© 1996 American Heart Association, Inc.
Articles |
Identification of Epoxyeicosatrienoic Acids as Endothelium-Derived Hyperpolarizing Factors
From the Departments of Pharmacology and Toxicology and Physiology and the Cardiovascular Research Center, Medical College of Wisconsin, 8701 Watertown Plank Rd, Milwaukee, WI 53226.
Correspondence to William B. Campbell, PhD, Department of Pharmacology and Toxicology, Medical College of Wisconsin, 8701 Watertown Plank Rd, Milwaukee, WI 53226.
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Abstract |
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Abstract Endothelial cells release several compounds, including prostacyclin, NO, and endothelium-derived hyperpolarizing factor (EDHF), that mediate the vascular effects of vasoactive hormones. The identity of EDHF remains unknown. Since arachidonic acid causes endothelium-dependent relaxations of coronary arteries through its metabolism to epoxyeicosatrienoic acids (EETs) by cytochrome P450, we wondered if the EETs represent EDHFs. Precontracted bovine coronary arteries relaxed in an endothelium-dependent manner to methacholine. The cytochrome P450 inhibitors, SKF 525A and miconazole, significantly attenuated these relaxations. They were also inhibited by tetraethylammonium (TEA), an inhibitor of Ca2+-activated K+ channels, and by high [K+]o (20 mmol/L). Methacholine also caused hyperpolarization of coronary smooth muscle (-27±3.9 versus -40±5.1 mV), which was completely blocked by SKF 525A and miconazole. In vessels prelabeled with [3H]arachidonic acid, methacholine stimulated the release of 6-ketoprostaglandin F1
, 12-HETE, and the EETs.
Arachidonic acid relaxed precontracted coronary
arteries, which were also blocked by TEA, charybdotoxin, another
Ca2+-activated K+ channel
inhibitor, and high [K+]o.
14,15-EET, 11,12-EET, 8,9-EET, and 5,6-EET relaxed precontracted
coronary vessels (EC50, 1x10-6
mol/L). The four regioisomers were equally active. TEA, charybdotoxin,
and high [K+]o attenuated the EET
relaxations. 11,12-EET hyperpolarized coronary smooth muscle
cells from -37±0.2 to -59±0.3 mV. In the
cell-attached mode of
patch clamp, both 14,15-EET and 11,12-EET increased the open-state
probability of a Ca2+-activated K+
channel in coronary smooth muscle cells. This effect was
blocked by TEA and charybdotoxin. These data support the hypothesis
that the EETs are EDHFs.
Key Words: cytochrome P450 • arachidonic acid • K+ channels • smooth muscle • membrane potential
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Introduction |
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TopAbstractIntroductionMaterials and Methods Results Discussion References |
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Endothelial cells release a variety of compounds that regulate vascular tone, including prostacyclin, EDRF, and endothelin.1 2 3 It is now recognized that EDRF is NO or a compound that releases NO.4 Feletou and Vanhoutte5 showed that acetylcholine causes endothelium-dependent hyperpolarization of coronary vascular smooth muscle that results in relaxation. This effect is mediated by a soluble transferrable factor.5 6 7 8 9 10 This substance has been called EDHF. It is distinct and may be distinguished from EDRF or NO in several ways. The release of EDHF is mediated by M1 muscarinic receptors, whereas the release of NO is mediated by M2 receptors.8 11 EDHF is inhibited by ouabain, but NO is not.5 Relaxation by EDHF is more prominent in arteries with smaller diameters, unlike NO, which is greater in larger vessels.12 13 Hemoglobin, gossypol, and arginine analogues, such as nitro-L-arginine, inhibit NO-mediated relaxations but do not alter EDHF.9 14 15 Acetylcholine-induced hyperpolarization appears to be mediated by the opening of K+ channels, since its effect is mimicked by cromakalim, a K+ channel opener, and inhibited by increasing [K+]o.15 16 In coronary and mesenteric arteries and aorta, the relaxation and hyperpolarization are blocked by TEA but not by glibenclamide.14 17 18 These data suggest that EDHF acts on the Ca2+-dependent K+ channels inhibited by TEA and not the ATP-sensitive K+ channels opened by cromakalim and inhibited by glibenclamide. Although most agree that NO and EDHF are distinct entities, several articles indicate that NO also hyperpolarizes vascular smooth muscle and stimulates K+ channel activity.19 20 21 22 23 These reports differ in the type of K+ channel affected by NO: two reports indicate inhibition by glibenclamide,19 22 whereas two other reports indicate inhibition by charybdotoxin.20 21
We have recently reported that arachidonic acid causes endothelium-dependent relaxation of bovine coronary arteries.24 A portion of the relaxation was inhibited by the cyclooxygenase inhibitor indomethacin, and the remainder was inhibited by an inhibitor of cytochrome P450. Coronary endothelial cells and coronary arteries metabolize arachidonic acid via the cyclooxygenase, lipoxygenase, and cytochrome P450 pathways.24 25 26 27 Prostacyclin is the major cyclooxygenase metabolite, whereas 14,15-EET, 11,12-EET, 8,9-EET, and 5,6-EET are the cytochrome P450 metabolites. Since both prostacyclin and the EETs relax coronary arteries,24 26 27 they were proposed to mediate the endothelium-dependent relaxations induced by arachidonic acid. Since EETs are synthesized and released by the endothelium and relax arteries, we examined the possibility that they represent EDHFs.
