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(Hypertension. 2004;43:1264.)
© 2004 American Heart Association, Inc.

Scientific Contributions

Cyclooxygenase Involvement in Thromboxane-Dependent Contraction in Rat Mesenteric Resistance Arteries

Manlio Bolla; Dong You; Laurent Loufrani; Bernard I. Levy; Sylviane Levy-Toledano; Aïda Habib; Daniel Henrion

From the Institut National de la Santé et de la Recherche Médicale (INSERM) Unit 348 (M.B, S.L.-T., A.H.) and Unit 541 (D.Y., L.L., B.I.L., D.H.), IFR Circulation-Paris-Nord, Paris, France.

Correspondence to Dr Daniel Henrion, PharmD, PhD, INSERM Unit 541, 41 bd de la chapelle, 75475 Paris, France. E-mail daniel.henrion{at}med.univ-angers.fr

	Abstract

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The influence of cyclooxygenase pathway activation following thromboxane-endoperoxide (TP) receptor stimulation was studied in rat mesenteric resistance arteries (n=6 to 10 per group). We studied isolated, perfused, and pressurized mesenteric resistance arteries (mean internal diameter 214 µm) using an arteriograph, enabling us to study arteries in physiological conditions of flow and pressure. Changes in diameter were continuously recorded, and contractions measured as internal diameter reduction. Release of cyclooxygenase pathway metabolites was also assessed by enzyme immunoassay (EIA) analysis of mesenteric bed perfusions. The thromboxane A2 (TxA₂) analog U-46619 (1 µmol/L) induced a significant contraction (108 µm maximal diameter reduction). Inhibition by 3 chemically different cyclooxygenase inhibitors (ie, flurbiprofen, indomethacin, and aspirin) potently reduced the contraction to 27%, 25%, and 6% of control, respectively. The selective cyclooxygenase-1 inhibitor SC-58560 inhibited U-46619 contraction, whereas selective cyclooxygenase-2 inhibition (SC-58236) had no effect. Thromboxane synthase inhibition (furegrelate) did not affect U-46619-induced contraction, but it was reduced by cytosolic phospholipase A2 inhibition. Measurement of cyclooxygenase derivatives produced by the isolated mesenteric bed showed that PGE₂ was produced after TxA₂-receptor stimulation with U-46619. Exogenous prostaglandin E₂ (in the presence of the TxA₂ receptor antagonist SQ 29 548) and U-46619 contracted mesenteric arteries with a similar potency (EC₅₀: 0.30 and 0.48 µmol/L, respectively). This study provides the first evidence that TxA₂-receptor-dependent contraction in a resistant artery involved cyclooxygenase stimulation and, at least in part, a PGE₂ formation. This mechanism of TxA₂-dependent contraction in resistant arteries might be of importance in the understanding of diseases affecting resistant arteries and involving TxA₂, such as hypertension.

Key Words: resistance • cyclooxygenase • prostaglandins • thromboxane

	Introduction

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Thromboxane A₂ (TxA₂), a lipid mediator originating from arachidonic acid (AA) metabolism through the cyclooxygenase (COX) pathway, is a powerful constrictor of vascular smooth muscle.¹ Enhanced TxA₂ production has been reported in several cardiovascular diseases, such as unstable angina,² acute myocardial infarction,² spontaneous hypertension,³ and pregnancy-induced hypertension.⁴ In resistance arteries, TxA₂ is produced on flow stimulation (shear stress) of the endothelium, and this production is increased in the case of hypertension.⁵ Similarly, the involvement of TxA₂ also increases the pressure-induced myogenic tone in hypertension.⁶

TxA₂ acts through specific G-protein coupled.¹ Activation of TxA₂ receptor (TP; also known as thromboxane-endoperoxide receptor) leads to phospholipase C activation, release of inositol triphosphate1 (IP3), and an increase in the intracellular Ca²⁺ level, thus triggering the smooth muscle contraction.⁷

