BJA Advance Access originally published online on February 1, 2007
British Journal of Anaesthesia 2007 98(3):323-330; doi:10.1093/bja/ael378
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Evidence that a prostanoid produced by cyclo-oxygenase-2 enhances contractile responses of the porcine isolated coronary artery following exposure to lipopolysaccharide
Department of Anaesthesia and Intensive Care Medicine, and School of Biomedical Sciences, Centre for Integrated Systems Biology and Medicine, Queens Medical Centre, University of Nottingham, Nottingham, UK
* Corresponding author: E-mail: ravi.mahajan{at}nottingham.ac.uk
Accepted for publication November 14, 2006.
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Abstract |
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BACKGROUND: Prolonged incubation of porcine isolated coronary artery (PCA) to lipopolysaccharide (LPS) causes a moderate reduction in vessel constrictive responsiveness. This has been attributed mainly to the induction of nitric oxide synthase (NOS). We aimed to investigate the role of induction of cyclo-oxygenase (COX) and expression of endothelin receptor 1-A (ET1A) in modulating the vascular responses of PCA in vitro.
METHODS: Segments of PCA were exposed to 100 µg ml–1 LPS overnight. L-Arginine 0.4 mM was included in the medium in some preparations to examine the influence of intracellular nitric oxide, and the influence of extracellular donor sodium nitroprusside (SNP) was also examined in separate experiments. After overnight incubation, the contractile function of the artery was evaluated by the isometric tension recording test. The non-selective NOS inhibitor (L-NAME), non-selective COX inhibitor (indomethacin), COX-1 inhibitor (FR 122047), COX-2 inhibitor (NS 398), and ET1A receptor antagonist (FR 139317) were added into the organ bath 30 min before eliciting contractile responses to KCl or U46619 [GenBank] separately or in combinations. Vascular relaxations to 10 nM Substance P (SP) were also assessed.
RESULTS: L-Arginine did not potentiate the effects of LPS. SNP caused a quantitatively larger reduction in the responsiveness to KCl and U46619 [GenBank] compared with 100 µg ml–1 LPS. Post exposure to a combination of indomethacin and FR 139317, indomethacin or NS 398 alone enhanced the inhibitory effects of LPS, but FR 122047 or FR 139317 alone failed to modify the responses to LPS. L-NAME fully reversed the changes induced by LPS combined with indomethacin and NS398. In terms of the relaxation by SP, LPS failed to change the magnitude; none of the agents used affected the response except L-NAME which abolished it.
CONCLUSION: NOS and COX-2 are both activated by overnight exposure to LPS in vascular smooth muscle from PCA in vitro. The prostanoid produced by COX-2 functionally antagonizes the effects of induction of NOS.
Keywords: arteries, coronary; complications, endotoxaemia; enzymes, cyclo-oxygenase
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionAcknowledgementsReferences |
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Prolonged exposure of vascular smooth muscle to lipopolysaccharide (LPS) and proinflammatory cytokines causes induction of a variety of enzymes capable of producing potent vasoactive substances. Nitric oxide synthase (NOS), cyclo-oxygenase-2 (COX-2), and endothelin converting enzyme (ECE) have been shown to be upregulated in vascular smooth muscle cells after incubation with endotoxin to produce nitric oxide, various prostanoids, and endothelin, respectively.1–4 To date, most attention has been focused on the functional significance of inducible NOS. L-NAME, an inhibitor of NOS,5 6 has been shown to reverse hypotension in humans during sepsis, offset reduced vasoconstrictor responses of omental resistance arteries excised from patients with fulminant sepsis, and reverse the suppression of vasoconstrictor responses produced by LPS and proinflammatory cytokines.7–10