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Materials and Methods |
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Vascular Studies
Bovine hearts (2 to 4 kg) were obtained from the local slaughterhouse. The left anterior descending coronary artery was dissected, cleaned of adhering fat and connective tissue, and placed in a Krebs' bicarbonate solution containing the following (mmol/L): NaCl 119, KCl 4.8, NaHCO3 24, KH2PO4 1.2, MgSO4 1.2, glucose 11, EDTA 0.02, and CaCl2 3.2.24 The vessels were cut into rings, and care was taken not to damage the endothelium. In some vessels, the endothelium was deliberately removed by gently rubbing the lumen with forceps. The rings were suspended on a pair of stainless steel hooks in a 15-mL water-jacketed organ chamber. One hook was anchored to a steel rod, and the other was attached to a force transducer (model FT-03C, Grass Instruments). Tension was recorded on a Grass model 7D polygraph. The organ chamber was filled with Krebs' bicarbonate solution, which was bubbled with 95% O2/5% CO2 and maintained at 37°C. Vessels were equilibrated for 1.5 hours under 2 g of resting tension. KCl (40 mmol/L) was added until reproducible contractions were obtained. The thromboxane mimetic U46619 (1x10-8 to 2x10-8 mol/L) was then administered to increase basal tone to
50% of maximum. Cumulative
additions of methacholine (10-9 to 10-6
mol/L), EETs (10-9 to 10-5 mol/L), or
arachidonic acid (10-9 to
10-5 mol/L) were made. To establish the mechanisms of
relaxation, some vessels were treated with SKF 525A (10-5
mol/L), miconazole (10-5 mol/L), TEA (0.3 or 1 mmol/L),
charybdotoxin (2x10-9 or 50x10-9
mol/L),
glibenclamide (2x10-6 mol/L), or vehicle, and the
concentration-response curve to an agonist was determined. Similar
experiments were performed with [K+] in the
Krebs'
solution reduced to 0 mmol/L or increased to 20 mmol/L. Equivalent
changes in [Na+] were made to maintain isotonicity.
Results were expressed as percent relaxation, with 100% relaxation
representing the basal pre-U46619 tension.
NOS Activity
Bovine coronary arteries were isolated and
homogenized in a HEPES buffer containing 11 mmol/L HEPES,
0.35 mol/L sucrose, 0.1 mmol/L EDTA, 1 mmol/L dithiothreitol, 10
µg/mL leupeptin, 2 µg/mL aprotinin, 10 µg/mL SBTI, 10 µg/mL
PMSF, 1% NP-40, and 10% glycerol, pH 7.4.28 Bovine
coronary artery endothelial cells were prepared
as previously described.25 Confluent monolayers were
washed in HEPES buffer, scraped into fresh buffer, and sonicated. The
conversion of [3H]arginine to
[3H]citrulline was used to assess NOS
activity.28 The reaction volume was 0.1 mL in a Tris
incubation buffer containing 50 mmol/L Tris-HCl (pH 7.5), 0.1 mmol/L
EDTA, 0.1 mmol/L EGTA, 0.1% mercaptoethanol, 100 µmol/L leupeptin, 1
mmol/L PMSF, 10 µg/mL SBTI, 2 µg/mL aprotinin, 10 nmol/L
calmodulin, 1 mmol/L NADPH, 3 µmol/L tetrahydrobiopterin,
10 µmol/L L-arginine, 0.2 µCi, 66 Ci/mmol
[3H]L-arginine (New England Nuclear), 2.5
mmol/L calcium chloride, and 100 µg protein.
Nitro-L-arginine (3x10-5 mol/L), SKF 525A
(10-5 mol/L), miconazole (10-5 mol/L), or
vehicle was added. All samples were incubated for 15 minutes at 37°C
in a shaking water bath, and the reaction was stopped by the addition
of 1 mL of ice-cold stop buffer containing 20 mmol/L HEPES (pH
5.5), 2 mmol/L EDTA, and 2 mmol/L EGTA. The
[3H]citrulline was separated from the
[3H]arginine by passing the sample over a Dowex AG50W-X8
(200 to 400 mesh) column (Na+ form) and measured by liquid
scintillation spectrometry. NOS activity was expressed as femtomoles of
citrulline per milligram protein. Protein was determined by the method
of Lowry et al.29
Perfused Coronary Artery
Coronary arteries were isolated as
described above,
cannulated on both ends, and placed in a tissue bath containing Krebs'
buffer at 37°C. The vessel was then perfused with Krebs' buffer at 3
mL/min in a nonrecirculating system. Perfusion pressure was maintained
at 60 mm Hg by an outflow restrictor and measured continuously by a
pressure transducer. The vessel was treated every 5 minutes over a
period of 30 minutes with KCl (20 mmol/L). After 1 hour,
[3H]arachidonic acid (5 µCi) was added
to the perfusate, and the perfusate was recirculated
through the vessel for 45 minutes. To remove unesterified
[3H]arachidonic acid, the vessel was then
perfused in a nonrecirculating system with fresh Krebs' buffer
containing fatty acid–free bovine serum albumin (2 mg/mL).
Once the amount of radioactivity in the perfusate stabilized,
the perfusate was collected for 10 minutes (control). The
vessel was then perfused with buffer containing methacholine
(10-5 mol/L), and the perfusate was collected for
10 minutes.
HPLC and Mass Spectrometry
Perfusate samples were acidified
to pH 3 with glacial
acetic acid and treated with ethanol to a final concentration of 15%.
The lipids were then extracted from the perfusates using
octadecylsilyl extraction columns (Analytichem) as previously
described.24 25 30 31 The
extracts were dried under
N2, redissolved in acetonitrile, and
chromatographed on a Nucleosil C-18 reverse-phase column (5
µm, 4.5x250 mm,
Phenomenex).24 25 30 31
Solvent A was
distilled water, and solvent B contained acetonitrile/glacial acetic
acid (999:1). A linear gradient from 50% solvent B in solvent
A to 100% solvent B was used for 40 minutes at a flow rate of 1
mL/min. The column effluent was collected in 0.2-mL fractions, and an
aliquot was analyzed for radioactivity by liquid scintillation
spectrometry. Known standards were analyzed in the same manner.
The fractions containing radiolabeled material comigrating with
authentic EETs were collected, pooled, and dried under N2.
They were then dissolved in acetonitrile containing pentafluorobenzyl
bromide (Pierce Chemical) and N,N-diisopropylethanolamine
(10:1:5 [vol/vol]) and incubated for 20 minutes at
room
temperature.31 The solvents were removed under
N2, and the residue was filtered through a column of
silicic acid using methylene chloride. The EET-PFB esters were
analyzed on a Hewlett-Packard model 5989A GC/MS in the
negative-ion chemical ionization mode.31 The GC used a
15-m DB-5 (0.25 µm) capillary column (J & W Scientific) with a linear
gradient from 190°C to 340°C at 8°C/min. Methane was used as the
reagent gas.
