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Vol. 304, Issue 1, 139-144, January 2003
Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Winston-Salem, North Carolina (A.W.M., C.D.T., D.W.B.); and Department of Internal Medicine, University of Iowa College of Medicine, Iowa City, Iowa (P.V.G.K., H.C.L., N.L.W.)
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Abstract |
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 Top
 Abstract
 Introduction
Materials and Methods
Results
Discussion
References
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We examined the mechanism of arachidonic acid-induced vasodilation in rat small mesenteric arteries and determined the primary arachidonic acid metabolites produced by these arteries. Responses to arachidonic acid in small mesenteric arteries from Sprague-Dawley rats were investigated in vitro in the presence or absence of endothelium or after pretreatment with inhibitors of nitric oxide (NO), cyclooxygenase, cytochrome P450, lipoxygenase, or K+ channels. In addition, the metabolism of arachidonic acid was examined by incubating arteries with [3H]arachidonic acid in the presence and absence of cyclooxygenase, cytochrome P450, or lipoxygenase inhibitors. Finally, the vascular response to both 12(S)-hydroxyeicosatetraenoic acid (HETE) and 12(S)-hydroperoxyeicosatetraenoic acid (HPETE) was determined. Arachidonic acid induced an endothelium-dependent vasodilation that was abolished by lipoxygenase inhibitors [cin-namyl-3,4-dihydroxy-cyanocinnamate (CDC) or 5,8,11-eicosatriynoic acid (ETI)] and KCl, whereas it was partially inhibited by either tetraethylammonium or iberiotoxin. In contrast, neither NO nor cytochrome P450 enzyme inhibitors affected arachidonic acid-mediated dilation, whereas inhibition of cyclooxygenase enhanced dilation. Biochemical analysis revealed that small mesenteric arteries primarily produce 12-HETE, a lipoxygenase metabolite. Moreover, CDC and ETI inhibited the production of 12-HETE. Finally, both 12(S)-HETE and 12(S)-HPETE induced a concentration-dependent vasodilation in mesenteric arteries. These findings provide functional and biochemical evidence that the lipoxygenase pathway mediates arachidonic acid-induced vasodilation in rat small mesenteric arteries through a K+ channel-dependent mechanism.
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Introduction |
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Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Endothelial
cells play an integral role in maintenance of vascular tone through the
production of vasoactive substances. The three primary vasodilatory
substances produced by the endothelium are nitric oxide (NO),
prostacyclin, and endothelium-derived hyperpolarizing factor (EDHF)
(Rubanyi, 1993
). In most arterial beds, particularly conduit arteries,
NO is the primary endothelium-derived relaxing factor. However, in some
resistance artery beds, it is thought that EDHF may be a more important
mediator of vasodilation (Hwa et al., 1994). The identity of EDHF is
currently unknown, but is likely several different substances dependent
on the vascular bed and model studied. Many investigators have
suggested that noncyclooxygenase metabolites of arachidonic acid meet
the criteria for an EDHF because they are produced by the endothelium
and can induce vascular smooth muscle hyperpolarization and thus
relaxation through the activation of K+ channels
(Garland et al., 1995; Fisslthaler et al., 1999, 2000). Endothelial
cells can metabolize arachidonic acid through several different
noncyclooxygenase pathways, most notably the cytochrome P450 and
lipoxygenase pathways. In endothelial cells, cytochrome P450 enzymes
metabolize arachidonic acid to four regioisomeric epoxyeicosatrienoic
acids, which can be rapidly hydrolyzed to dihydroxyeicosatrienoic acids (Oltman et al., 1998; Weintraub et al.,
1999). Both of these groups of metabolites have been shown to induce
vascular smooth muscle hyperpolarization and are putative EDHFs (Oltman
et al., 1998; Campbell et al., 2001). Moreover, three lipoxygenases
have been described in endothelial cells: 5-, 12-, and 15-lipoxygenase.
Each of these enzymes generates a stereospecific
hydroperoxyeicosatetraenoic acid (HPETE), which are highly unstable
compounds that are rapidly reduced by cellular peroxidases to the
corresponding hydroxyeicosatetraenoic acid (HETE) (Soberman et al.,
1985). These metabolites have been reported to have various vasoactive
properties, encompassing both vasodilation and vasoconstriction (Uotila
et al., 1987; Uski and Hogestatt 1992; Pfister et al., 1998; DelliPizzi
et al., 2000; Faraci et al., 2001; Zink et al., 2001). Recently, a
12-lipoxygenase metabolite, 12(S)-HETE, has been shown to
possess EDHF-like characteristics (Pfister et al., 1998; Faraci et al.,
2001; Zink et al., 2001).