In contrast to NOS, the functional role of COX-2 and ECE in sepsis has not been examined in detail, although both have been implicated indirectly. There is evidence that levels of circulating endothelin are elevated in experimental endotoxemia in pigs11 and healthy volunteers,12 and bosentan, a selective inhibitor of endothelin receptors, has been reported to improve microcirculatory blood flow in septic pigs.13 Similarly, a combination of bosentan and diclofenac has been reported to reduce pulmonary hypertension in endotoxic pigs,14 and indomethacin was found to improve the sensitivity of omental arteries from septic patients to vasoconstrictor agents.6
We have recently noted that exposure of the porcine isolated coronary artery (PCA) to a high concentration of LPS resulted in impaired contractions to KCl and U46619 [GenBank] that persisted after removal of the toxin.15 However, the magnitude of the changes in vascular responsiveness was markedly less pronounced than that reported in other blood vessels, despite evidence that the effects were prevented or reversed by exposure to either dexamethasone or L-NAME, respectively. Indeed, the effects of LPS have been shown to be variable in different vascular beds. We hypothesize that the relative lack of inhibitory effect of LPS on contractility of the PCA is due to associated upregulation of a ‘vasoconstrictor’ influence. In an earlier study of pulmonary arteries from the pig and from humans, we established that endothelial prostanoids in the porcine artery exert a vasoconstrictor effect, whereas the opposite was true for the human pulmonary artery.16 Also endothelin has been shown to be vasoconstrictive.17 Therefore, we considered the possibility of LPS-induced upregulation of either COX-2 or ECE or both. In this study, we aimed to use selective inhibitors of the COX-1 and COX-2, FR 122047 and NS 398, respectively,18 and a potent antagonist of ETA receptors, FR 139317,17 to functionally evaluate the contribution of vasoconstrictor prostanoids and endothelin to LPS-induced changes in vascular responsiveness. As part of this study, we also compared the effect of LPS treatment and sodium nitroprusside (SNP) to establish the maximum possible effect of nitric oxide-mediated modulation of contractile responses.
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Methods |
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Porcine hearts were obtained from a local abattoir and transported to the laboratory within 1 h in Krebs–Henseleit (K–H) solution maintained at 4°C. The anterior descending branch of the coronary artery was dissected from the hearts, cleaned of connective tissues, and then divided into 5 mm long segments. Paired segments of the coronary artery were incubated in 2 ml K–H solution (previously gassed with 95% O2 and 5% CO2 for 5 min) containing ficoll 2% and a combination of 60 µg ml–1 benzyl penicillin and 20 µg ml–1 streptomycin sulphate, either in the presence or absence of 100 µg ml–1 LPS (Escherichia coli O111:B4). The solution and segment were sealed in a sterilized glassvial and stored overnight at 37°C for 16–18 h. All dissection instruments were washed immediately after use and stored in 70% industrial methylated spirit until required. In preliminary experiments, 0.4 mM L-arginine was also included in the incubation medium to assess whether the conditions employed resulted in a significant loss of cellular L-arginine.
After overnight storage, segments were taken out of the incubation solution and prepared for isometric tension recording. The segments were suspended between two stainless steel wires (0.4 mm diameter) supported and placed in a 15 ml isolated organ bath containing K–H solution (pH 7.4) gassed with 95% O2 and 5% CO2 and maintained at 37°C. The lower support was fixed to a glass holder, whereas the upper support was connected to a Grass FT03 isometric force transducer by cotton thread. Some laxity in the suspended segment was maintained for approximately 40 min before the application of resting tension. The force transducer was connected to a MacLab Bridge amplifier and linked via a four-channel MacLab unit to a Macintosh LC4 computer running Chart 3.5.