Membrane Potential
Bovine coronary arteries were isolated,
cannulated, and
perfused with Krebs' solution in the direction of flow in vivo at
37°C from a pressurized reservoir.10 32 The
pressure of
the vessel was maintained at 60 mm Hg by an outflow resistor. Smooth
muscle cells of the perfused vessel were impaled with microelectrodes
for the measurement of intracellular membrane potential as previously
described.10 32 These studies used a glass
microelectrode
filled with 3 mol/L KCl with a tip resistance of 50 to 80 M
and tip
potential of <3 mV. Electrode polarization was eliminated by Ag/AgCl
half cells. The main criteria for a successful impalement include a
sharp drop in voltage from baseline on entry of the microelectrode into
the cell, a membrane potential of <-25 mV, and a sharp return to zero
of the voltage upon exit from the cell. Methacholine (10-6
mol/L) was added to the perfusate in the presence and absence
of SKF 525A or miconazole (10-5 mol/L). Similar studies
were performed in which 11,12-EET (100 nmol/L) was added to the
perfusate, and changes in membrane potential were measured.
Patch-Clamp Methods
Coronary arterial smooth muscle cells
were
prepared as previously described33 and placed in a 1-mL
perfusion chamber on an inverted microscope stage. The bathing solution
consisted of (mmol/L) KCl 145, CaCl2 1.8, MgCl2
1.1, HEPES 5, and EGTA 10 at pH 7.4, and the pipette solution contained
(mmol/L) KCl 145, CaCl2 1.8, MgCl2 1.1, and
HEPES 5, at pH 7.4. By using a hydraulic manipulator, the tip of a
heat-polished borosilicate glass pipette was positioned on the
membrane of a cell. A high-resistance seal (1 to 10 G) was
formed between the pipette and the cell membrane by applying a slight
suction. After the cell-attached or inside-out configuration
was formed, the bath containing the cells or patches was superfused
with the control solution by gravity flow from a reservoir at 5 mL/min.
Cells were superfused with 14,15-EET, 11,12-EET, or
arachidonic acid in various concentrations.
Inside-out patches were superfused with miconazole
(10-5 mol/L) or SKF 525A (10-5 mol/L).
Single-channel currents were recorded using a List EPC-7
patch-clamp amplifier.33 Data were
low-pass–filtered at 1 kHz, digitized at a sampling rate of 3
kHz, analyzed by pClamp software (version 5.5), and stored on
an IBM-compatible 386 computer for off-line analysis. Ion
channels were identified by determining the current-voltage
relationship, voltage-dependent activation, and Ca2+
sensitivity of the channel in inside-out membrane patches. The
current-voltage relationship was determined by varying the patch
potential between -60 and +60 mV. A large-conductance (240-pS)
single K+ channel current, which had an open-state
probability that increased with depolarization and increased with the
concentration of Ca2+, was observed. It was blocked
by TEA (1 mmol/L) and charybdotoxin (2 or 50 nmol/L). This channel,
therefore, possesses the characteristics of a large-conductance
Ca2+-activated K+ channel.
Cyclic Nucleotide Assays
Bovine coronary artery rings were
incubated in HEPES
buffer (mmol/L: HEPES 10, NaCl 150, KCl 5, CaCl2 1.8,
MgCl2 1, and glucose 5.5, at pH 7.4) for 5 minutes at
37°C in the presence of
isobutylmethylxanthine (0.1 mmol/L) before the
addition of the EETs (10-5 mol/L), sodium nitroprusside
(10-7 mol/L), isoproterenol (10-6 mol/L), or
vehicle.34 35 After a 5-minute incubation, the tissue
was
removed and immersed in liquid N2. The frozen tissue was
placed in 7% trichloroacetic acid in water and frozen in a dry
ice/methanol bath. The samples were stored at -80°C until assayed by
radioimmunoassay. Before assay, the tissues were
homogenized with a Tissuemizer (Janke-Knuckel, GMBH and Co)
and centrifuged, and the supernatant was removed. The
supernatant was extracted with water-saturated ether three times,
dried under N2, and resuspended in assay buffer.
cAMP and cGMP were measured by radioimmunoassay as previously
described.34 35
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Bovine coronary vessels that were precontracted with U46619 produced a concentration-related relaxation to methacholine (Fig 1A
). No relaxations occurred to methacholine in
vessels without an intact endothelium. Pretreatment
with miconazole (10-5 mol/L) or SKF 525A
(10-5 mol/L), inhibitors of cytochrome
P450, did not alter basal tension or contractions to
U46619. However, they blocked the relaxations to methacholine. The
relaxations were also blocked by TEA, an inhibitor of
Ca2+-activated K+ channels, and by high
[K+]o (20 mmol/L) (Fig
1A). Membrane
potential was measured in smooth muscle cells of coronary
arteries with an intact endothelium under similar
conditions (Fig 1B). The resting membrane potential was
-56±3.4 mV
and decreased to -27±3.9 mV by pretreatment with U46619. In these
pretreated vessels, methacholine increased the membrane potential to
-40±5.1 mV (P<.01). The methacholine-induced
hyperpolarization was blocked by miconazole as well
as SKF 525A. Thus, methacholine produces
endothelium-dependent relaxation and
hyperpolarization of the vascular muscle, which
apparently are mediated by a metabolite(s) of cytochrome
P450.
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Coronary artery homogenates and bovine
coronary endothelial cell lysates had a basal
NOS activity of 27±2 and 702±13 fmol citrulline per milligram
protein, respectively (Table 1). Miconazole and SKF 525A
were without effect on NOS activity. For comparison,
nitro-L-arginine inhibited NOS activity by 40% and
90% in the artery homogenates and cell lysates,
respectively. These agents were also tested on K+ channel
activity in inside-out patches of coronary smooth muscle
cells using patch clamp (Table 1). Neither miconazole nor SKF
525A
changed the open-state probability of K+
channels. However, charybdotoxin, an inhibitor of
Ca2+activated K+ channels,
significantly inhibited K+ channel activity. Thus, the
inhibitory effects of these agents on
methacholine-induced relaxations and
hyperpolarization are not due to inhibition of NO
synthesis or a direct action on K+ channels.
