Published online before print August 23, 2004, doi: 10.1161/01.CIR.0000140985.89766.CB
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(Circulation. 2004;110:1320-1325.)
© 2004 American Heart Association, Inc.
Original Articles |
Aspirin-Triggered, Cyclooxygenase-2–Dependent Lipoxin Synthesis Modulates Vascular Tone
From the Mucosal Inflammation Research Group (P.-Y.v.d.W., M.D.H., J.L.W.), University of Calgary, Calgary, Alberta, Canada, and the Department of Gastroenterology and Hepatology (S.F.), University of Perugia, Perugia, Italy.
Correspondence to Dr John L. Wallace, Department of Pharmacology and Therapeutics, University of Calgary, 3330 Hospital Dr NW, Calgary, Alberta, T2N 4N1 Canada. E-mail wallacej{at}ucalgary.ca
Received March 31, 2004; revision received May 17, 2004; accepted May 19, 2004.
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Abstract |
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Background— Aspirin-triggered production of 15-(R)-epilipoxin A4 (ATL) has been shown to exert potent antiinflammatory effects and gastric-protective effects, but little is known of its actions on the vasculature. In the present study, we have assessed the contribution of ATL to changes in vascular tone induced by aspirin and have examined the role of nitric oxide (NO) as a mediator of such effects.
Methods and Results— Intravenous administration of lipoxin A4 resulted in a short-lived (3 to 4 minutes) reduction in blood pressure (BP; 
13 mm Hg at 2.5 µg/kg). Aspirin administered alone resulted in a significant increase in serum ATL and an increase in BP of 10 mm Hg. When ATL synthesis was inhibited by pretreatment with a selective cyclooxygenase-2 inhibitor (celecoxib) or a 5-lipoxygenase inhibitor (zileuton), the aspirin-induced increase in BP was significantly augmented. These agents alone did not affect BP. A lipoxin receptor antagonist, Boc2, also increased the pressor effects of aspirin. Moreover, immunodepletion of neutrophils, a major source of 5-lipoxygenase, resulted in a significant reduction of ATL formation and augmented aspirin’s pressor effects. Studies of rat aortic and mesenteric artery ring segments confirmed the vasorelaxant effects of lipoxin A4 and showed them to be endothelium dependent.
Conclusions— Aspirin-triggered lipoxin synthesis can modulate vascular tone, possibly contributing to changes in regional blood flow during inflammatory reactions, and to the modulation of systemic BP.
Key Words: inflammation • muscle, smooth • nitric oxide • vasodilation • endothelium
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Introduction |
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Cyclooxygenase (COX), the primary enzyme responsible for the synthesis of prostanoids, exists in at least 2 isoforms. COX-2 has been suggested to be the isoform primarily responsible for synthesis of prostaglandins (PGs) in the context of inflammation.1 Thus, selective inhibitors of COX-2 were developed with the aim that they would be as effective as traditional nonsteroidal antiinflammatory drugs (NSAIDs) but would not be as damaging to the gastrointestinal tract by virtue of not inhibiting the primarily COX-1–dependent PG synthesis in those tissues. Inhibition of the 2 isoforms of COX by aspirin differs in a significant manner from the interaction of most NSAIDs with these enzymes. Aspirin acetylates a serine residue near the active site in both COX-1 and COX-2; the resulting conformational changes lead to inhibition of the oxidation of arachidonic acid to PGH2 (the precursor to the other PGs and thromboxanes). However, in the case of COX-2, aspirin acetylation does not totally inhibit its catalytic activity, and the enzyme can still metabolize arachidonic acid to 15(R)-hydroxyeicosatetraenoic acid (HETE).2 This metabolite can be converted further, via 5-lipoxygenase (5-LO), to 15(R)-epilipoxin A4, also know as "aspirin-triggered lipoxin" (ATL).2
ATL shares many of the biological actions of its epimeric counterpart, lipoxin A4 (LXA4). Both LXA4 and ATL suppress a variety of neutrophil functions, including chemotaxis, adherence, transmigration, and superoxide anion production.3 LXA4 can protect the stomach from damage induced by aspirin, an effect that is abolished by pretreatment with a nitric oxide (NO) synthase inhibitor.4
The observation that at least some actions of lipoxins are mediated via NO raises the possibility that lipoxins modulate vascular tone. There is surprisingly little published information about the vascular actions of lipoxins, and what is available is somewhat contradictory. Feuerstein and Siren5 reported that intravenous LXA4 and LXB4 dose-dependently constricted mesenteric vessels but did not alter arterial blood pressure (BP) or heart rate. Katoh et al6 reported that LXA4 dose-dependently increased renal plasma flow and glomerular filtration rate. Aspirin, like other NSAIDs, can alter vascular tone, leading to small but significant increases in systemic BP, which can have important clinical consequences.7 The present study examined the hypothesis that ATL can contribute to the short-term effects of aspirin on systemic BP. We also asked the question: What effect might LXA4 itself have on vascular tone and on systemic BP? The results suggest that aspirin-triggered lipoxin, at least in part through an NO- and an endothelium-dependent process, acts to counteract the pressor effects of aspirin.