An initial resting tension of 8 g wt was slowly applied to each segment at the end of the equilibration period and the recorded tension declined to 4–6 g wt over a further 40 min period. To test segment contractility, each preparation was exposed to 60 mM KCl for 15 min until a constant response was obtained, followed by washout and a further 15 min equilibration. This procedure was repeated until exposure to 60 mM KCl produced reproducible contractions. The preparations were then exposed cumulatively to increasing concentration of either KCl (6–60 mM) or U46619
[GenBank]
(a stable thromboxane mimetic analogue, 9,11-dideoxy-9
,11-methanoepoxyprostaglandin F2, 2–500 nM) in the presence or absence of different inhibitors (discussed later). At the end of the experiment, when each preparation was exposed to a maximally effective concentration of U46619
[GenBank]
, Substance P (SP) (10 nM) was added to evaluate the integrity of the endothelium.
To assess the scope for cyclic guanosine 5'-monophosphate (GMP)-dependent mechanisms to modify KCl and U46619 [GenBank] -induced contractions, 3 and 30 µM SNP were added before construction of concentration–response curves. To determine the participation of nitric oxide on the effect of LPS-induced changes in vascular responsiveness, L-NAME (NW-nitro-L-arginine methyl ester, 100 µM), a non-selective inhibitor of NOS, was added 30 min before constructing concentration–response curves to either KCl or U46619 [GenBank] .
The role of COX-derived prostanoids was examined by using the non-selective COX inhibitor, indomethacin (3 µM), the selective COX-2 inhibitor NS 398 [N-(2-cyclohexyloxy-4-nitrophenyl) methanesulphonamide, 1 µM], and the selective COX-1 inhibitor FR 122047 {1-[4,5-bis(4-methoxyphenyl)-2-thiazolyl]-4-methylpiperazinehydrochloride, 3 µM}. Each agent was added 30 min before construction of the agonist concentration–response curve. The selective antagonist for ETA receptors, FR 139317 [N-(N-{N-[(hexahydro-1H-azepin-1-yl)carbonyl]-L-leucyl}-1-methyl-D-tryptophyl)-3-(2-pyridinyl)-D-alanine, 1 µM] was used to evaluate the role of endothelin; in some experiments the effect of a combination of FR 139317 and NS 398 was examined.
Solutions and drugs
The composition of K–H solution is (in mM): NaCl, 118; KCl, 4.8; MgSO4 · 7H2O, 1.2; CaCl2 · 2H2O, 1.3; NaHCO3, 25.0; KH2PO4, 1.2. Benzyl penicillin, streptomycin sulphate, L-NAME, ficoll, LPS, and indomethacin were all obtained from Sigma-Aldrich Company Ltd (Poole, Dorset, UK). SP was obtained from Bachem (UK) Chemical Company (Delphe Court, Merseyside, UK). U46619
[GenBank]
was obtained from Alexis Corporation (Nottingham, UK). FR 139317, FR 122047, and NS 398 were all obtained from Tocris Cookson Ltd (Avonmouth, UK). FR 139317 and NS 398 were dissolved in DMSO at a concentration of 10 mM, whereas indomethacin was dissolved in absolute ethanol at a concentration of 10 mM and the volume of solvent included in any experiment never exceeded 0.1% v/v. Unless indicated otherwise, all other drugs were dissolved in distilled water.
Data analysis and statistics
Contractions produced by U46619
[GenBank]
and KCl were measured as g wt force. Responses have been expressed as the maximum contraction (Emax), and potency determined as the negative logarithm of the concentration causing 50% of the maximum response (–log EC50, or pD2) using the logistic equation (Kaleidagraph, Version 3.6 Synergy Software). The values are shown as the mean (SEM). The differences between mean values were assessed by a Student's paired t-test (two-tailed) or, where there was more than one treatment condition, by ANOVA followed by post-hoc Dunnett's test. P-value < 0.05 was considered statistically significant.
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Results |
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KCl and U46619 [GenBank] elicited concentration-related contractions of the PCA that were significantly reduced by the presence of 3 µM SNP (Fig. 1). The maximum response to KCl and U46619 [GenBank] were significantly reduced by 33.2 (SEM 10.3%), SNP n = 7 and 26.9 (10.6%), n = 6, respectively. A 10-fold increase in concentration caused a larger [51.7 (11.6%), n = 7] reduction in the maximum response to KCl, but failed to further alter the maximum response to U46619 [GenBank] (Fig. 1). Both concentrations of SNP caused a two- to five-fold reduction in the potency of the vasoconstrictor agents.