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In perfused coronary arteries in which the cellular lipids were
prelabeled with [3H]arachidonic acid, the
basal release of [3H]arachidonic acid and
its 3H metabolites was very low (Fig 2A).
Treatment with methacholine (10-5 mol/L) greatly increased
the release of 3H metabolites (Fig 2B).
Specifically,
methacholine stimulated the release of several
arachidonic acid metabolites, including prostacyclin
(measured as its stable metabolite 6-ketoprostaglandin
F1), 12-HETE, and the EETs. The fractions
containing the EETs were collected, derivitized to PFB esters, and
analyzed by GC/MS. The derivitized sample comigrated on GC with
authentic EET-PFB standards, with both eluting at 16.1 minutes. They
also gave similar mass spectra. The major ions in the mass spectrum
were 319 (loss of PFB) and 301 (loss of PFB and H2O) and
indicated a molecular weight of 320 (Fig 2C). These findings
confirm
the release of EETs from the perfused vessel with methacholine. The
synthesis of the EETs was shown previously to be inhibited by SKF 525A
and miconazole.24 36
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Like methacholine, arachidonic acid relaxes
coronary vessels in an
endothelium-dependent manner, and these relaxations
are inhibited 50% by SKF 525A.24 The relaxations to
arachidonic acid are also inhibited by pretreatment
with TEA (Fig 3B), charybdotoxin (Fig 3B), and
increasing [K+]o (20 mmol/L) (Fig
3A). The
cytochrome P450 metabolites, 14,15-EET, 11,12-EET, 8,9-EET,
and 5,6-EET, caused a concentration-related relaxation of
precontracted coronary arteries (Fig 4A). The
four regioisomers were equipotent, with a threshold relaxation
occurring at 10-8 mol/L. This effect of the EETs
occurred in the presence and absence of the endothelium
(control: ED50, 4.3x10-5 mol/L;
denuded: ED50, 4.8x10-5 mol/L;
P=NS). Additionally, 11,12-EET (100 nmol/L) increased the
membrane potential from -37±0.2 to -59±0.3 mV
(n=8,
P<.001). Thus, EETs, like methacholine, relaxed
coronary arteries and hyperpolarized coronary smooth
muscle.
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The EET-induced relaxations were inhibited by pretreatment with TEA,
charybdotoxin, and increasing [K+]o but
not
by glibenclamide. 11,12-EET caused a concentration-related
relaxation (Fig 4B
). Eliminating
[K+]o
shifted the concentration-response curve to 11,12-EET to the left,
whereas increasing [K+]o to 20 mmol/L
blocked
the relaxations to EET. 5,6-EET–induced relaxations are shown in Fig
4C. Glibenclamide, an inhibitor of ATP-sensitive
K+ channels, had no significant effect on
5,6-EET–induced
relaxations. 8,9-EET also relaxed coronary arteries, and
pretreatment with TEA (0.3 and 1 mmol/L) shifted the
concentration-response curve to the right (Fig 5). A
similar result was observed with charybdotoxin (2 or 50 nmol/L). Using
the patch clamp technique in the cell-attached mode, a
high-conductance single-channel K+ current was
recorded from isolated coronary smooth muscle cells. The
current-voltage relationship of the K+ channel was
linear over a voltage range from -60 to +60 mV and had a
conductance
of 130 pS with physiological K+ in the
recording pipette and 240 pS with symmetrical K+.
The activity of this K+ channel was inhibited by TEA (1
mmol/L) and charybdotoxin (2 and 50 nmol/L) (Fig 6).
With TEA, the amplitude of the single K+ channel was
reduced from 10±0.2 to 2.07±0.01 pA (P<.001). The
open-state probability of the channel was significantly reduced by
charybdotoxin (P<.001) (Fig 6 and Table
1). Fig 7 illustrates the K+
channel activity under
control conditions and after treatment with 14,15-EET. 14,15-EET (1
nmol/L) increased K+ channel activity markedly. Data from
multiple cells indicate that 14,15-EET increased the number of
K+ channel openings and the probability of channel opening
in a concentration-related manner, with significant increases
(P<.05) occurring with 1 nmol/L 14,15-EET. Similar results
were obtained with 11,12-EET (data not shown). This K+
channel activity was inhibited by TEA (1 mmol/L). In contrast,
arachidonic acid failed to alter K+ channel
activity in concentrations between 10 nmol/L and 10 µmol/L (data not
shown). The effect of the EETs did not appear to be due to a change in
cyclic nucleotide production (Table 2). 5,6-EET increased the
intracellular accumulation of
cAMP slightly, whereas the other regioisomers were without effect.
11,12-EET, 8,9-EET, and 5,6-EET decreased the accumulation of cGMP
slightly. In contrast, isoproterenol significantly increased the
accumulation of cAMP, and sodium nitroprusside increased cGMP. When
coronary arteries were incubated with 14C-labeled
EETs, the only metabolites observed were their respective hydrolysis
products, the vic-dihydroxyeicosatrienoic
acids.24 This hydrolysis was only 10% of the added EET
over a 30-minute incubation. Thus, the EETs must act by a direct action
on the K+ channel and must not involve cyclic
nucleotide second messengers or the production of
secondary metabolites of the EETs.