Cyclooxygenases are important enzymes in the formation of prostaglandins and TxA₂. They present a double enzymatic activity, cyclooxygenase before and peroxidase after, producing, from the precursor AA, the unstable endoperoxide intermediates PGG₂ and PGH₂, respectively. PGH₂ itself already possesses activity,^1,8 or, alternatively, it may be metabolized by different isomerases or synthases into prostaglandins, prostacycline (PGI₂), or TxA₂.^1,9 Two isoforms of COX are known: one constitutive (COX-1); the second one inducible (COX-2).^10,11

Resistance arteries are known to play an important role in the generation of peripheral vascular resistance and are involved in the control of local blood distribution and capillary pressure.^12,13 Their vascular tone is regulated by the sympathetic nervous system, circulating hormones, and vasoactive metabolites produced by endothelial cells, among them TxA₂.¹⁴ TxA₂ contributes to the homeostasis of normal resistance arteries, and an alteration of its synthesis or release was shown in pathological states, such as hypertension.^5,6

Involvement of COX in the vascular response of resistance arteries to different stimuli has been demonstrated. Vasoactive agents like angiotensin II,¹⁵ endothelin,¹⁶ and phenylephrine¹⁷ have been shown to activate and, in part, to induce contraction through the COX pathway. The aim of our work was to evaluate the influence of COX on the response of resistance arteries under conditions of regulated flow and pressure, following TP receptor stimulation by the stable agonist U46619, and to identify the COX metabolite important to the TP-dependent contraction.

	Methods

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Mesenteric Artery in Vitro
Male Wystar Kyoto rats (WKY; Iffa Credo, France), aged 8 to 10 weeks were used. Rats were anesthetized with sodium pentobarbital (50 mg/kg), and their gut excised. The investigation was in accordance with the European Community standards on the care and use of laboratory animals. A second-order mesenteric artery (214±13 µm, internal diameter, 3 to 5 mm length) was cannulated at both ends and mounted in a video-monitored perfusion system as previously described¹⁷ and according to Halpern and Kelley.¹⁸ The arterial segment was bathed in a physiological salt solution (PSS)¹⁷ and superfused (2 mL/min). Perfusion of the artery was set at a rate of 90 µL/min; flow was set at 90 µL/min and pressure at 50 mm Hg. Arterial diameter was measured and recorded continuously using a video monitoring system (Living System Instrumentation Inc). Data were collected, recorded, and analyzed (AcqKnowledge software, Biopac) with the results given in micrometers for arterial inner diameters.

Vessels first were allowed to stabilize for at least 30 minutes and were then stimulated with 60 mmol/L KCl to verify vessel viability. Next, endothelium integrity was assessed by testing the vasodilator effect of acetylcholine (Ach; 1 µmol/L) after preconstriction with phenylephrine (Phe; 1 µmol/L). The response to U-46619 (0.01 to 10 µmol/L or a single dose of 1 µmol/L), a selective and stable thromboxane receptor agonist, was assessed at least twice to obtain a stable and constant contraction. In some experiments, the preparation was preincubated with one of the following drugs: flurbiprofen, indomethacin, diclofenac, and aspirin (used to inhibit COX activity)¹; furegrelate (to block TxA₂ synthesis)¹⁹; SC-58560 (to inhibit COX-1); SC-58236²⁰ (to prevent COX-2 activation)²⁰; or SC-19220 (an EP1 receptor antagonist).²¹ After pretreatment, contraction to U-46619 was repeated and compared with the previous stable contraction to U-46619. At the end of all experiments, a contraction to 60 mmol/L KCl was performed, thus showing no change in vessel reactivity compared with the first. In a separate series of experiments, the effect of indomethacin and flurbiprofen was tested on phenylephrine (1 µmol/L), endothelin-1 (10 nmol/L), PGE₂ (1 µmol/L), and PGF₂ (1 µmol/L). These latter agonists as well as U-46619 were added to PSS so that the PSS superfusing and perfusing the arteries contained the concentration of each drug, as indicated in parentheses above.

Mesenteric Bed Perfusion
Mesenteric beds were prepared as previously described.^22,23 Briefly, the abdomen of anesthetized rats was opened and the gut exposed. The superior mesenteric artery was separated from surrounding fat tissue in the region of the aorta. The rat was then euthanized by exsanguination, cutting the abdominal aorta. A polyethylene catheter (diameter 0.5 mm) was inserted distally into the artery at its origin from the aorta, and the catheter fixed with surgical thread. The intestine was separated from the mesentery and the cannulated mesentery perfused (2.0 mL/min, 37°C). The perfusion pressure was monitored continuously (see Mesenteric Artery In Vitro).