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Overnight exposure of the PCA to 100 µg ml–1 LPS inhibited the maximum response to KCl by 24.3 (7.3%), n = 8 (Fig. 2A) and caused a two-fold reduction in the potency of U46619 [GenBank] without altering the maximum response (Fig. 2B). SP (10 nM) caused a transient relaxation of the maximal contractions to U46619 [GenBank] [67.5 (5.4%), n = 11] that was not significantly altered by prior exposure to 100 µg ml–1 LPS [52.4 (5.8%), n = 11]. The inclusion of 100 µM L-NAME in the bathing medium caused a small contraction (
5% of the response to 60 mM KCl) and reversed the effect of prior exposure to LPS on contractile responses to KCl (Fig. 2A) and U46619
[GenBank]
(Fig. 2B). Furthermore, relaxations to SP were significantly reduced [5.7 (2.7%), n = 5].
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The qualitative and quantitative difference between the effect of SNP and LPS on both agonist responses prompted an experiment to evaluate whether the incubation conditions employed resulted in significant depletion of cellular L-arginine.19 We examined the effect of U46619 [GenBank] alone after overnight incubation in K–H solution containing 100 µg ml–1 LPS with or without 400 µM L-arginine. Neither the potency of U46619 [GenBank] [LPS pD2 7.28 (0.04); LPS and L-arginine pD2 7.26 (0.04), n = 7] nor the maximum response [LPS Emax 14.1 (1.2) g wt; LPS and L-arginine Emax 12.6 (1.2) g wt] was significantly altered by inclusion of L-arginine in the incubating medium overnight, suggesting that another factor was responsible for the discrepancy between the effect of SNP and LPS on responses to KCl and U46619 [GenBank] .
Indomethacin (3 µM) did not significantly affect contractions elicited by either KCl or U46619 [GenBank] in segments of the PCA stored overnight (Table 1). However, following exposure to 100 µg ml–1 LPS responses to KCl (Fig. 3A) and U46619 [GenBank] (Fig. 3B) were further inhibited by 3 µM indomethacin; the maximum response to KCl was reduced by 32.6 (4.1%), n = 12, while the potency of U46619 [GenBank] declined two-fold (Table 1). Table 1 also shows that 3 µM FR 122047, a selective inhibitor of COX-1, did not affect responses to either KCl or U46619 [GenBank] after exposure to 100 µg ml–1 LPS. In marked contrast, 1 µM NS 398, a selective inhibitor of COX-2, significantly reduced submaximal and maximal responses [35.4 (8.9%), n = 8] to KCl (Fig. 4A). NS 398 also caused a two-fold rightward displacement of the U46619 [GenBank] -induced contractions in LPS-treated segments, which was also associated with a 31.1 (6.0%), n = 8 reduction in the maximum response (Fig. 4B). While 3 µM FR 122047 did not significantly affect responses to KCl or U46619 [GenBank] in control arterial segments (Table 1), 1 µM NS 398 caused a small but significant reduction in the potency of both agonists.
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Indomethacin, FR 122047, NS 398, and FR 139317, did not affect the magnitude of SP-induced relaxations in either control preparations or in LPS-treated segments (data not shown).
Addition of 100 µM L-NAME reversed the inhibitory effect of 1 µM NS 398 on KCl-induced contractions following treatment with 100 µg ml–1 LPS and reduced the inhibitory effect on U46619 [GenBank] -induced contractions (Fig. 5). Interestingly, KCl exhibited greater potency in LPS-treated segments with L-NAME and NS 398 compared with control segments (Table 2 and Fig. 5), whereas U46619 [GenBank] -induced contractions were not similarly affected; LPS-treated segments in the presence of L-NAME and NS 398 were less sensitive to U46619 [GenBank] compared with control segments (Table 2 and Fig. 5).