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Discussion |
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TopAbstractIntroductionMaterials and Methods Results Discussion References |
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The endothelium has emerged as an important regulator of vascular tone.1 2 3 Several soluble mediators released by the endothelium are involved in these vascular effects. These mediators include prostacyclin, EDRF or NO, and EDHF. The activity of EDHF may be distinguished from NO in that EDHF activity is blocked by inhibitors of Ca2+-activated K+ channels, such as TEA or charybdotoxin, or by high [K+]o but is not blocked by arginine analogues that inhibit NOS or glibenclamide, an inhibitor of ATP-sensitive K+ channels.9 14 17 18 Relaxations mediated by EDRF are blocked by arginine analogues. In small coronary arteries, methacholine causes endothelium-dependent relaxations and endothelium-dependent hyperpolarization of smooth muscle cells.5 14 15 16 17 18 These relaxations are blocked by TEA and high [K+]o. Thus, it has been proposed that methacholine stimulates coronary endothelial cells to release EDHF, which acts on coronary smooth muscle cells to open K+ channels, hyperpolarize the cell membrane, inhibit voltage-dependent Ca2+ influx, and induce relaxation. We have recently reported that arachidonic acid causes endothelium-dependent relaxation of bovine coronary arteries.24 A portion of the relaxation is inhibited by a cyclooxygenase inhibitor, and the remainder is inhibited by an inhibitor of cytochrome P450. To identify the mediators of arachidonic acid–induced relaxations, we studied the metabolism of arachidonic acid by coronary endothelial cells and coronary arteries. They metabolize arachidonic acid via the cyclooxygenase, lipoxygenase, and cytochrome P450 pathways.24 25 Prostacyclin is the major cyclooxygenase metabolite, whereas 14,15-EET, 11,12-EET, 8,9-EET, and 5,6-EET are the major metabolites from cytochrome P450. Since both prostacyclin and the EETs relax coronary arteries,24 26 27 they appear to mediate the endothelium-dependent relaxations induced by arachidonic acid.
Since coronary endothelial cells contain cytochrome P450 activity37 and metabolize arachidonic acid to known cytochrome P450 products (the EETs) that relax coronary arteries,24 25 26 27 38 we hypothesized that the EETs may represent EDHFs. In support of this hypothesis, we found that methacholine-induced relaxation and hyperpolarization are blocked by inhibitors of cytochrome P450. The relaxations to methacholine are also blocked by TEA and high [K+]o. Methacholine stimulates the release of several arachidonic acid metabolites, including prostacyclin, 12-HETE, and the EETs. The identity of the material released by methacholine as EETs is indicated by its comigration with authentic EET standards on reverse-phase HPLC, comigration of the derivitized material with EET-PFB ester standards on GC, and a characteristic EET-PFB mass spectrum. In previous studies, the synthesis of the EETs was inhibited by SKF 525A and miconazole.24 36 Arachidonic acid also relaxes coronary arteries in an endothelium-dependent manner, and these relaxations are blocked by inhibitors of cytochrome P45024 as well as TEA, charybdotoxin, and high [K+]o. Along these lines, others have reported that quinacrine and metyrapone, inhibitors of phospholipase and cytochrome P450, respectively, reduce acetylcholine-induced relaxation39 and that indomethacin enhances the hyperpolarization produced by acetylcholine.5 Similarly, the relaxations to bradykinin are inhibited by quinacrine and inhibitors of cytochrome P450 as well as K+ channel blockers.38 These studies also link EDHF to arachidonic acid metabolism.
These studies rely in part on inhibitors of cytochrome P450 to assess the contribution of the EETs to the relaxations and hyperpolarizations stimulated by methacholine and arachidonic acid.24 We were concerned that these inhibitors might have other actions that could contribute to the observed effects. As a result, we tested their effect on the NOS activity of coronary artery homogenates and the K+ channel activity of coronary smooth muscle. Both miconazole and SKF 525A were without effect on NOS activity in the concentrations used in these studies. Since both drugs were equally effective in blocking methacholine-induced relaxations and hyperpolarization in concentrations that did not alter NOS activity, inhibition of NOS could not account for these observed effects. Neither drug affected the activity of the Ca2+-activated K+ channel in inside-out patches of coronary arterial smooth muscle cells. These findings eliminate the possibility that these agents are blocking relaxations by a direct effect on K+ channels.
We found that the four regioisomeric EETs relax coronary
arteries in a concentration-related manner. Significant relaxations
to the EETs occur with nanomolar concentrations. As with methacholine
and arachidonic acid, the relaxations to the EETs are
blocked by TEA, charybdotoxin, and high
[K+]o. In contrast, the relaxations to
the
EETs are not endothelium dependent. Similar effects to
the EETs have been reported in canine and porcine coronary
arteries; however, micromolar concentrations of the EETs are required
for relaxation in these studies.26 38 This difference
in
EET potency may be due to the use of large epicardial vessels in the
previous studies. The EETs are more potent in relaxing smaller
coronary arteries than larger ones,24 27 as others
have reported for EDHF.12 13 The relaxation to the
EET is
associated with an increase in membrane potential and the opening of
Ca2+-activated K+ channels. The
threshold concentration of EET for increases in K+ channel
activity is 1 nmol/L. The effects of the EETs on K+
channel activity are blocked by TEA. Thus, EETs, like EDHF, seem to act
on Ca2+-dependent K+ channels to relax
coronary arteries. The exact mechanism by which the EETs open
K+ channels is not known. However, unlike NO and
prostacyclin, their effects are not associated with an increase in
cyclic nucleotides.
Charybdotoxin, a reversible inhibitor of the
Ca2+-activated K+
channel,40 failed to completely block the relaxations to
8,9-EET at a concentration of 50 nmol/L. Instead, the toxin caused a
10-fold shift in the EET concentration-response curve to the right.
This result may be because higher concentrations of the EETs overcome
the charybdotoxin blockade or because this concentration of
charybdotoxin does not cause complete blockade of the channel (see Fig
6). Similar results have been reported with charybdotoxin on
ß-agonist–induced relaxation of the isolated trachea and
inhibition of myogenic tone in rat mesenteric
arteries.41 42 For example, charybdotoxin (60 nmol/L)
caused a 4.8-fold shift in the isoproterenol concentration-response
curve in isolated trachea.
In summary, these findings indicate that EETs have many of the known properties of EDHF: they are (1) produced by the endothelium, (2) released by methacholine, (3) relax arteries, (4) hyperpolarize vascular smooth muscle, and (5) open Ca2+-activated K+ channels, and (6) their effects are blocked by TEA, charybdotoxin, and high [K+]o but not glibenclamide.9 14 17 18 24 Thus, these data suggest that EETs represent an EDHF and that these cytochrome P450 metabolites of arachidonic acid may mediate the endothelium-dependent relaxations to methacholine in small coronary arteries.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This study was supported by grants from the National Heart, Lung, and Blood Institute (HL-51055 and HL-33833) and by a grant from the Veterans Administration. The authors thank Joe James for his technical assistance, Dr Kasem Nithipatikom for his help with the GC/MS analysis, and Gretchen Barg for her secretarial assistance. They also thank Drs J.R. Falck, Sandra Pfister, and William Edgemond for their helpful discussions.
