(Hypertension. 1996;27:43-48.)
© 1996 American Heart Association, Inc.
Articles |
Role of Endothelium-Derived Metabolites of Arachidonic Acid in Enhanced Pulmonary Artery Contractions in Female Rabbits
From the Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee.
Correspondence to Sandra L. Pfister, PhD, Department of Pharmacology and Toxicology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226.
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Abstract |
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Abstract Previous studies reported sex differences in production of endothelium-derived substances and suggested that these compounds may be involved in regulation of vascular tone under both normal and pathological conditions. The present study was designed to compare the effects of endothelium-dependent contractions in pulmonary artery vessels obtained from male and female rabbits. Rings of intrapulmonary arteries were suspended under isometric tension in oxygenated Krebs' buffer. In male rabbit pulmonary artery, arachidonic acid and methacholine elicited endothelium-dependent, concentration-related contractions (maximal contraction, 79±4% and 54±4% of the KCl contractions, respectively). In contrast, endothelium-dependent arachidonic acid– and methacholine-induced contractions were greater in female pulmonary arteries (maximal response, 113±7% and 101±6% of the KCl contractions, respectively). There was no difference in KCl-induced contractions in female and male pulmonary arteries (1.2±0.1 versus 1.3±0.1 g, respectively). In male rabbits, the vasoconstrictor responses to arachidonic acid and methacholine were inhibited by the cyclooxygenase inhibitor indomethacin. We have previously identified thromboxane A2 as the endothelium-dependent contracting factor in male rabbits. However, indomethacin only partially inhibited arachidonic acid–induced contractions in female pulmonary arteries (maximal inhibition, 46% of the control response) suggesting that a noncyclooxygenase metabolite of arachidonic acid mediates contraction in female rabbits. Likewise, indomethacin only partially inhibited methacholine-induced contractions of female pulmonary arteries. The combined cyclooxygenase/lipoxygenase inhibitor BW 755C and the lipoxygenase inhibitor nordihydroguaiaretic acid completely blocked arachidonic acid–induced contractions in females. Furthermore, both basal and stimulated production of thromboxane B2, as measured by radioimmunoassay, were similar in female and male pulmonary arteries. When segments of pulmonary arteries obtained from female and male rabbits were incubated with 14C-arachidonic acid and the extracted metabolites were resolved by reverse-phase high-performance liquid chromatography, there was an enhanced production of metabolites in females. Pretreatment with indomethacin attenuated metabolism of all products in the males but enhanced production of some compounds in vessels from the females. These observations suggest that the enhanced vasoconstrictor response to arachidonic acid in female pulmonary arteries is due to a lipoxygenase metabolite of arachidonic acid.
Key Words: gender • arachidonic acids • endothelium-derived factor • lipoxygenase
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Introduction |
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TopAbstractIntroductionMethods Results Discussion References |
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Vascular endothelial cells derived from a variety of blood vessels synthesize a large number of vasoactive compounds, including the vasodilators prostacyclin and endothelium-derived relaxing factor and the vasoconstrictors endothelin and endothelium-derived contracting factor.1 2 These compounds are believed to be involved in regulation of vascular tone, and alterations in the production of these compounds may be associated with cardiovascular diseases, including atherosclerosis, coronary vasospasm, and hypertension. In pulmonary hypertension, which can occur either as a primary disorder or secondary to other conditions such as cardiac or pulmonary disease, studies have shown that vascular tone is modulated by factors released from the endothelium.3 The cause of primary pulmonary hypertension is not known, but it has been suggested that an underlying lesion exists that causes severe vasoconstriction.3 The first functional changes may occur in endothelial or vascular smooth muscle cells. If the defect occurs in the endothelial cell, this could alter the release of both relaxing and contracting factors.