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Discussion |
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Prolonged exposure of the PCA to LPS was associated with a reduction in responsiveness to vasoconstrictor agents similar to that reported previously.15 Maximum contraction following the opening of voltage-sensitive L-type Ca2+ channels by KCl was significantly reduced by this treatment, and the potency of U46619 [GenBank] , an activator of thromboxane A2 receptors, was reduced even though the maximum response was unaffected. Both of these effects were overcome by the presence of L-NAME, an inhibitor of NOS,20 suggesting an enhanced role for nitric oxide, soluble guanylyl cyclase, and cyclic GMP in regulating vascular tone.4 21 However, the magnitude of the changes produced by LPS was less pronounced than that noted for stimulation of guanylyl cyclase with SNP, with SNP causing a significant reduction in the maximum response to U46619. [GenBank] We initially considered the possibility that the incubation medium employed (K–H solution) resulted in a depletion of cellular L-arginine stores,19 but even the inclusion of 0.4 mM L-arginine in the medium did not alter the subsequent effect of LPS on U46619 [GenBank] -induced contractions. Another factor therefore appeared to account for the limited impairment of contractile responses in the coronary artery mediated by nitric oxide after exposure to LPS. The importance of this point is that a characteristic feature of the effects of LPS on many isolated blood vessels, from both pigs7 22–24 and humans9 21 is the surprisingly modest reduction in sensitivity to vasoconstrictor agents.
In light of the wealth of evidence from cultured vascular smooth muscle cells that LPS can induce both cyclo-oxygenase-21 25 and endothelin-converting enzyme,2 26 we considered the possibility that vasoactive products produced by these enzymes counteracted the full inhibitory effect of the induction of NOS. The approach adopted was to use pharmacological agents at concentrations with known selectivity for the enzyme/receptor of interest and examine their effects on control and LPS-treated segments. Indomethacin was used as an inhibitor of cyclooxygenase, while FR 122047 and NS 398 were used as selective inhibitors of cyclooxygenase 1 (COX-1) and cyclooxygenase 2 (COX-2), respectively.18 FR 139317 was employed as a selective antagonist of ETA receptors that mediate the contractile responses to ET.17
None of the agents used in this study to inhibit COX or ET effects changed basal tone of the coronary artery, nor did they significantly affect the magnitude of endothelium-dependent relaxations to SP in control and LPS-treated segments. In contrast, L-NAME caused a small, endothelium-dependent contraction of coronary artery under baseline conditions and greatly reduced SP-induced relaxation (present study). These findings suggest that indomethacin, FR 122047, NS 398, and FR 139317 have relatively little effect on coronary endothelial cell function. With the exception of NS 398, these agents also failed to influence contractile responses to KCl and U46619 [GenBank] in control preparations at the concentrations used.