Received July 13, 1995; accepted November 8, 1995.
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References |
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D. Ai, Y. Fu, D. Guo, H. Tanaka, N. Wang, C. Tang, B. D. Hammock, J. Y.-J. Shyy, and Y. Zhu Angiotensin II up-regulates soluble epoxide hydrolase in vascular endothelium in vitro and in vivo PNAS, May 22, 2007; 104(21): 9018 - 9023. [Abstract] [Full Text] [PDF]
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R. H. P. Hilgers and R. C. Webb Reduced expression of SKCa and IKCa channel proteins in rat small mesenteric arteries during angiotensin II-induced hypertension Am J Physiol Heart Circ Physiol, May 1, 2007; 292(5): H2275 - H2284. [Abstract] [Full Text] [PDF]
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X.-Y. Yi, K. M. Gauthier, L. Cui, K. Nithipatikom, J. R. Falck, and W. B. Campbell Metabolism of adrenic acid to vasodilatory 1{alpha},1beta-dihomo-epoxyeicosatrienoic acids by bovine coronary arteries Am J Physiol Heart Circ Physiol, May 1, 2007; 292(5): H2265 - H2274. [Abstract] [Full Text] [PDF]
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M. Focardi, G. M. Dick, A. Picchi, C. Zhang, and W. M. Chilian Restoration of coronary endothelial function in obese Zucker rats by a low-carbohydrate diet Am J Physiol Heart Circ Physiol, May 1, 2007; 292(5): H2093 - H2099. [Abstract] [Full Text] [PDF]
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 J. Chen, J.-K. Chen, J. R. Falck, S. Anjaiah, J. H. Capdevila, and R. C. Harris Mitogenic Activity and Signaling Mechanism of 2-(14,15- Epoxyeicosatrienoyl)Glycerol, a Novel Cytochrome P450 Arachidonate Metabolite Mol. Cell. Biol., April 15, 2007; 27(8): 3023 - 3034. [Abstract] [Full Text] [PDF]
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 T. C. DeLozier, G. E. Kissling, S. J. Coulter, D. Dai, J. F. Foley, J. A. Bradbury, E. Murphy, C. Steenbergen, D. C. Zeldin, and J. A. Goldstein Detection of Human CYP2C8, CYP2C9, and CYP2J2 in Cardiovascular Tissues Drug Metab. Dispos., April 1, 2007; 35(4): 682 - 688. [Abstract] [Full Text] [PDF]
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A. A. Spector and A. W. Norris Action of epoxyeicosatrienoic acids on cellular function Am J Physiol Cell Physiol, March 1, 2007; 292(3): C996 - C1012. [Abstract] [Full Text] [PDF]
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W. B. Campbell and J. R. Falck Arachidonic Acid Metabolites as Endothelium-Derived Hyperpolarizing Factors Hypertension, March 1, 2007; 49(3): 590 - 596. [Abstract] [Full Text] [PDF]
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K. A. Hagedorn, C.-L. Cooke, J. R. Falck, B. F. Mitchell, and S. T. Davidge Regulation of Vascular Tone During Pregnancy: A Novel Role for the Pregnane X Receptor Hypertension, February 1, 2007; 49(2): 328 - 333. [Abstract] [Full Text] [PDF]
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P. K. Mehta and K. K. Griendling Angiotensin II cell signaling: physiological and pathological effects in the cardiovascular system Am J Physiol Cell Physiol, January 1, 2007; 292(1): C82 - C97. [Abstract] [Full Text] [PDF]
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S. A. Phillips, O. A. Hatoum, and D. D. Gutterman The mechanism of flow-induced dilation in human adipose arterioles involves hydrogen peroxide during CAD Am J Physiol Heart Circ Physiol, January 1, 2007; 292(1): H93 - H100. [Abstract] [Full Text] [PDF]
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A. Drouin, N. Thorin-Trescases, E. Hamel, J. R. Falck, and E. Thorin Endothelial nitric oxide synthase activation leads to dilatory H2O2 production in mouse cerebral arteries Cardiovasc Res, January 1, 2007; 73(1): 73 - 81. [Abstract] [Full Text] [PDF]
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D. Sacerdoti, M. Bolognesi, M. Di Pascoli, A. Gatta, J. C. McGiff, M. L. Schwartzman, and N. G. Abraham Rat mesenteric arterial dilator response to 11,12-epoxyeicosatrienoic acid is mediated by activating heme oxygenase Am J Physiol Heart Circ Physiol, October 1, 2006; 291(4): H1999 - H2002. [Abstract] [Full Text] [PDF]
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J. J. Olearczyk, M. B. Field, I.-H. Kim, C. Morisseau, B. D. Hammock, and J. D. Imig Substituted Adamantyl-Urea Inhibitors of the Soluble Epoxide Hydrolase Dilate Mesenteric Resistance Vessels J. Pharmacol. Exp. Ther., September 1, 2006; 318(3): 1307 - 1314. [Abstract] [Full Text] [PDF]
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I. Fleming Realizing Its Potential: The Intermediate Conductance Ca2+-Activated K+ Channel (KCa3.1) and the Regulation of Blood Pressure Circ. Res., September 1, 2006; 99(5): 462 - 464. [Full Text] [PDF]
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T. Lu, D. Ye, X. Wang, J. M. Seubert, J. P. Graves, J. A. Bradbury, D. C. Zeldin, and H.-C. Lee Cardiac and vascular KATP channels in rats are activated by endogenous epoxyeicosatrienoic acids through different mechanisms J. Physiol., September 1, 2006; 575(2): 627 - 644. [Abstract] [Full Text] [PDF]
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T. Yada, H. Shimokawa, O. Hiramatsu, Y. Haruna, Y. Morita, N. Kashihara, Y. Shinozaki, H. Mori, M. Goto, Y. Ogasawara, et al. Cardioprotective role of endogenous hydrogen peroxide during ischemia-reperfusion injury in canine coronary microcirculation in vivo Am J Physiol Heart Circ Physiol, September 1, 2006; 291(3): H1138 - H1146. [Abstract] [Full Text] [PDF]