After a 30-minute stabilization period, the preparation was stimulated with 1 µmol/L Phe, followed by 1 µmol/L Ach to check the integrity of the preparations for vascular smooth muscle and endothelial responses. The perfusate was collected for 5 minutes. (10 mL total volume) for the basal and different stimuli.

Perfusate Extraction and Enzyme Immunoassay Analysis
To 10 mL of perfusate samples and 10 µL of formic acid were added 10 000 cpm of [³H]TxB₂ (NEN) for extraction recovery and 1 mL of methanol. After vortexing, samples were centrifuged at 1200g at 4°C for 10 minutes. Supernates were loaded onto C18 Bakerbond silica columns (3 mL), washed with 5 mL water, and then eluted with 3 mL of methanol. Samples were dried under a vacuum and resuspended in 1 mL of enzyme immunoassay (EIA) buffer (EIA buffer: phosphate buffer 0.1 mol/L, pH 7.4 containing 0.15 mol/L NaCl, 1 mmol/L EDTA, and 0.1% bovine serum albumin). Radioactivity was counted in a 100 µL aliquot for recovery and the sample frozen at –20°C until measurement of prostanoids.

EIA Analysis
EIA of 6-keto-PGF₁, the breakdown product of PGI₂ as well as PGE₂ and PGF₂, was performed as previously described.²⁴

Statistical Analysis
Results are expressed as means±SEM of n measurements. The significance of the different treatments was determined by ANOVA or 2-tailed Student paired t test. P<0.05 was considered significant.

Drugs
SC-58560 and SC-58236 were kindly provided by Dr Peter Isakson (Searle Monsanto, St Louis, Mo). HEPES, ACh, Phe, acetylsalicylic acid (ASA), indomethacin, and flurbiprofen were purchased from Sigma. Methyl arachidonylfluorophosphate (MAFP) was purchased from Calbiochem. Other reagents were purchased from Prolabo (Paris, France). Other prostanoids were purchased from Cayman Chemical (Ann Arbor, Mich).

	Results

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Isolated Mesenteric Arteries
Perfused and pressurized rat mesenteric arteries responded to TP receptor stimulation with U-46619 by a concentration-dependent contraction (EC₅₀=0.48±0.06 µmol/L, maximal response: 108±8 µm decrease in diameter, n=10). Pretreatment with 3 chemically nonrelated nonsteroidal anti-inflammatory drugs (NSAIDs), flurbiprofen (1 µmol/L), indomethacin (1 µmol/L), and aspirin (10 µmol/L) inhibited U-46619-induced (1 µmol/L) contraction to 27±6, 25±5, and 6±3% of control, respectively (Figure 1). Indomethacin (1 µmol/L) and flurbiprofen (1 µmol/L) also inhibited, at least in part, Phe (1 µmol/L) and endothelin-1-induced (10 nmol/L) contraction (Figure 1C). PGE₂-induced (1 µmol/L) contraction was also inhibited by aspirin (10 µmol/L, 79±7% of control, n=4), indomethacin (1 µmol/L, 84±8% of control, n=4), and flurbiprofen (1 µmol/L, 84±9% of control, n=4). PGF₂-induced (1 µmol/L) contraction was inhibited by aspirin (10 µmol/L, 68±7% of control, n=5) and indomethacin (1 µmol/L, 78±9% of control, n=4), but not by flurbiprofen (1 µmol/L, 94±8% of control, n=5).