In marked contrast, indomethacin inhibited responses to KCl in LPS-treated segments and reduced both the potency and maximum responses to U46619. [GenBank] Qualitatively similar effects were noted with NS 398 but not FR 122047. The magnitude of these changes produced by the cyclo-oxygenase inhibitors in LPS-treated segments are greater than those noted in the rat thoracic aorta treated with IL-1ß.3 Interestingly, inducible NOS appears to be more important in rat blood vessels following LPS treatment than that noted in the PCA.8 27 Collectively these data suggest that after exposure of the PCA to LPS, vasoconstrictor prostanoids (produced by COX-2) support contractions arising from the opening of voltage-sensitive L-type Ca2+ channels (KCl) and G protein coupled receptors (U46619 [GenBank] ). The proconstrictor effect of prostanoids appears to offset the full inhibitory effect arising from nitric oxide produced by induced NOS. The absence of any major effect of FR 139317 on responses to KCl and U46619 [GenBank] after exposure to LPS suggests that any induction of endothelin-converting enzyme is not of functional importance in this blood vessel. This is underlined by the finding that FR 139317 was still devoid of effect in LPS-treated segments after inhibition of COX-2 (unpublished observations). It should be noted, however, that the protocol adopted for this study involves removal of proinflammatory stimuli before assessment of vascular responsiveness. This approach relies on there being significant on-going production of vasoactive substances for activity to be detected, rather than simply measuring cumulative generation.2 26 Alternatively, as noted in other studies, a role for endothelin in modulating vascular responses may become more obvious with longer periods of incubation with LPS.26
Smooth muscle cells have the potential to generate different prostanoids,1 28 but most earlier studies concerning the effect of prolonged exposure to proinflammatory stimuli (as a model for sepsis) concentrated on measuring the production of vasodilator prostanoids.1 29 30 However, Jourdan and colleagues28 noted that human pulmonary smooth muscle cells have the potential to produce both dilator (PGE2) and constrictor (8-iso-PGF2) prostanoids after the induction of COX-2. Thus, in the absence of knowledge of the potency of each prostanoid at their respective receptor, it is not easy to predict whether the net effect of the proinflammatory stimuli will cause an enhancement or an impairment of vascular responsiveness. Interestingly, 8-iso-PGF2 has been reported to be a potent vasoconstrictor in porcine arteries,31 32 whereas the overall response to 8-iso-PGE2 is dependent on prevailing vascular tone.32 As 8-iso PGF2 activates thromboxane A2 receptors, this may explain why contractions elicited by U46619
[GenBank]
are less affected by indomethacin and NS 398 than those elicited by KCl: there being less potential for the prostanoid to enhance constrictor responses. Although the present study provides strong evidence for the presence of a COX-2 dependent vasoconstrictor prostanoid in PCA exposed to LPS, one of the limitations of this study is a lack of direct demonstration of this prostanoid. Further confirmation of the findings of this study will require direct demonstration, using a different methodology, that the coronary artery produces significant amounts of 8-iso PGF2 following prolonged exposure to LPS and that this effect is blocked by exposure to a selective inhibitor of COX-2 (e.g. NS 398).
As indicated, the principal observation in this study suggests that COX-2 induced by LPS produces proconstrictor prostanoids in the PCA. This finding contrasts with isolated omental arteries from patients diagnosed with sepsis, where indomethacin enhanced contractions to both noradrenaline and U46619. [GenBank] This suggests that the net effect of the induction of COX was the production of vasodilator prostanoids.6 It remains to be determined whether porcine omental arteries respond to LPS with the production of vasodilator prostanoids.
Our observations indicate that LPS-induced changes in the PCA primarily arise from opposing effect of the induction of NOS and COX-2. Thus, we also examined the effect of combined inhibition of the enzymes on responses to KCl and U46619 [GenBank] after exposure to LPS, with the expectation that this would result in the restoration of ‘normal’ vascular responsiveness. However, the combination of L-NAME and NS 398 failed to restore the sensitivity of the LPS-treated artery to that observed in control preparations. Intriguingly, responses to U46619 [GenBank] and KCl were differentially affected, indicating that the activity of voltage-sensitive L-type Ca2+ channels is actually enhanced after treatment with LPS. This observation suggests that a further factor may be implicated in LPS-induced derangement of vascular responsiveness.
In summary, we have established that for PCA, exposure to LPS induces both NOS and COX-2 in the smooth muscle, with negligible effect on endothelial cell function. Prostanoids produced by COX-2 promote constriction and oppose the effect of nitric oxide on vascular responses. Further studies are warranted on other blood vessels, particularly resistance arteries and veins where the contribution of COX-2 to changes in vascular responsiveness may be greater,1 to establish the significance of these findings.
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We wish to thank Woods Ltd, Clipstone, Nottinghamshire, for the supply of porcine hearts. Some results were presented at the ARS meeting held in Leicester 2005.
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