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Methods |
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Animals
Male Wistar rats weighing 175 to 200 g (for in vivo studies) or Sprague-Dawley rats weighing 250 to 400 g (for in vitro studies) were obtained from Charles River Breeding Farms (Montreal, Canada, or Monza, Italy). The rats were fed standard laboratory chow and tap water. All experimental procedures described herein were approved by our institutional animal research committees and were performed in accordance with nationally approved guidelines for the treatment of laboratory animals. Unless otherwise mentioned, in all experiments described, the sample size per group was at least 5.
BP Measurements
Rats were anesthetized with sodium pentobarbital (60 mg/kg IP), and a cannula was inserted into a jugular vein for continuous recording of BP, as described previously.8 After a baseline recording of at least 15 minutes, the rats were treated (intraperitoneally, unless otherwise stated) with one of the following agents or vehicle (0.9% saline): NG-nitro-L-arginine methyl ester (L-NAME; 25 mg/kg IV), celecoxib (10 mg/kg), zileuton (10 mg/kg), or Boc2 (10 µg/kg). L-NAME is a nonselective inhibitor of NO synthase, celecoxib is a selective COX-2 inhibitor, zileuton is a 5-LO inhibitor, and Boc2 is a lipoxin receptor antagonist. All of these agents have been used at doses previously shown to produce the desired pharmacological effect.8–11 Thirty minutes after administration of one of these drugs or vehicle, aspirin (50 mg/kg) was injected intraperitoneally. The BP response to aspirin was monitored for the subsequent 60 minutes. In addition to noting the maximal change in BP, the time required for the BP to return to baseline was recorded.
Additional experiments were performed in which LXA4 was injected intraperitoneally at doses of 0.6 or 2.5 µg/kg, and the BP response was monitored for up to 60 minutes. The effects of administration of a selective COX-1 inhibitor, SC-560 (10 mg/kg IP), on BP were also assessed.
To assess the contribution of neutrophils to the BP effects of aspirin, rats were rendered neutropenic through treatment with rabbit anti-rat neutrophil serum, as described previously.12 Treatment with this antiserum 24 and 2 hours before the experiment reduced circulating neutrophil numbers by >95% while not significantly affecting circulating numbers of monocytes, macrophages, lymphocytes, or eosinophils.12
ATL Production
Rats were prepared as in the BP studies. Thirty minutes after administration of L-NAME, zileuton, celecoxib, or vehicle, aspirin (50 mg/kg) or vehicle was administered intraperitoneally. Fifteen minutes later, blood was drawn through a carotid cannula into one of 2 glass tubes. One tube of blood from each rat was used for measurement of whole-blood thromboxane synthesis.13 The other tube of blood was centrifuged (1000g, 10 minutes), and then the serum was diluted 1:5 with water and acidified to pH 3.5 with 1N HCl. The samples were applied to a preconditioned C18 Sep-Pak column (Waters Corp), and after being washed with 1 mL of water followed by 1 mL of petroleum ether, lipoxins were eluted with 2 mL of methyl formate. The sample was then dried under a stream of nitrogen and reconstituted in assay buffer. Concentrations of 15(R)-epi-LXA4 in the samples were measured with a highly specific ELISA.14 We have previously characterized this assay and confirmed the high degree of selectivity for 15-(R)-epi-LTA4, as well as confirming the identity of this lipoxin by high-performance liquid chromatography.15
Studies of Mesenteric Artery Segments In Vitro
Male Sprague-Dawley rats were euthanized by intracardiac injection of pentobarbital followed by cervical dislocation or decapitation. Note that the different strain of rats used for in vitro studies was purely due to there being greater experience with Sprague-Dawley rats in previous studies of this type. The small intestine and attached mesentery were rapidly removed and placed in modified Krebs-Henseleit buffer of the following composition (mmol/L): CaCl2, 2.5; KCl, 4.7; MgCl2, 1.2; NaCl, 118; NaHCO3, 25; KH2PO4, 1.2; and glucose, 10. The pH was maintained at 7.4 by constant bubbling with 95% O2/5% CO2.