In women, the incidence of certain forms of pulmonary hypertension is twofold to fourfold greater than that observed in men.4 Hormonal changes may contribute to the pathogenesis of the disease; this hypothesis is based on studies that showed that in a small percentage of women taking oral contraceptives, pulmonary hypertension developed.5 6 It is not known whether an altered production of endothelium-derived vasoactive substances occurs in women with pulmonary hypertension. Animal studies also have suggested that females exhibit changes in pulmonary vasculature function.7 8 9 10 11 12 13 For example, Farhat and Ramwell8 showed that in isolated perfused rat lungs, the TXA2 mimetic U46619 produced a greater response in females than in males.
We previously showed that arachidonic acid and methacholine mediated endothelium-dependent contractions in male pulmonary arteries via production of the cyclooxygenase metabolite TXA2.14 Clinical studies showed that in primary pulmonary hypertension, there is an increased synthesis of TXA2 and decreased synthesis of prostacyclin.15 TXA2 also has been shown to be involved in pulmonary vasoconstriction observed in a number of animal models of pulmonary hypertension.16 17 18 19 In fact, administration of the thromboxane mimetic U46619 is used to induce pulmonary hypertension in sheep.16 It is important to emphasize that in many studies of pulmonary hypertension, no distinction was made between female and male responses. In addition to TXA2, arachidonic acid is also metabolized by vascular cells to additional cyclooxygenase, lipoxygenase, and cytochrome P450 epoxygenase products.20 The identity and potential biological activity of some of these arachidonic acid metabolites have been determined20 ; however, many metabolites have not been well characterized, either structurally or biologically. More specifically, little is known about the role of these compounds in regulation of pulmonary vascular tone. The present study was designed to characterize the relation of vascular reactivity and arachidonic acid metabolism in pulmonary arteries obtained from female rabbits compared with those obtained from male rabbits.
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Methods |
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Animals
Three-month-old female and male NZW rabbits were obtained from New Franken Rabbitry (New Franken, Wis). A total of 60 rabbits were used for the studies. The animals were housed in the Medical College of Wisconsin Animal Care Facilities, maintained on a standard rabbit chow diet, and given tap water ad libitum.
Vascular Reactivity
Pulmonary artery tissue was isolated as
previously
described.14 Briefly, female and male NZW rabbits were
killed (sodium pentobarbital, 120 mg/kg IV), and the heart and lungs
were removed as a unit and placed immediately in a Krebs' bicarbonate
buffer of the following composition (mmol/L): NaCl 118, KCl 4,
CaCl2 3.3, NaHCO3 24,
KH2PO4 1.4, MgSO4 1.2, and glucose
11, pH 7.4. The main pulmonary artery was identified at its
origin from the right ventricle, and both left and right
pulmonary arteries were dissected to their most distal end. The
pulmonary artery distal to the first branching of the left or
right pulmonary artery was used, and this is referred to as the
intrapulmonary artery. After dissection, the tissue was
cleaned of adherent lung parenchyma and connective tissue, with care
taken not to disturb the endothelial layer. Rings of
intrapulmonary artery were obtained (2 to 3 mm) and
suspended in 15-mL organ baths containing Krebs' bicarbonate buffer
that was warmed to 37°C and continuously aerated with a 95%
O2/5% CO2 mixture. Isometric tension
was measured with force-displacement transducers (Grass Instrument
Co) and recorded with a Grass polygraph (model 7D). Resting tension
was adjusted to the length-tension maxima for each rabbit by
increasing the length of the rings in a stepwise fashion and measuring
the active tension generated by exposing the rings to 20 mmol of KCl
per liter. Resting tension was 2.5 g and did not differ between female
and male rabbits. Vessels were allowed to equilibrate at resting
tension for 1 hour. Contractions were produced by raising the KCl
concentration of the baths to 40 mmol/L. After the vessels had
reproducible, stable contractions in response to KCl, cumulative
concentration-response curves to arachidonic acid
(10-8 to
10-5 mol/L) and methacholine
(10-8 to
10-4 mol/L) were determined. In some
experiments, vessels were pretreated with the
cyclooxygenase inhibitor
indomethacin (10-5
mol/L), the dual
cyclooxygenase/lipoxygenase
inhibitor BW 755C (5x10-5
mol/L), or the lipoxygenase inhibitor
NDGA (5x10-5 mol/L), or the
endothelium was carefully removed before administration
of the vasoactive compounds. To standardize for any minor differences
in size of the tissue, contractile responses were expressed as a
percentage of the maximal response to 40 mmol of KCl per liter.