Previous studies in small rat mesenteric arteries have demonstrated
that endothelium-dependent vasodilation is primarily mediated by nitric
oxide-independent vasodilators (Chen and Cheung, 1997; Doughty et al.,
1999; Katakam et al., 1999). Thus, the role of arachidonic acid and its
metabolites in this vascular bed is physiologically relevant. However,
the mechanism by which arachidonic acid induces relaxation in rat
mesenteric arteries is currently unclear. Therefore, the purpose of the
current study was to determine the mechanism of arachidonic
acid-induced vasodilation in small rat mesenteric arteries and to
determine the primary arachidonic acid metabolites produced by these arteries.
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Materials and Methods |
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Abstract
Introduction
Materials and Methods
Results
Discussion
References
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The Animal Care Committees at the Wake Forest University School of Medicine and the University of Iowa College of Medicine approved the current protocol. Ten-week-old male Sprague-Dawley rats (n = 54) were anesthetized with pentobarbital (50 mg/kg i.p.) and anticoagulated with heparin (500 units i.p.). A midline incision was made and a section of the small intestine was clamped, removed, and placed in a chilled oxygenated modified Krebs-Ringer bicarbonate solution (118.3 mM NaCl, 4.7 mM KCl, 2.5 mM CaCl2, 1.2 mM MgSO4, 1.2 mM KH2PO4, 25 mM NaHCO3, and 11.1 mM dextrose). Fourth order branches of the superior mesenteric artery were isolated from surrounding perivascular tissue and removed from the mesenteric vascular bed for functional and biochemical studies.
Mechanisms of Vascular Responsiveness to Arachidonic Acid.
Small mesenteric arteries (
2 mm in length) isolated from the
mesenteric vascular bed were transferred to a vessel chamber and
mounted and secured between two glass micropipettes with 10-0 ophthalmic suture. The vessel chamber was transferred to an inverted light microscope stage coupled to a video dimension analyzer (Living Systems Instrumentation, Burlington, VT). The video dimension analyzer
was connected to both a video monitor (for visualization of the vessel)
and to a strip chart recorder for constant recording of the
intraluminal diameter of the vessel. Oxygenated (20%
O2, 5% CO2) Krebs'
solution maintained at 37°C was continuously circulated through the
vessel bath. In addition, the lumen of the vessel was filled with
Krebs' solution through the micropipettes and maintained at a constant
pressure of 60 mm Hg. Only one concentration-response experiment was
performed per artery; however, several arteries were taken from each rat.
1
receptor agonist. Concentration-response experiments to arachidonic
acid (10
8-5 × 105 mol/l) were performed in control (intact
endothelium) arteries, arteries pretreated with 100 µM
N-nitro-L-arginine, and arteries denuded of endothelium. Endothelial denudation was performed by perfusing air through the lumen of the artery and was verified by the
absence of a dilator response to acetylcholine and viability was tested
by vasodilator response to sodium nitroprusside. We have previously
documented this method of endothelium removal by electron microscopy
(Miller et al., 2001).
Because arachidonic acid can be metabolized by three different enzyme
systems to generate vasoactive products, we inhibited each of these
systems individually in endothelium-intact arteries to determine the
mechanism of vasodilation by arachidonic acid. To determine the role of
cyclooxygenase products arteries were pretreated with 10 µM
indomethacin, whereas the role of cytochrome P450 products was
determined by pretreatment with either 10 µM miconazole or 10 µM
17-octadecynoic acid. Moreover, to assess the role of the lipoxygenase
products we pretreated arteries with either 100 nM
cin-namyl-3,4-dihydroxy-cyanocinnamate (CDC) or 10 µM
5,8,11-eicosatriynoic acid (ETI).
Vasodilatory metabolites of arachidonic acid are often reported to
induce vascular relaxation through their ability to activate potassium
channels (Adeagbo and Malik, 1991; Faraci et al., 2001). Moreover, EDHF
is characterized as inducing vascular smooth muscle hyperpolarization
and vasodilation through the activation of potassium channels (Feletou
and Vanhoutte 1999, 2000). Thus, to assess whether K+ channels contribute to arachidonic
acid-induced vasodilation, 50 mM KCl rather than PE was used to
constrict arteries. Furthermore, to assess the role of
KCa or ATP-dependent K+
channels in arachidonic acid-induced vasodilation we pretreated arteries with either 1 mM tetraethylammonium or 10 µM glibenclamide before PE constriction. To specifically assess the role of the large
conductance KCa, we pretreated the arteries with
0.1 µM iberiotoxin before PE constriction.