Second- and third-order arteries (internal diameter, 130 to 190 µm) were isolated from the mesentery. Two adjacent segments (length of 1 to 2 mm) were dissected out of 2 vessels and suspended in the 4 chambers of a Mulvany-Halpern–style organ bath (Model 610 multimyograph system, J.P. Trading) between a micropositioner and a force transducer with stainless steel wire (diameter 40 µm). Resting tension was set at 2 mN, and a period of 45 minutes was allowed for equilibration. Isometric tension was recorded online on a computer with an analog-to-digital converter (PowerLab/4SP, ADInstruments). The preparations were routinely contracted with 114 mmol/L KCl to determine their viability and then precontracted with 1 µmol/L U46619. Relaxing responses to acetylcholine (ACh) were determined to assess the responsiveness of the endothelium. LXA4 was applied as a control in the chambers containing one of the adjacent segments from each of the 2 arteries and in the 2 other chambers in which either the endothelium had been removed from the segments or the segments had been pretreated for 30 minutes with an NO synthase inhibitor (NG-nitro-L-arginine; L-NA). The endothelium was removed by gently rubbing the intimal surface of the vessel with a human hair.16
Studies of Aortic Ring Segments In Vitro
An endothelium-intact rat aortic-ring assay was used to monitor the responses to LXA4.17 In brief, male Sprague-Dawley rats (250 to 300 g) were euthanized by cervical dislocation. Clot-free portions of aorta were dissected free of adherent connective tissue, and endothelium-intact rings (2 mm lengthx2 mm outer diameter) were cut for use in the bioassay. Aortic rings were equilibrated at 1 g resting tension for 1 hour at 37°C in a gassed (5% CO2/95% O2) modified Krebs-Henseleit buffer. The relaxant action of LXA4 was measured in endothelial-intact aortic rings that were precontracted with 1 µmol/L phenylephrine. A relaxant response to 10 µmol/L ACh (60% to 95% of phenylephrine contraction) was taken as a positive index for an intact endothelium. To assess the contribution of the endothelium to the relaxation response, endothelium-free preparations were used.17 Reagents were added directly to the organ bath (4-mL plastic cuvette), and the development of tension and subsequent relaxation exhibited by the rings was monitored by either Grass or Statham force-displacement transducers.
Materials
LXA4 was obtained from Calbiochem. Celecoxib and SC-560 were kindly provided by NicOx SA (Sophia Antipolis, France) and Boehringer-Ingelheim (Ingelheim, Germany), respectively. Zileuton, ACh, L-NAME, L-NA, and Boc2 were obtained from Sigma Chemical Co. Rabbit anti-rat neutrophil serum was obtained from Accurate Chemical Co. ELISA kits for thromboxane B2 were obtained from Cayman Chemical Co, whereas those for 15-(R)-epi-LXA4 were obtained from Neogen.
Statistical Analysis
Data are presented as mean±SEM. Comparisons among groups of data were made with a 1-way ANOVA, followed by a Dunnett multiple-comparison test, or a Student t test. An associated probability of 5% was considered significant.
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Results |
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BP Effects of LXA4
Intravenous administration of LXA4 at a dose of 0.6 µg/kg did not produce a significant change in systemic arterial BP (+1.1±0.5 mm Hg). However, at a dose of 2.5 µg/kg, LXA4 administration resulted in a decrease in BP of 14.3±3.7 mm Hg within 10 to 20 seconds (P<0.05 versus basal). The effects were transient, with a return to baseline BP within 3 to 4 minutes. Administration of L-NAME resulted in an increase in systemic arterial BP of 21±4 mm Hg and abolished the hypotensive response to subsequent administration of LXA4 (–1.6±0.4 mm Hg).
Serum Levels of ATL
Serum levels of ATL were negligible in rats treated with vehicle (Figure 1). However, intraperitoneal administration of aspirin caused a significant increase in serum ATL levels (20-fold), which was largely inhibited by pretreatment with celecoxib or zileuton. Administration of aspirin to neutropenic rats did not cause a significant increase in serum ATL levels. Pretreatment with L-NAME did not significantly affect serum levels of ATL after aspirin administration (Figure 1).
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P<0.05 vs group treated with vehicle+aspirin. Abbreviations are as defined in text.