Radioimmunoassay of TXB2
Strips of rabbit
intrapulmonary artery (8 mg wet
weight) from female and male rabbits were incubated in HEPES buffer
containing arachidonic acid
(10-5 mol/L) for 15 minutes. Synthesis of
TXB2 was measured by specific radioimmunoassays by use of
the method of Campbell and Ojeda.21 The antibody for
TXB2 was produced in rabbits in our laboratory. Sensitivity
of the assay is 1 pg/0.3 mL for TXB2, and
cross-reactivity of the antisera with known
arachidonic acid metabolites is <0.1%.
Identification of Arachidonic Acid
Metabolites
To identify the arachidonic acid metabolites
produced by female and male pulmonary arteries, segments of
intrapulmonary artery (70 mg wet weight) were obtained and
incubated in HEPES buffer (in mmol/L: HEPES 10, NaCl 150, KCl 6,
CaCl2 2, MgCl2 1, and glucose 6, pH 7.4)
containing 14C-arachidonic acid (0.05
µCi, 10-7 mol/L) and the calcium
ionophore A23187 (20 µmol/L) for 15 minutes at 37°C. In some
experiments, vessels were pretreated with various
inhibitors before administration of
14C-arachidonic acid. After incubation, the
HEPES buffer was removed, acidified to pH 2.0 with glacial acetic acid,
and extracted over BondElut octadecylsilica extraction columns as
previously described.22 Briefly, the columns were washed
sequentially with 5 mL water and ethanol. The acidified sample (made
15% vol/vol with ethanol) was then added to the column and washed with
5 mL each of 15% ethanol, water, and petroleum ether. The
arachidonic acid metabolites were eluted with 6 mL
ethyl acetate, evaporated to dryness under nitrogen, and stored at
-40°C until analysis by reverse-phase HPLC (Beckman
Instruments). Recovery of arachidonic acid metabolites
by this extraction procedure is >95%. Separation of the metabolites
of arachidonic acid was accomplished with
reverse-phase HPLC and solvent system I, where solvent A was water
and solvent B was acetonitrile containing 0.1% glacial acetic acid.
The program consisted of a 40-minute linear gradient from 50% B in A
to 100% B. The reverse-phase separations were performed with use
of a Nucleosil C18 column (5 µmol/L, 4.6x250 mm, Phenomenox Inc),
with a flow rate of 1 mL/min. Radioactivity of the column eluate was
monitored with a Ramona-D (Raytest USA Inc) radioactivity detector.
Statistics
Data are expressed as mean±SEM. Statistical
analysis of
the data was performed with ANOVA to determine differences within the
groups and with Student's t test to determine differences
between groups.
Materials
14C-Arachidonic acid was obtained
from New England Nuclear; 3H-TXB2 was from
Amersham Corp. Arachidonic acid, methacholine, A23187,
NDGA, and indomethacin were from Sigma Chemical Co.
Unless otherwise specified, drugs were dissolved in distilled water
such that volumes of 0.05 mL were added to the tissue baths.
Arachidonic acid was prepared in ethanol previously
sparged with nitrogen. The stock solution and dilutions were made fresh
for each experiment and were kept on ice under a nitrogen atmosphere.
Indomethacin, BW 755C, and NDGA were dissolved in
ethanol. The final ethanol concentration of the bath was <0.07%.