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J. M. Seubert, C. J. Sinal, J. Graves, L. M. DeGraff, J. A. Bradbury, C. R. Lee, K. Goralski, M. A. Carey, A. Luria, J. W. Newman, et al. Role of Soluble Epoxide Hydrolase in Postischemic Recovery of Heart Contractile Function Circ. Res., August 18, 2006; 99(4): 442 - 450. [Abstract] [Full Text] [PDF]
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 S. Taddei, D. Versari, A. Cipriano, L. Ghiadoni, F. Galetta, F. Franzoni, A. Magagna, A. Virdis, and A. Salvetti Identification of a Cytochrome P450 2C9-Derived Endothelium-Derived Hyperpolarizing Factor in Essential Hypertensive Patients J. Am. Coll. Cardiol., August 1, 2006; 48(3): 508 - 515. [Abstract] [Full Text] [PDF]
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R. M. Bryan Jr., J. You, S. C. Phillips, J. J. Andresen, E. E. Lloyd, P. A. Rogers, S. E. Dryer, and S. P. Marrelli Evidence for two-pore domain potassium channels in rat cerebral arteries Am J Physiol Heart Circ Physiol, August 1, 2006; 291(2): H770 - H780. [Abstract] [Full Text] [PDF]
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D. J. Granville and R. A. Gottlieb Having a heart attack? Avoid the "HETE"! Am J Physiol Heart Circ Physiol, August 1, 2006; 291(2): H485 - H487. [Full Text] [PDF]
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A. Dhanasekaran, R. Al-Saghir, B. Lopez, D. Zhu, D. D. Gutterman, E. R. Jacobs, and M. Medhora Protective effects of epoxyeicosatrienoic acids on human endothelial cells from the pulmonary and coronary vasculature Am J Physiol Heart Circ Physiol, August 1, 2006; 291(2): H517 - H531. [Abstract] [Full Text] [PDF]
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E. M. Sokoya, A. R. Burns, C. T. Setiawan, H. A. Coleman, H. C. Parkington, and M. Tare Evidence for the involvement of myoendothelial gap junctions in EDHF-mediated relaxation in the rat middle cerebral artery Am J Physiol Heart Circ Physiol, July 1, 2006; 291(1): H385 - H393. [Abstract] [Full Text] [PDF]
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R. H. P. Hilgers, J. Todd Jr., and R. C. Webb Regional heterogeneity in acetylcholine-induced relaxation in rat vascular bed: role of calcium-activated K+ channels Am J Physiol Heart Circ Physiol, July 1, 2006; 291(1): H216 - H222. [Abstract] [Full Text] [PDF]
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M. A. Carroll, A. B. Doumad, J. Li, M. K. Cheng, J. R. Falck, and J. C. McGiff Adenosine2A receptor vasodilation of rat preglomerular microvessels is mediated by EETs that activate the cAMP/PKA pathway Am J Physiol Renal Physiol, July 1, 2006; 291(1): F155 - F161. [Abstract] [Full Text] [PDF]
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M. Feletou and P. M. Vanhoutte Endothelium-Derived Hyperpolarizing Factor: Where Are We Now? Arterioscler Thromb Vasc Biol, June 1, 2006; 26(6): 1215 - 1225. [Abstract] [Full Text] [PDF]
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 C. R. Lee, K. E. North, M. S. Bray, M. Fornage, J. M. Seubert, J. W. Newman, B. D. Hammock, D. J. Couper, G. Heiss, and D. C. Zeldin Genetic variation in soluble epoxide hydrolase (EPHX2) and risk of coronary heart disease: The Atherosclerosis Risk in Communities (ARIC) study Hum. Mol. Genet., May 15, 2006; 15(10): 1640 - 1649. [Abstract] [Full Text] [PDF]
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Z. Yu, V. Y. Ng, P. Su, M. M. Engler, M. B. Engler, Y. Huang, E. Lin, and D. L. Kroetz Induction of Renal Cytochrome P450 Arachidonic Acid Epoxygenase Activity by Dietary {gamma}-Linolenic Acid J. Pharmacol. Exp. Ther., May 1, 2006; 317(2): 732 - 738. [Abstract] [Full Text] [PDF]
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D. Ye, W. Zhou, T. Lu, S. G. Jagadeesh, J. R. Falck, and H.-C. Lee Mechanism of rat mesenteric arterial KATP channel activation by 14,15-epoxyeicosatrienoic acid Am J Physiol Heart Circ Physiol, April 1, 2006; 290(4): H1326 - H1336. [Abstract] [Full Text] [PDF]
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J. Bellien, R. Joannides, M. Iacob, P. Arnaud, and C. Thuillez Evidence for a basal release of a cytochrome-related endothelium-derived hyperpolarizing factor in the radial artery in humans Am J Physiol Heart Circ Physiol, April 1, 2006; 290(4): H1347 - H1352. [Abstract] [Full Text] [PDF]
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I. Fleming and R. Busse Endothelium-Derived Epoxyeicosatrienoic Acids and Vascular Function Hypertension, April 1, 2006; 47(4): 629 - 633. [Abstract] [Full Text] [PDF]
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B. T. Larsen, H. Miura, O. A. Hatoum, W. B. Campbell, B. D. Hammock, D. C. Zeldin, J. R. Falck, and D. D. Gutterman Epoxyeicosatrienoic and dihydroxyeicosatrienoic acids dilate human coronary arterioles via BKCa channels: implications for soluble epoxide hydrolase inhibition Am J Physiol Heart Circ Physiol, February 1, 2006; 290(2): H491 - H499. [Abstract] [Full Text] [PDF]
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N. Ben-Amor, P. C. Redondo, A. Bartegi, J. A. Pariente, G. M. Salido, and J. A. Rosado A role for 5,6-epoxyeicosatrienoic acid in calcium entry by de novo conformational coupling in human platelets J. Physiol., January 15, 2006; 570(2): 309 - 323. [Abstract] [Full Text] [PDF]
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 R. C. Koehler, D. Gebremedhin, and D. R. Harder Role of astrocytes in cerebrovascular regulation J Appl Physiol, January 1, 2006; 100(1): 307 - 317. [Abstract] [Full Text] [PDF]