BP Effects of Aspirin
Intraperitoneal administration of aspirin resulted in a rapid increase in systemic arterial BP (10 mm Hg; Figure 2) and a gradual return toward baseline over the next 10 to 15 minutes (Table). Pretreatment with celecoxib did not significantly affect BP, but the increase in BP observed after subsequent administration of aspirin was significantly increased (Figure 2). The time for return of BP to baseline levels was increased 3-fold (Table). Pretreatment with the 5-LO inhibitor zileuton produced an effect similar to that of celecoxib, augmenting the pressor response to aspirin (Figure 2) and markedly delaying the return of BP to baseline levels (Table). Likewise, pretreatment with the lipoxin receptor antagonist Boc2 produced effects similar to those observed with celecoxib pretreatment (Figure 2; Table).
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In rats in which circulating neutrophils had been immunodepleted, the pressor response to aspirin was significantly increased relative to controls (Figure 3). Likewise, inhibition of NO synthesis resulted in significant augmentation of the pressor response to aspirin (Figure 3). Neither induction of neutropenia nor NO synthase inhibition altered the BP response to injection of vehicle, although the latter caused an increase in baseline BP of 20 mm Hg.
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Effects of Selective COX-1 Inhibition
Administration of the selective COX-1 inhibitor SC-560 elicited a rise in systemic arterial BP of 8.0±2.7 mm Hg, comparable to the effect of aspirin. The time to return of BP to pretreatment levels (10.3±2.7 minutes) was also comparable to that observed with aspirin administration. Pretreatment with the selective COX-2 inhibitor celecoxib did not significantly affect the pressor response to SC-560 (9.4±1.6 mm Hg). Aspirin and SC-560 exhibited comparable effects on whole-blood thromboxane synthesis, which is an index of COX-1 activity.16 In vehicle-treated rats, mean whole-blood thromboxane synthesis was 357±43 ng/mL, whereas with aspirin and SC-560, it was reduced significantly to 24±14 ng/mL and 32±10 ng/mL, respectively (P<0.01).
LXA4-Induced Relaxation of Mesenteric Arteries
In rat mesenteric arteries that had been precontracted with a thromboxane mimetic, exposure to LXA4 (1 µmol/L) resulted in a relaxation response (29±4%; Figure 4). At a higher concentration (3 µmol/L), the relaxation induced by LXA4 reached 79±5% (n=3), a value comparable to that obtained in response to 10 µmol/L ACh (Figure 4). Like ACh-induced relaxation, the response to LXA4 was significantly decreased in vessels denuded of their endothelium. However, the response to LXA4 was not affected by coincubation with an NO synthase inhibitor (L-NA; 300 µmol/L), in contrast to the response to ACh, which was significantly decreased when NO synthesis was inhibited. Similarly, L-NA failed to inhibit relaxation in preparations exposed to 3 µmol/L LXA4 (relaxation of 89±3% of control).
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; 1 µmol/L) or ACh (
; 10 µmol/L), applied for duration of time indicated by horizontal bars, in control conditions (top traces), in endothelium-denuded vessel (bottom trace, A), and in presence of L-NA (300 µmol/L; bottom trace, B). C, Histograms summarizing relaxation to LXA4 and ACh under control conditions, in endothelium-denuded vessels, and in presence of L-NA (300 µmol/L). *P<0.05 compared with corresponding control group. Abbreviations are as defined in text.
LXA4-Induced Relaxation of Aortas
As in the mesenteric artery preparation, application of LXA4 (1 µmol/L) to rat aortic rings, which had been precontracted with phenylephrine, resulted in significant relaxation (Figure 5A). This relaxation was not observed when LXA4 was applied to aortic rings in which the endothelium had been removed (Figure 5B). In contrast to the mesenteric arteries, the relaxation induced by LXA4 in aortic rings was abolished when the rings were preexposed to an inhibitor of NO synthase (L-NAME, 100 µmol/L; Figure 5A).
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; 0.1 mmol/L), were preconstricted with phenylephrine (
; PE,1 µmol/L) and then exposed to ACh (
, 1 µmol/L). Tracings are representative of 3 or more experiments done with ring preparations obtained from different rats. Other abbreviations are as defined in text. |
Discussion |
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There is considerable evidence that ATL contributes to the antiinflammatory effects of aspirin2,18,19 and that lipoxin exerts actions in the stomach that counteract the mucosa-damaging effects of aspirin.15,20,21 The latter has also been reported to be an NO-dependent effect of ATL.4 In the present study, one of the main findings was that ATL also counteracts aspirin’s systemic pressor effects by promoting vasodilation in an NO-dependent manner. Celecoxib (a selective inhibitor of COX-2), administered concurrently with aspirin, suppressed the generation and thus the counterregulatory action of ATL. COX-2 inhibition caused a doubling of the hypertensive response to aspirin and a tripling of the duration of the hypertensive response. Consistent with the evidence that ATL is generated from 5-HETE through the action of 5-LO, zileuton (a 5-LO inhibitor) also suppressed ATL production and augmented the magnitude and duration of the pressor effects of aspirin.