Control experiments indicated that ethanol vehicle had no effect on
basal tone or on the response of the vasoactive compounds. In addition,
NDGA had no effect on KCl-induced contractions in either intact or
denuded vessels from male or female rabbits.
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Results |
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TopAbstractIntroductionMethods Results Discussion References |
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There was no difference in KCl-induced contractions in vessels from female rabbits compared with males (1.2±0.1 g versus 1.3±0.1 g, respectively). Arachidonic acid elicited an endothelium-dependent, concentration-related contraction of pulmonary artery from both female and male rabbits; however, contractions were greater in the female rabbits (maximal response, 113±7% versus 79±4%, female versus male rabbits, Fig 1
). Likewise, methacholine caused
concentration-related contractions in pulmonary arteries
from both female and male rabbits, but the response to methacholine was
enhanced in female rabbits (maximal response, 101±6% versus
59±4%,
female versus male, Fig 1). Although the data are not shown,
when the
endothelial layer from the pulmonary arteries
was carefully removed, no contractions to arachidonic
acid or methacholine were observed in either male or female
rabbits.
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Production of TXB2, the stable metabolite of
TXA2, was measured in segments of pulmonary
arteries from female and male rabbits. As shown in the
Table, basal release of TXB2 did not differ
between female and male rabbits. If the vessels were stimulated with
arachidonic acid, TXB2 production
increased in both sets of vessels. However, there was no difference in
arachidonic acid–stimulated TXB2
synthesis between female and male rabbits.
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The next experiments investigated the effect of the
cyclooxygenase inhibitor
indomethacin on vascular contractions in female
compared with male rabbits. In male rabbits (Fig 2,
bottom), indomethacin completely blocked contractions
in response to the lower concentrations of arachidonic
acid in pulmonary arteries. At
10-5 mol/L arachidonic
acid, a 75% inhibition of contractions was observed. In contrast, in
female rabbit pulmonary arteries (Fig 2, top),
arachidonic acid–induced contractions were only
partially blocked. At all concentrations of arachidonic
acid administered, the contractions measured were significantly greater
than basal tension. At 10-5 mol/L
arachidonic acid, only a 46% inhibition of
contractions was observed. Indomethacin had similar
inhibitory effects in pulmonary arteries from
female and male rabbits contracted with methacholine (69% versus 89%,
respectively, Fig 3).
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Next, contractions in response to arachidonic acid and
methacholine in vessels were examined in the presence or absence of the
dual
cyclooxygenase/lipoxygenase
inhibitor BW 755C. In female rabbit pulmonary
arteries, BW 755C elicited a 100% inhibition of contractions in
response to arachidonic acid (Fig 2
, top). This
inhibition was greater than that with indomethacin. In
male rabbit pulmonary arteries, BW 755C also attenuated
contractions to arachidonic acid to the same extent as
indomethacin (Fig 2, bottom). At
10-5 mol/L arachidonic
acid, there was still a 25% contractile response observed. BW 755C
inhibited contractions in response to methacholine in female and male
rabbit pulmonary arteries (Fig 3). However, the inhibition was
greater in vessels from females than from males (84% versus 58%,
respectively).
The effect of a more specific lipoxygenase
inhibitor, NDGA, on vascular contractions of female rabbit
pulmonary arteries was examined. As shown in Fig 4, NDGA
elicited an 83% reduction in
arachidonic acid–induced contractions of female
rabbit pulmonary arteries. NDGA had no effect on
arachidonic acid–induced contractions in male
pulmonary arteries (data not shown).