Metabolism of Radiolabeled Arachidonic Acid by Mesenteric Arteries. Rat small mesenteric arteries were harvested and pooled from three animals for each incubation experiment. The arteries were placed in a test tube containing 1 ml of Krebs-Ringer bicarbonate supplemented with 0.1 µM fatty acid-free bovine serum albumin and maintained in a 5% CO2 incubator (37°C). After 1 h, vehicle (dimethyl sulfoxide), the combination of indomethacin + miconazole (10 µM each), 10 µM CDC, or 10 µM ETI was added, and the incubations were continued for 30 min. The Krebs-Ringer bicarbonate solution was then removed, and fresh Krebs-Ringer bicarbonate solution containing 1.7 µM [3H]arachidonic acid was then added along with vehicle or inhibitor compounds. One hour later, 2 µM A23187 was added to induce arachidonic acid mobilization and metabolism, and after 30 min, the incubation was terminated by removal of the Krebs-Ringer bicarbonate solution.
The radioactivity present in the Krebs-Ringer bicarbonate solution after the incubation was measured by liquid scintillation counting. Lipids contained in the medium were extracted twice with 4 volumes of ice-cold ethyl acetate saturated with water, the extracts were combined, the solvent was evaporated under N2, and the residue was dissolved in acetonitrile. The lipids were separated by reverse-phase HPLC using a Gilson dual pump gradient system equipped with model 306 pumps, a model 117 dual wavelength UV detector, a model 231 XL automatic sample injector (Gilson Medical Electronics, Middleton, WI), and a Discovery C18 column (5 µm, 4.6 × 150 mm) obtained from Supelco (Bellefonte, PA). The elution profile consisted of water adjusted to pH 4.0 with formic acid and an acetonitrile gradient that increased from 30 to 57% over 60 min and then from 57 to 65% over 25 min, at which time the acetonitrile was taken to 100% and held constant for 15 min. The distribution of radioactivity was measured by combining the column with scintillator solution and passing the mixture through an on-line flow detector (IN/US Systems, Inc., Tampa, FL) (Weintraub et al., 1997; Faraci
et al., 2001; Zink et al., 2001).
Normal-phase HPLC was carried out using an isocratic mobile phase
consisting of n-heptane/isopropyl alcohol/formic acid
(100:0.4:0.03, v/v/v) at a flow rate of 1.0 ml/min (Weintraub et al.,
1997; Faraci et al., 2001; Zink et al., 2001). The column was an
Econosphere silica column (4.6 × 250 mm; Alltech-Applied Science
Labs, State College, PA) with 5-µm pore size. The scintillator
was mixed with the column effluent at a ratio of 3.5 to 1.
Vascular Response to Metabolic Products.
Based on the
above-mentioned biochemical studies we assessed the vascular response
to both exogenous 12(S)-HETE and 12(S)-HPETE in
small mesenteric arteries. Arteries were isolated and prepared as
described previously. After preconstriction with PE to 40% of
baseline, concentration-response experiments
(1010-106 M) were
determined for both of the above-mentioned lipoxygenase metabolites.
Data Analysis. Data from vascular reactivity studies are expressed as percentage of relaxation after preconstriction. All data are expressed as mean ± S.E.M. All concentration-response curves were evaluated for changes in maximal response and differences at each concentration using analysis of variance with repeated measures followed by a Fisher's pairwise least significant difference test for multiple comparisons. The criterion for significance was p < 0.05.
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Results |
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Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Resting intraluminal diameter of small mesenteric arteries was 210 ± 6 µm. Percentage of arterial constriction after phenylephrine or KCl was similar with 39 ± 2% for PE and 36 ± 2% for KCl. Neither endothelial denudation nor pharmacological inhibition significantly altered the resting diameter compared with the arteries in the control (without intervention) group. The percentage of constriction in experiments with endothelial denudation or pharmacological inhibition also did not differ compared with control arteries, although the concentration of PE used to induce preconstriction was decreased by approximately one-half to induce the same amount of tone in these arteries. For example, arteries that were denuded of endothelium required 1.08 ± 0.07 µM PE to induce preconstriction, whereas arteries with intact endothelium required 2.17 ± 0.03 µM.
Mechanisms of Vascular Responsiveness to Arachidonic Acid.