View larger version (17K): [in this window] [in a new window]   Figure 1. A, Concentration-response curves to U-46619 obtained in isolated perfused and pressurized rat mesenteric arteries. Concentration-response curves to U-46619 were repeated in the presence of the nonselective COX inhibitor indomethacin (Indo 1 µmol/L, n=6 per group). B, Inhibitory effect of 3 chemically nonrelated nonsteroidal anti-inflammatory drugs indomethacin (1 µmol/L, Indo), flurbiprofen (1 µmol/L, Flur), and aspirin (10 µmol/L, ASA) on U-induced 46619 (1 µmol/L) contraction. C, Inhibitory effect of indomethacin (1 µmol/L, Indo) and flurbiprofen (1 µmol/L, Flur) on phenylephrine- (Phe, 1 µmol/L) and endothelin-induced 1 (ET-1, 10 nmol/L) contraction. Contraction was obtained in perfused and pressurized rat mesenteric resistance arteries (n=10 per group). *P<0.05 2-tailed Student paired t test.

Removing the endothelium did not affect the inhibitory effect of indomethacin (1 µmol/L) on U-46619-induced contraction (108±9 µm decrease in diameter versus 18±4, n=5). The selective COX-1 inhibitor SC-58560 concentration dependently decreased concentration-response curve (CRC) to U-46619, whereas the COX-2 selective inhibitor (SC-58236) was mainly ineffective (Figure 2).

View larger version (20K): [in this window] [in a new window]   Figure 2. Changes in diameter in response to increasing concentrations of the thromboxane-endoperoxide (TP) receptor agonist U-46619 in perfused and pressurized rat mesenteric resistance arteries (n=8 per group, mean±SEM). A, Concentration-response curves to U-46619 were repeated in the presence of the selective COX-1 inhibitor SC-58560 or (B) in the presence of the COX-2 selective inhibitor (SC-58236). Control experiments were conducted in the presence of the solvent (<0.1% dimethyl sulfoxide). *P<0.05; 2-factor ANOVA.

Phospholipase A2 (PLA2) inhibition with MAFP (10 µmol/L) reduced to 13% of the control the maximal response to U-46619 (20±5 µm loss in diameter after MAFP versus 155±15 µm in control, n=6). This inhibition completely overlapped inhibition given by the NSAIDS. By contrast, Phe-induced (1 µmol/L) contraction was only reduced to 54±6% (n=4) of the control by MAFP (10 µmol/L).

Thromboxane synthase inhibition (furegrelate, 10 µmol/L) left the maximal response unchanged to U-46619 (84±9 µm contraction in the presence of furegrelate versus 89±10 µm in control, n=6). On the other hand, Phe (1 µmol/L) and endothelin-1-induced (10 nmol/L) contraction were decreased, respectively, to 46±7% (n=4) and 41±7% of control by furegrelate (10 µmol/L).

PGF₂ and PGE₂ are 2 other possible COX-derived compounds that might be involved in U-46619-induced contraction in mesenteric resistance arteries. CRC to exogenous PGF₂ showed a contractile response only at high concentrations (Figure 3). The response to PGF₂ (10 µmol/L) was abolished by the TP receptor antagonist SQ 29 548 (10 µmol/L) (Figure 4).

View larger version (23K): [in this window] [in a new window]   Figure 3. Changes in diameter in response to increasing concentrations (1 nmol/L to 0.1 µmol/L) of the TP receptor agonist U-46619, PGF2, or PGE2 in perfused and pressurized rat mesenteric resistance arteries (n=8 per group, mean±SEM). *P<0.05; 2-tailed Student t test.

View larger version (15K): [in this window] [in a new window]   Figure 4. Inhibitory effect of the TP receptor antagonist SQ 29,548 (SQ, 10 µmol/L) on U-46619- (U46, 1 µmol/L), PGF2- (10 µmol/L), or PGE2-induced (1 µmol/L) contraction. Contraction was obtained in perfused and pressurized rat mesenteric resistance arteries (n=8 per group). *P<0.05; 2-tailed Student t test.

The second exogenous metabolite tested was PGE₂ (Figure 3). The contraction elicited by PGE₂ (1 µmol/L) was not significantly affected by SQ 29 548 (Figure 4), suggesting a direct contractile action of PGE₂. The TP receptor antagonist SQ 29 548 induced no significant inhibition of Phe-induced contraction (data not shown), but it induced a 34±5% (n=5) inhibition of endothelin-1-induced tone.