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The final series of experiments compared the ability of
pulmonary vessels from female and male rabbits to metabolize
14C-arachidonic acid. Segments of vessels
were incubated with 14C-arachidonic acid,
and metabolites were resolved by reverse-phase HPLC. A
representative chromatogram of
arachidonic acid metabolism in
pulmonary arteries obtained from female and male rabbits is
shown in Fig 5. Both female and male rabbit
pulmonary arteries synthesized radioactive metabolites that
comigrated with the prostaglandins. In addition,
radioactive peaks were evident in regions that corresponded to the
DHETs, DiHETEs, and HETEs (Fig 5, left). When equal amounts of
tissue
were incubated, there was an enhanced production of
arachidonic acid metabolites in female rabbit
pulmonary arteries compared with male rabbits. In four separate
experiments, similar results were obtained. Female
pulmonary arteries synthesized 335±64, 120±38, and 236±62
cps/mg tissue for prostaglandins, DiHETEs, DHETs, and
HETEs, respectively. These values were approximately 1.5-fold
greater than what was measured in male pulmonary arteries
(220±90, 70±26, and 146±63 cps/mg tissue for
prostaglandins, DiHETEs, DHETs, and HETEs, respectively).
In the presence of indomethacin (Fig 5, middle), the
metabolism of arachidonic acid was
attenuated in male rabbits. However, in female rabbits, many
metabolites were not suppressed and, in fact, there was an
enhanced production of some compounds. A major
radioactive peak was observed at 7 minutes in female pulmonary
artery incubations. This metabolite was not observed in male
pulmonary artery incubations. Radioactive products
migrating with the HETEs also were apparent in female but not in male
pulmonary arteries. Pretreatment with BW 755C decreased the
synthesis of all arachidonic acid metabolites in both
female and male rabbit pulmonary arteries (Fig 5, right).
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Discussion |
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TopAbstractIntroductionMethods Results Discussion References |
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This study is the first to demonstrate enhanced endothelium-dependent contractions to arachidonic acid and methacholine in pulmonary arteries from female rabbits compared with those from male rabbits. Several studies have suggested that a cyclooxygenase metabolite of arachidonic acid mediates endothelium-dependent contractions of blood vessels.14 23 24 However, pretreatment with the cyclooxygenase inhibitor indomethacin only partially blocked contractions in females, compared with an almost complete attenuation in males. The combined cyclooxygenase/lipoxygenase inhibitor BW 755C and the lipoxygenase inhibitor NDGA completely blocked contractions in females, indicating that a lipoxygenase metabolite of arachidonic acid may be the factor that mediates the enhanced contractions. Previous work by Cunard and coworkers7 investigated the role of the endothelium in pulmonary artery contractions of female and male rats. In these studies,7 contractions in response to the TXA2 mimetic U46619 were similar in males and females. However, when the endothelial layer was removed before administration of U46619, the maximal contraction was reduced in the female rats but not in the male rats. These results7 suggested that pulmonary artery endothelial cells from female rats may produce a vasoconstrictor factor in response to U46619. No inhibitors of arachidonic acid metabolism were tested in animals in that study,7 nor was the identity of the factor determined.
Because TXA2 is a potent pulmonary vasoconstrictor14 and has been implicated in certain forms of pulmonary hypertension,15 16 17 18 19 we first hypothesized that an enhanced production or release of TXA2 may mediate the increased contractions in female rabbits. Measurement of the stable metabolite TXB2, either under basal conditions or in vessels stimulated with arachidonic acid, indicated that this hypothesis was incorrect. Female rabbit pulmonary arteries did not have an enhanced production or release of TXA2 compared with male arteries. These results instead support the vascular reactivity experiments that indicated that a lipoxygenase metabolite of arachidonic acid is involved in female rabbit pulmonary artery contractions.