The observation that Boc2, a lipoxin receptor antagonist,9 produced a similar augmentation of aspirin-induced pressor response to that observed with the COX-2 and 5-LO inhibitors further supports the hypothesis that ATL acts as a vasorelaxant. These effects appear to be mediated via the generation of NO, because L-NAME produced a similar augmentation of the pressor effects of aspirin as seen with celecoxib and zileuton but did not affect ATL generation. In rat aortic rings, LXA4 elicited relaxation, which was abolished by an NO synthase inhibitor or by prior denudation of the endothelium. In rat mesenteric arteries, the relaxant effect of LXA4 was confirmed to be endothelium dependent but was not affected by inhibition of NO synthase activity (see below).
ATL generation is proposed to occur via transcellular metabolism of arachidonic acid.2 In the endothelium (and possibly other cells), COX-2–dependent metabolism of arachidonic acid to 5-HETE is followed by diffusion of this mediator to other cells. In neutrophils (and possibly other cells), 5-HETE is further metabolized by 5-LO to ATL. Thus, the studies performed with neutropenic rats support the hypothesis that ATL occurs via transcellular metabolism, with the neutrophil being the major cellular source of 5-LO. The neutropenic rats did not form ATL after aspirin administration, and the vascular response to aspirin was similar to that observed in rats treated with a 5-LO inhibitor.
Most of the present study focused on the effects of ATL with regard to BP. However, LXA4 can be formed independently of aspirin administration and could similarly affect systemic or local vascular tone. LXA4 binds to the same receptor as ATL and exerts similar effects on neutrophil function.2,19,22,23 The present studies showed that, in addition to relaxing vascular smooth muscle in vitro, bolus injection of LXA4 resulted in a transient decrease in systemic BP, consistent with its short in vivo half-life.23 LXA4 produced in the context of inflammation, therefore, could have significant effects on regional blood flow and possibly on systemic BP. It is important to note that the receptor for LXA4 also binds other endogenous mediators, including annexin-1 and serum amyloid protein A, raising the possibility that other agonists could also influence regional blood flow, and possibly systemic BP, in the context of inflammation.
As mentioned earlier, studies in aortic rings and mesenteric arteries confirm that LXA4 can relax vascular smooth muscle. These effects were endothelium dependent, and in the case of the aortic rings, NO dependent. Inhibition of NO synthase in the mesenteric artery preparation did not result in a significant diminution of the relaxant response to LXA4. This observation is consistent with the reported inability of NO synthase inhibitors to abolish agonist-induced, endothelium-dependent relaxation in rat small mesenteric arteries. In these vessels, NO contributes very little to the relaxation response to substances such as ACh and bradykinin,24,25 and the vasorelaxation has been shown to be mainly caused by an "endothelium-derived hyperpolarizing factor," the identity of which remains controversial.26 A more important role has been nonetheless attributed to NO in ACh-induced relaxation when intact, buffer- or blood-perfused rat mesenteric preparations were used.16,27,28 The reasons for the differences are unclear, but the latter set of studies may support the present findings and suggest that although NO was not shown to play any role in LXA4-induced relaxation of mesenteric arteries, it may make a more important contribution to such responses in vivo.
In summary, the results of the present study identify a previously unrecognized contribution of lipoxin to the pressor effects of aspirin. Inhibition of aspirin-triggered lipoxin synthesis with a COX-2 inhibitor or 5-LO inhibitor results in a significantly increased pressor response to aspirin, both in terms of magnitude and duration of the response. Aspirin-triggered lipoxin synthesis may also contribute to regional alterations in blood flow after aspirin administration, and LXA4 may contribute to inflammation-associated changes in vascular perfusion.
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Acknowledgments |
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Drs von der Weid and Wallace are supported by awards from the Alberta Heritage Foundation for Medical Research (Scholar and Senior Scientist, respectively). This work was supported by grants from the Canadian Institutes of Health Research (to P.v.d.W. and J.L.W.) and the Heart and Stroke Foundation of Alberta and Nunavit (to M.D.H.).
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