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J. Andresen, N. I. Shafi, and R. M. Bryan Jr. Endothelial influences on cerebrovascular tone J Appl Physiol, January 1, 2006; 100(1): 318 - 327. [Abstract] [Full Text] [PDF]
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Y. Liu, A. H. Bubolz, Y. Shi, P. J. Newman, D. K. Newman, and D. D. Gutterman Peroxynitrite reduces the endothelium-derived hyperpolarizing factor component of coronary flow-mediated dilation in PECAM-1-knockout mice Am J Physiol Regulatory Integrative Comp Physiol, January 1, 2006; 290(1): R57 - R65. [Abstract] [Full Text] [PDF]
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X. Fang, S. Hu, B. Xu, G. D. Snyder, S. Harmon, J. Yao, Y. Liu, B. Sangras, J. R. Falck, N. L. Weintraub, et al. 14,15-Dihydroxyeicosatrienoic acid activates peroxisome proliferator-activated receptor-{alpha} Am J Physiol Heart Circ Physiol, January 1, 2006; 290(1): H55 - H63. [Abstract] [Full Text] [PDF]
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X. Tang, E. M. Edwards, B. B. Holmes, J. R. Falck, and W. B. Campbell Role of phospholipase C and diacylglyceride lipase pathway in arachidonic acid release and acetylcholine-induced vascular relaxation in rabbit aorta Am J Physiol Heart Circ Physiol, January 1, 2006; 290(1): H37 - H45. [Abstract] [Full Text] [PDF]
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W. B. Campbell, B. B. Holmes, J. R. Falck, J. H. Capdevila, and K. M. Gauthier Regulation of potassium channels in coronary smooth muscle by adenoviral expression of cytochrome P-450 epoxygenase Am J Physiol Heart Circ Physiol, January 1, 2006; 290(1): H64 - H71. [Abstract] [Full Text] [PDF]
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M. I. Kotlikoff EDHF Redux: EETs, TRPV4, and Ca2+ Sparks Circ. Res., December 9, 2005; 97(12): 1209 - 1210. [Full Text] [PDF]
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S. Earley, T. J. Heppner, M. T. Nelson, and J. E. Brayden TRPV4 Forms a Novel Ca2+ Signaling Complex With Ryanodine Receptors and BKCa Channels Circ. Res., December 9, 2005; 97(12): 1270 - 1279. [Abstract] [Full Text] [PDF]
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 U. R. Michaelis, B. Fisslthaler, E. Barbosa-Sicard, J. R. Falck, I. Fleming, and R. Busse Cytochrome P450 epoxygenases 2C8 and 2C9 are implicated in hypoxia-induced endothelial cell migration and angiogenesis J. Cell Sci., December 1, 2005; 118(23): 5489 - 5498. [Abstract] [Full Text] [PDF]
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D. X. Zhang, K. M. Gauthier, and W. B. Campbell Mechanisms of histamine-induced relaxation in bovine small adrenal cortical arteries Am J Physiol Endocrinol Metab, December 1, 2005; 289(6): E1058 - E1063. [Abstract] [Full Text] [PDF]
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Y. Liu, Y. Zhang, K. Schmelzer, T.-S. Lee, X. Fang, Y. Zhu, A. A. Spector, S. Gill, C. Morisseau, B. D. Hammock, et al. The antiinflammatory effect of laminar flow: The role of PPAR{gamma}, epoxyeicosatrienoic acids, and soluble epoxide hydrolase PNAS, November 15, 2005; 102(46): 16747 - 16752. [Abstract] [Full Text] [PDF]
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W. G. Schrage, B. W. Wilkins, V. L. Dean, J. P. Scott, N. K. Henry, M. E. Wylam, and M. J. Joyner Exercise hyperemia and vasoconstrictor responses in humans with cystic fibrosis J Appl Physiol, November 1, 2005; 99(5): 1866 - 1871. [Abstract] [Full Text] [PDF]
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H. Wang, J. L. Garvin, J. R. Falck, Y. Ren, S. S. Sankey, and O. A. Carretero Glomerular Cytochrome P-450 and Cyclooxygenase Metabolites Regulate Efferent Arteriole Resistance Hypertension, November 1, 2005; 46(5): 1175 - 1179. [Abstract] [Full Text] [PDF]
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J. Vriens, G. Owsianik, B. Fisslthaler, M. Suzuki, A. Janssens, T. Voets, C. Morisseau, B.D. Hammock, I. Fleming, R. Busse, et al. Modulation of the Ca2 Permeable Cation Channel TRPV4 by Cytochrome P450 Epoxygenases in Vascular Endothelium Circ. Res., October 28, 2005; 97(9): 908 - 915. [Abstract] [Full Text] [PDF]
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J. L. Losapio, R. S. Sprague, A. J. Lonigro, and A. H. Stephenson 5,6-EET-induced contraction of intralobar pulmonary arteries depends on the activation of Rho-kinase J Appl Physiol, October 1, 2005; 99(4): 1391 - 1396. [Abstract] [Full Text] [PDF]
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G. J. Gross, J. R. Falck, E. R. Gross, M. Isbell, J. Moore, and K. Nithipatikom Cytochrome P450 and arachidonic acid metabolites: Role in myocardial ischemia/reperfusion injury revisited Cardiovasc Res, October 1, 2005; 68(1): 18 - 25. [Abstract] [Full Text] [PDF]
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J. D. Imig Epoxide hydrolase and epoxygenase metabolites as therapeutic targets for renal diseases Am J Physiol Renal Physiol, September 1, 2005; 289(3): F496 - F503. [Abstract] [Full Text] [PDF]
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J. M. Seubert, F. Xu, J. P. Graves, J. B. Collins, S. O. Sieber, R. S. Paules, D. L. Kroetz, and D. C. Zeldin Differential renal gene expression in prehypertensive and hypertensive spontaneously hypertensive rats Am J Physiol Renal Physiol, September 1, 2005; 289(3): F552 - F561. [Abstract] [Full Text] [PDF]
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