In pulmonary arteries obtained both from male and from female rabbits, arachidonic acid was metabolized to products that comigrated with the authentic HETE standards on reverse-phase HPLC. Pretreatment with indomethacin at a concentration that only partially blocked arachidonic acid– and methacholine-induced contractions in females did not inhibit formation of metabolites that migrated with the HETEs. An oxygenation reaction catalyzed by specific lipoxygenase enzymes converts arachidonic acid to HPETEs.25 The HPETEs are short-acting compounds that are further metabolized to HETEs, hepoxilins, lipoxins, and leukotrienes. Not all tissues contain the same lipoxygenases, and therefore different tissues synthesize different lipoxygenase metabolites. Greenwald and coworkers26 demonstrated that rabbit aorta converted exogenous arachidonic acid to a lipoxygenase metabolite that was characteristic of an HETE. We later characterized these metabolites as 15-, 12-, and 11-HETE.22 Synthesis of these compounds was enhanced by the cyclooxygenase inhibitor indomethacin and inhibited by lipoxygenase inhibitors or by removal of the endothelium. Other studies have shown that fetal calf aorta also synthesized 12-, 15-, and 11-HETEs by an endothelium-dependent mechanism.27 In contrast to the studies with rabbit aorta, indomethacin blocked 15- and 11-HETE formation, and 12-HETE synthesis was blocked by a lipoxygenase inhibitor. Thus, depending on the source of the vascular tissue, the 11- and 15-HETEs can be lipoxygenase or cyclooxygenase products of arachidonic acid.
Biological actions of the HPETEs and, to a lesser degree, the HETEs include vasorelaxation,28 vasoconstriction,29 30 inhibition of prostacyclin synthetase,31 and chemotaxis.32 Burhop and coworkers30 found that both 5- and 15-HETE induced pulmonary vasoconstriction in isolated perfused lungs obtained from guinea pigs. Although the identity of the HETE products has not been characterized in female pulmonary arteries, it is possible that these products may be involved in the enhanced contractile response observed in female rabbits. Female pulmonary arteries also produced a noncyclooxygenase metabolite of arachidonic acid that migrated with the prostaglandins on reverse-phase HPLC. This polar metabolite was not observed in male pulmonary arteries. The identity or potential biological activity of this product has not been determined.
The present study was not designed to investigate the mechanism of enhanced contractions in females compared with males. However, other studies suggested the possibility that estrogens may modulate vascular reactivity. For example, Miller and Vanhoutte33 reported that the chronic administration of 17ß-estradiol to ovariectomized rabbits caused an increased contractile response to arachidonic acid and norepinephrine in aortic vascular rings. These contractions were reduced by pretreatment with indomethacin, suggesting that the effect of estrogen may be mediated by an arachidonic acid metabolite. A recent report by Farhat and Ramwell8 showed that in isolated perfused rat lungs, the TXA2 mimetic U46619 produced a greater pressor response in females than in males. Infusion of 17ß-estradiol into the rat lung potentiated the pressor response to estradiol. Clinical studies also reported that estrogens may be involved in the pathogenesis of certain forms of pulmonary hypertension in females.4 5 6 34 Again, although the present study did not directly address the role of estrogen in pulmonary artery contractions, the observation that responses were greater in females than in males would suggest a role for steroid regulation of pulmonary vascular tone.
In summary, the present study characterized arachidonic acid– and methacholine-induced contractions in female and male rabbit pulmonary arteries. Enhanced contractions in female rabbits are not mediated by an increased synthesis or release of the vasoconstrictor TXA2. Instead, inhibition studies indicated that a lipoxygenase metabolite of arachidonic acid is involved. Further studies are necessary to identify arachidonic acid metabolites that may mediate the response. Because women have an increased incidence of pulmonary hypertension compared with men, identification of these factors may aid in the understanding of the pathophysiology of the disease in women and ultimately may help improve the treatment of pulmonary hypertension in both men and women.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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Support for these studies was provided by a grant from the American Heart Association (92009440) and a grant from the National Heart, Lung, and Blood Institute (HL-37981). The authors would like to thank Joseph James, Donna Kotulock, and Lori Ivy for their invaluable technical assistance and Gretchen Barg for her excellent secretarial assistance.
Received June 19, 1995; first decision August 16, 1995; accepted September 19, 1995.
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