Arachidonic acid produced a concentration-dependent vasodilation in
control mesenteric arteries with a maximal relaxation of 89 ± 5%
(Fig. 1). This vasodilation was not
significantly altered in the presence of the NO synthase inhibitor
N-nitro-L-arginine (maximal relaxation
83 ± 6%; Fig. 1). In contrast, arachidonic acid-induced
vasodilation was nearly abolished after endothelium denudation (maximal
relaxation 13 ± 3%; p < 0.01) (Fig. 1),
illustrating that the vascular responsiveness to arachidonic acid in
rat mesenteric arteries is primarily endothelium-dependent.
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Metabolism of [3H]Arachidonic Acid by Mesenteric
Arteries.
To examine the profile of arachidonic acid metabolites
produced by rat small mesenteric arteries, pooled arteries (three
animals per experiment) were incubated with
[3H]arachidonic acid, followed by extraction of
lipids from the incubation solution and separation by reverse-phase
HPLC. The main radiolabeled products detected in the incubation
solution were arachidonic acid and an unknown metabolite that
comigrated with authentic 12-HETE standard (Fig.
4). In control experiments (vehicle-treated) there was a 4.5 ± 1.5% conversion
(n = 8) to the unknown metabolite. In one experiment,
tissue-associated lipids were extracted using chloroform/methanol,
saponified, and separated by reverse-phase HPLC. The only radiolabeled
peak detected was arachidonic acid, suggesting that the unknown product
was preferentially released into the incubation solution rather than
retained in cell lipids (data not shown). Pretreatment with
indomethacin + miconazole did not inhibit the formation of the unknown
metabolite (n = 3) (Fig. 4). In contrast, production of
the unknown was abolished by pretreatment of arteries with either CDC
(n = 2; Fig. 4) or ETI (n = 1; data not
shown).
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Vascular Response to Metabolic Products.
Both
12(S)-HETE and 12(S)-HPETE induced a
concentration-dependent vasodilation of small mesenteric arteries, with
maximal dilations of 50 ± 10 and 59 ± 10%, respectively
(Fig. 6). These experiments demonstrate
that the primary metabolite produced by small rat mesenteric arteries
(12-HETE) and its immediate precursor (12-HPETE) are indeed
vasodilators in this arterial bed.
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Discussion |
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Abstract
Introduction
Materials and Methods
Results
Discussion
References
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There are three major new findings from this study. First, arachidonic acid induces an endothelium-dependent dilation of small rat mesenteric arteries that is abolished by inhibitors of lipoxygenase, but not by inhibitors of NO synthase, cyclooxygenase, or cytochrome P450. Second, biochemical studies suggest that lipoxygenase-derived 12-HETE is a major product of arachidonic acid metabolism in rat small mesenteric arteries. Moreover, vascular studies with exogenous 12(S)-HETE demonstrate that it acts as a vasodilator in this vascular bed. Third, arachidonic acid-mediated vasodilation was also inhibited by depolarization with KCl or pretreatment with either tetraethylammonium or iberiotoxin. Together, these findings suggest that arachidonic acid produces dilation of rat small mesenteric arteries through a mechanism dependent upon lipoxygenase and activation of KCa channels.
To our knowledge only one prior study has assessed arachidonic
acid-induced vasodilation in rat mesentery, whereas no studies have
evaluated arachidonic acid metabolism using biochemical techniques in
this vascular bed. In an isolated perfused mesenteric arterial preparation, vascular dilation via arachidonic acid was shown to be
primarily endothelium-dependent (Adeagbo and Malik, 1991). Moreover,
cyclooxygenase inhibitors enhanced arachidonic acid-induced dilation,
whereas cytochrome P450 inhibitors had no effect (Adeagbo and Malik,
1991) All of these findings are very consistent with those in the
present study. In contrast, however, the previous study evaluated one
lipoxygenase enzyme inhibitor,
2,3,5-trimethyl-6-(12-hydroxy-5,10-dodeca-diynyl)-1,40-benzoquinone (AA861), that did not alter vasodilation to arachidonic acid (Adeagbo and Malik, 1991). However, biochemical assessment of the efficacy of
lipoxygenase inhibition by AA861, which is reported to be more selective for 5-lipoxygenase, was not demonstrated. Therefore, the role
of the lipoxygenase enzyme system was not fully evaluated in the prior
study (Adeagbo and Malik, 1991). Regarding potassium channel
activation, the prior study, like our own, showed that arachidonic acid
decreased vascular resistance through the activation of
K+ channels (Adeagbo and Malik, 1991).