The EP1 receptor antagonist SC-19220 (10 µmol/L) significantly inhibited U-46619-induced contraction to a level equivalent to 48% of control (94±7 versus 45±9 µm decrease in diameter, n=6). On the other hand, endothelin-1-induced contraction was not significantly reduced by SC-19220 (105±17 versus 88±12 µm decrease in diameter, n=4). In the absence of endothelium, SC-19220 (10 µmol/L) inhibited a similarly U-46619-induced contraction (112±10 µm decrease in diameter versus 61±7, n=5).

EIA Analysis of Perfused Mesenteric Beds
An immunometric measurement for 6-keto-PGF₁ (the stable metabolite of PGI₂), PGF₂, and PGE₂ was performed in the perfusate of isolated mesenteric beds. Unfortunately, U-46619 interferes with the dosage of 6-keto-PGF₁, and PGF₂ and the amount of U-46619 present in the PSS collected from perfused mesenteric beds made it impossible to determine this metabolite. Nevertheless, PGI₂ is more likely to induce dilation in mesenteric resistance arteries.⁵ However, a rise in 6-keto-PGF₁ immunoreactivity was shown after cholinergic receptor stimulation with Ach, confirming that the endothelial layer was intact. A second confirmation was recognized in the fall of perfusion pressure from 81±6 mm Hg to 32±5 mm Hg in the presence of acetylcholine after phenylephrine-induced precontraction (n=6). On the contrary, a 2-fold rise in PGE₂ secretion was observed in the presence of U-46619 stimulation (Figure 5), with a very low (<1% of the final amount calculated) interference of U-46619 in assaying PGE₂.

View larger version (14K): [in this window] [in a new window]   Figure 5. EIA of PGE2 was done using specific antibodies and tracers in the presence or in the absence (control) of U-46619 in a PSS collected from rat perfused mesenteric beds. *P<0.05; 2-tailed Student t test.

	Discussion

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The present study brings new insights in the comprehension of the physiological role of TxA₂ in resistance arteries. Surprisingly, contractions induced by the stable TP receptor agonist U-46619 were strongly attenuated by nonselective COX inhibitors and by a selective COX-1 inhibitor. Further analysis showed that PGE₂ may be, at least in part, the mediator involved in U-46619-induced contraction in rat mesenteric resistance arteries.

Resistance arteries determine vascular resistance, and, hence, have a key role in the control of local blood flow.¹³ There is an increasing number of studies showing that TxA₂ may have a significant role in the vascular homeostasis in several vascular beds.^3,5,6 This involvement of TxA₂ in controlling vascular tone is enhanced in pathological situations such as hypertension.^3–6 In addition, we have shown that TP receptor activation does not desensitize in resistance arteries.¹⁷ Our finding that U-46619-induced contraction was almost abolished by COX inhibition is surprising, as TxA₂ production itself depends on COX activation. COX derivatives have been involved in agonist-induced contraction because of angiotensin II,¹⁵ endothelin-1,¹⁶ or -adrenoreceptor stimulation.¹⁷ In most cases the mediator involved is probably TxA_2, PGH₂, or both, as contraction was blocked by COX inhibition and by a TP receptor antagonist. In the present study, TP receptor activation by U-46619 also depended on COX derivatives to produce a contraction. This was confirmed by the use of 3 nonselective and chemically different cyclooxygenase inhibitors (aspirin, flurbiprofen, and indometacin) and by the use of a selective COX-1 inhibitor (SC-58560); COX-2 inhibition was ineffective. In addition, PLA2 inhibition also prevented U-46619-induced contraction, thus further supporting the involvement of a COX and arachidonic acid-derivative.

