase
inhibition aggravates ischemia-reperfusion injury in the perfused guinea pig
heart: involvement of isoprostanes. J Am Coll Cardiol
31:
1687–1694.
Mobert J, Becker BF, Zahler S, and Gerlach E (1997)
Hemodynamic effects of isoprostanes (8-iso-prostaglandin F2alpha and E2) in
isolated guinea pig hearts. J Cardiovasc Pharmacol
29:
789–794.[CrossRef][Medline]
Oguogho A, Mehrabi M, and Sinzinger H (1999) Increased
plasma, serum and urinary 8-epi-prostaglandin F2 alpha in heterozygous
hypercholesterolemia. Wien Klin Wochenschr
111:
113–118.[Medline]
Pomposiello S, Rhaleb NE, Alva M, and Carretero OA
(1999) Reactive oxygen species: role in the relaxation induced by
bradykinin or arachidonic acid via EDHF in isolated porcine coronary arteries.
J Cardiovasc Pharmacol
34:
567–574.[CrossRef][Medline]
Pratico D, Iuliano L, Mauriello A, Spagnoli L, Lawson JA, Rokach J,
Maclouf J, Violi F, and FitzGerald GA (1997) Localization of
distinct F2-isoprostanes in human atherosclerotic lesions. J Clin
Investig 100:
2028–2034.[Medline]
Rodriguez-Martinez MA, Garcia-Cohen EC, Baena AB, Gonzalez R,
Salaices M, and Marin J (1998) Contractile responses elicited by
hydrogen peroxide in aorta from normotensive and hypertensive rats.
Endothelial modulation and mechanism involved. Br J
Pharmacol 125:
1329–1335.[CrossRef][Medline]
Takahashi K, Nammour TM, Fukunaga M, Ebert J, Morrow JD, Roberts
LJ, Hoover RL, and Badr KF (1992) Glomerular actions of a free
radical-generated novel prostaglandin, 8-epi-prostaglandin F2à, in the
rat: evidence for interaction with thromboxane A2 receptors. J Clin
Investig 90:
136–141.
Thannickal VJ and Fanburg BL (2000) Reactive oxygen
species in cell signaling. Am J Physiol Lung Cell Mol
Physiol 279:
L1005–L1028.
Watkins MT, Patton GM, Soler HM, Albadawi H, Humphries DE, Evans
JE, and Kadowaki H (1999) Synthesis of 8-epi-prostaglandin
F2alpha by human endothelial cells: role of prostaglandin H2 synthase.
Biochem J 344 (Pt 3):
747–754.
Weintraub NL, Stephenson AH, Sprague RS, McMurdo L, and Lonigro AJ
(1995) Relationship of arachidonic acid release to porcine
coronary artery relaxation. Hypertension
26:
684–690.
White R and Hiley CR (1997) A comparison of
EDHF-mediated and anandamide-induced relaxations in the rat isolated
mesenteric artery. Br J Pharmacol
122:
1573–1584.[CrossRef][Medline]
Yang ZH, von Segesser L, Bauer E, Stulz P, Turina M, and Luscher TF
(1991) Different activation of the endothelial L-arginine and
cyclooxygenase pathway in the human internal mammary artery and saphenous
vein. Circ Res 68:
52–60.
Zygmunt PM, Hogestatt ED, Waldeck K, Edwards G, Kirkup AJ, and
Weston AH (1997) Studies on the effects of anandamide in rat
hepatic artery. Br J Pharmacology
122:
1679–1686.[CrossRef][Medline]
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; n = 14),
30 mM (
; n = 7), or 60 mM KCl (
; n = 4). *,
p < 0.05; **, p < 0.01