Lipoxygenase as a Vasodilator Pathway.
In addition to the
current data, recent findings from other species and vascular beds have
also suggested that lipoxygenase mediates arachidonic acid-induced
vasodilation in some preparations. Studies in rabbit and rat aorta have
demonstrated that arachidonic acid produces relaxation by activation of
the lipoxygenase pathway (Uotila et al., 1987; Pfister et al., 1998).
Moreover, Zink and colleagues have shown that porcine coronary
microvascular endothelial cells metabolize arachidonic acid to
12(S)-HETE. Furthermore, these investigators went on to show
that this lipoxygenase product induced potent vasodilation of porcine
coronary microvessels via vascular smooth muscle hyperpolarization
(Zink et al., 2001). Finally, a recent study completed in rat basilar
artery demonstrated, similar to our study, that arachidonic
acid-induced vasodilation was abrogated by lipoxygenase enzyme
inhibitors and that the major product detected by HPLC analysis of
[3H]arachidonic acid metabolism was indeed
12(S)-HETE (Faraci et al., 2001).
; Pfister et al., 1998; Zink et al., 2001).
Moreover, lipoxygenase enzymatic activity can lead to generation of
reactive oxygen species, which themselves can induce vasodilation by
activation K+ channels (Fleming et al., 2001).
Thus, although we detected 12-HETE in our assay system and have shown
that both exogenous 12(S)-HETE and 12(S)-HPETE
induce vasodilation in this arterial bed, our results do not exclude
the possibility that trihydroxyeicosatrienoic acids or other
lipoxygenase products are mediators of dilation to arachidonic acid in
rat mesenteric arteries.
Role of Potassium Channels.
The current study showed that
arachidonic acid metabolites produced by the mesenteric arteries induce
vasodilation through potassium channels. Specifically, we demonstrated
that either depolarization with KCl or pretreatment with either
tetraethylammonium or iberiotoxin markedly inhibited the vascular
responses to arachidonic acid, whereas glibenclamide pretreatment had
no effect. These findings suggest that lipoxygenase metabolites of
arachidonic acid induce vasodilation through KCa,
but not ATP-dependent K+ channels. These data are
consistent with recent findings in rat basilar arteries and rabbit
aorta (Pfister et al., 1998; Faraci et al., 2001). Moreover, in rat
basilar arteries, investigators not only showed that arachidonic
acid-mediated dilation could be inhibited by tetraethylammonium or
iberiotoxin but also demonstrated that the hyperpolarization of
vascular smooth muscle was abolished in the presence of
tetraethylammonium (Faraci et al., 2001). Finally, in porcine coronary
microvessels, the effect of 12(S)-HETE was specifically
evaluated and was not only shown to induce vasodilation but also
induced vascular smooth muscle hyperpolarization through activation of
the large conductance KCa channel (Zink et al., 2001). These results are supportive of our findings and suggest that
lipoxygenase metabolites likely induce vasodilation by activating vascular smooth muscle KCa channels.
Summary. The present study is the first to elucidate a specific mechanism by which arachidonic acid produces dilation of rat small mesenteric arteries. Both pharmacological and biochemical studies suggest that the lipoxygenase pathway is a functionally active mechanism for control of vasomotor tone in this vascular bed. Based on these findings, lipoxygenase may function as a putative EDHF synthase in small rat mesenteric arteries.
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Footnotes |
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Accepted for publication September 10, 2002.
Received for publication July 16, 2002.
This work was supported by the American Heart Association (0140212N to A.W.M.; 0270114N to D.W.B.) and the National Institutes of Health (HL66074 to A.W.M.; HL30260, HL46558, and HL50587 to D.W.B.; HL49264 and HL62984 to N.L.W.; and HL63754 to H.C.L.).
DOI: 10.1124/jpet.102.041780
Address correspondence to: Dr. Allison W. Miller, Department of Physiology/Pharmacology, Wake Forest University School of Medicine, Medical Center Blvd., Winston-Salem, NC 27157. E-mail: amiller{at}wfubmc.edu
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Abbreviations |
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NO, nitric oxide; EDHF, endothelium-dependent hyperpolarizing factor; HPETE, hydroperoxyeicosatetraenoic acid; HETE, hydroxyeicosatetraenoic acid; PE, phenylephrine; CDC, cinnamyl-3,4-dihydroxy-cyanocinnamate; ETI, 5,8,11-eicosatriynoic acid; KCa, calcium-dependent potassium channel; HPLC, high-performance liquid chromatography.
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References |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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