Among the COX-derivatives that may be produced in resistance arteries, TxA₂, PGF₂, and PGE₂ are the main vasoconstrictor products. In the arteries used in the present study, PGF₂ was not potent enough to be involved in U-46619-induced contraction, as it only induced a contraction for concentrations higher than 1 µmol/L, possibly interacting with TP receptor (twice the EC₅₀ for U-46619). On the other hand, PGE₂ produced a contraction comparable to that of U-46619. PGE₂ has been shown to enhance vasoconstrictor responses to pressure stimuli in the rat mesenteric artery.²⁴ It is also a potent vasoconstrictor in the rat tail artery²⁵ and the aorta.²⁶ We performed an EIA assay of PGE₂ in mesenteric arterial beds perfused with U-46619 to further investigate the potential involvement of PGE₂ in TP receptor activation-dependent contraction. Under U-46619 stimulation, the PSS perfused in the mesenteric beds contained twice the baseline PGE₂ concentration, further support that PGE₂ may be involved in the contraction induced by TP receptors stimulation. The technique used to measure COX derivatives in perfused mesenteric arteries has been previously validated in a study showing that more TxA₂ and less PGI₂ were produced in the PSS flowing through the arterial bed from hypertensive rats compared with normotensive animals.⁵ In this latter study, we have shown that 6-keto-PGF₁ (1.5 ng/mL, the stable metabolite of PGI₂), PGF₂ (0.6 ng/mL), and TxB₂ (1.5 ng/mL, stable metabolite of TxA₂) were also produced by the mesenteric circulation in the absence of exogenous stimulation. The amount of PGI₂, PGF₂, and TxA₂ previously found⁵ is comparable to the amount of PGE₂ found in the present study (1 to 2 ng/mL).

Interactions between different pathways may also occur. Although COX inhibitors almost completely inhibited U-46619-dependent contraction, they also partially inhibited the contraction induced by endothelin-1 and Phe, without affecting PGE₂-induced tone. In parallel, TP receptor blockade, which totally inhibited U46169- and PGF₂-induced contractions, also inhibited endothelin-1 and Phe-dependent tone to a lesser extent. Indeed, the contractile effect of these vasoactive agents (U46169, endothelin-1, and phenylephrine) depends on the activation of PLA2 induced by the rise in calcium concentration following receptor activation.¹ Then, arachidonic acid release and COX activation lead to the production of different COX derivatives. Concerning U-46619 in mesenteric resistance arteries, COX activation induced the production of PGE₂, which was responsible for a large part of the contraction. On the other hand, endothelin-1-induced contraction, also inhibited in a great part by PLA2 and COX antagonists, was strongly reduced by TP receptor blockade and unaffected by EP1 inhibition. Thus, TP receptor activation by TxA₂/PGH₂ is involved in endothelin-1-induced contraction, not in induced contraction due to PGE_2. This also applies to Phe-induced contraction, but to a lesser extent (PLA2 and COX inhibition only reduced Phe-induced contraction by 50%). Thus, the different contractile agents studied involved COX derivatives, but to a different degree. In addition, they required either PGE₂ or TxA₂/PGH₂ to produce a large part of their contractile effect.

Perspectives
This finding might be of importance in the pathophysiology of vascular diseases such as hypertension. In hypertension, TxA₂ has been shown to be involved in the control of vascular tone in arterial beds where it is normally (in the normotensive state) not involved or involved to a lesser degree. For example, a higher TxA₂ production in response to shear stress is likely to reduce flow-mediated dilation in mesenteric resistance arteries.⁵ Similarly, in rat gracilis muscle, resistance arteries TxA₂ contribute to the elevation in myogenic tone found in spontaneously hypertensive rats.⁶ Thus, elevated TxA₂ production may contribute to the changes in local blood flow found in hypertension, thereby, contributing to the injury produced in end-organs.

Considering the importance of TxA₂ in the local control of vascular tone, at least in some arterial beds, the present finding may enhance our understanding of vascular diseases as well as assist in focusing on potential treatments. In that respect, it may be important to decrease the vasoconstrictor capacity of TxA₂ without affecting its other properties. The potential importance of TP receptor blockade in other diseases has been recently discussed in a review,²⁷ the issue being of importance in atherogenesis.^27,28

	Acknowledgments

 
M.B. was a recipient of a European Community fellowship (Marie Curie Human Train Mobility of Researcher). L.L. was a recipient of the French Foundation for Medical Research (FRM, Paris, France). A.H. was supported by the Association Against Cancer (ARC, France), grant No. 5884. This work is dedicated to the memory of Jacques Maclouf who initiated and supported it. He shall always be remembered as a great scientific mentor, collaborator, and friend.

Received April 23, 2003; first decision May 14, 2003; accepted March 25, 2004.

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