Functional Studies of Leukotriene Receptors in Vascular Tissues

LAURENCE WALCH, XAVIER NOREL, JEAN-PIERRE GASCARD, and CHARLES BRINK

CNRS ESA 8078, 92350 Le Plessis Robinson, France

	INTRODUCTION

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Allergen inhalation by patients with atopic asthma provokes a reduction in airflow (bronchoconstriction), which is either immediate or delayed. However, allergens do not contract airway smooth muscle directly. Therefore, the airway narrowing and obstruction observed in these patients are due to other factors. Allergic inflammatory responses are associated with increased blood flow, extravasation of plasma, and the recruitment of circulating leukocytes into the tissue compartment. Such inflammatory events in the airways have been documented not only as a prominent feature of fatal asthma attacks but also in bronchial biopsies of patients with mild asthma.

Dale and Laidlaw (1) demonstrated that the hallmarks of extreme anaphylactic reactions were not only dyspnea but also severe hypotension. These investigators observed that anaphylactic shock was initiated by a marked alteration in vascular tone. Thus a cardinal sign of activation of inflammatory cells by allergen is a modification of vascular muscle tone. The presence of blood elements in the tissue compartment of the lung as well as in the biological fluids derived from the lumen of the airways of patients with asthma, even during the stable periods of the disease, provides pertinent evidence that vascular smooth muscle tone has been modified. The hypothesis that inflammatory cell migration, extravasation of plasma, and modification of bronchial secretions can occur only under conditions in which vascular tone has been modified warrants further investigation.

	ALLERGEN CHALLENGE IN THE HUMAN LUNG

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Historically, the antigenic stimulation of sensitized tissues was always associated with the release of slow-reacting substance of anaphylaxis (SRS-A). Schild and coworkers (2) demonstrated that human lung from patients with asthma released SRS-A when stimulated with an appropriate antigen. Confirmation of this initial observation was provided by the work of Brocklehurst (3) and Dahlén and coworkers (4). Reports based on human lung tissues passively sensitized (5) and then challenged with antigen provided further evidence that tissues from the human lung produced and released this mediator. Since the original description of SRS-A (6), this entity is now known (7) to be a composite of cysteinyl-leukotrienes (LTC₄, LTD₄, and LTE₄), which are metabolites of arachidonic acid via the 5-lipoxygenase enzymatic pathway.

Circumstantial evidence in support of the concept that these mediators may play a pivotal role in airway disease such as asthma was derived from clinical observations that several cell types that produce cysteinyl-leukotrienes (mast cells, basophils, and eosinophils) are present in increased numbers in the lungs of patients with asthma. In addition, the detection of these metabolites in biological fluids from subjects with asthma after allergen provocation in clinical studies further supported this concept. In the sputum obtained from patients with asthma, Lam and coworkers (8) detected both LTC₄ and LTB₄. However, these investigators were unable to measure the 5-lipoxygenase metabolites in sputum from patients with other lung diseases. Taylor and coworkers (9) measured urinary LTE₄ levels and reported an elevated level in patients with asthma after antigen inhalation. These observations have been confirmed by a number of other investigators in peripheral blood samples (10), urine (11), and bronchoalveolar lavage fluid (12, 13) and demonstrate the release of cysteinyl-leukotrienes in patients with asthma.

	CYSTEINYL-LEUKOTRIENES AND THE PULMONARY VASCULAR BED IN VIVO

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Several reports have shown that injection of cysteinyl-leukotrienes markedly increased pulmonary vascular resistance in sheep (14) as well as in mature guinea pigs and rats (15). In the monkey, transient pulmonary hypertension has also been observed after an injection of cysteinyl-leukotrienes (16). In addition, Gause and coworkers (17) demonstrated that the pulmonary arterial pressure was elevated in lambs (in utero) and that this elevated pressure was reduced significantly after a bolus injection of FPL-55712. In adult pig, Ohtaka and co-workers (18) demonstrated that cysteinyl-leukotrienes, specifically LTC₄, had a marked constrictor effect on the porcine pulmonary circulation. Together these results suggest that the cysteinyl-leukotrienes induce a direct contractile effect in the pulmonary vascular bed. However, there may be important species differences in the pulmonary vascular response to cysteinyl-leukotriene challenge since only modest effects subsequent to LTD₄ challenge were observed in the cat, whereas in sheep a potent constrictor effect has been reported (19).

Indirect evidence that the cysteinyl-leukotrienes may be involved in pulmonary vascular modifications was provided by Stenmark and coworkers (13), who detected these mediators in the bronchoalveolar lavage fluid derived from infants with elevated pulmonary arterial pressure. Serraf and coworkers (20) determined the circulating levels of LTE₄ in infants before and during open heart surgery for correction of congenital heart lesions. These investigators demonstrated that LTE₄ could be detected in peripheral whole blood samples prior to surgery in infants with and without increased pulmonary blood flow and pulmonary hypertension. During the surgical intervention, LTE₄ measurements were performed in the blood samples obtained from the pulmonary arterial catheter and compared with samples derived from the catheter placed in the left atrium. There was no increase in LTE₄ levels after the passage of blood through the lungs, suggesting that the human lung, in situ, does not release this mediator into the circulation. The levels of LTE₄ remained constant for the duration of the surgical intervention. Whether the quantities of cysteinyl-leukotrienes are increased in the tissue compartment rather than in the blood has yet to be determined. In fact, a previous report has shown that after instillation of cysteinyl-leukotrienes in the rat lung only a small percentage could be detected in the lavage fluid (21), suggesting that these mediators may be retained and/or degraded by the lung tissue.

	CYSTEINYL-LEUKOTRIENE PRODUCTION IN VASCULAR PREPARATIONS IN VITRO

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Brocklehurst (3) demonstrated the release of SRS-A from the aorta of sensitized guinea pigs. Piper and coworkers (22) detected the release of cysteinyl-leukotrienes from the porcine pulmonary artery during ionophore stimulation, and these investigators also showed that human pulmonary arteries released cysteinyl-leukotrienes when stimulated with anti-IgE. Gorenne and coworkers (23) confirmed these results by demonstrating that the release of cysteinyl-leukotrienes was observed not only in pulmonary arteries but also in human pulmonary veins. Furthermore, the quantities of cysteinyl-leukotrienes released from pulmonary arteries and veins were increased in preparations treated with indomethacin. These results suggest that the local production of cyclooxygenase metabolites regulated the amounts of cysteinyl-leukotrienes released. While these data provide evidence of the capacity of both pig and human pulmonary vessels to release cysteinyl-leukotrienes in vitro, the involvement of the release in anaphylactic reactions in vivo remains to be established. In the isolated perfused rat lung, Sertl and coworkers (24) demonstrated an increase in plasma exudation in the trachea and proximal bronchial airways subsequent to antigenic stimulation. In contrast, Shibamoto and colleagues (25) showed that Ascaris suum injection in the canine blood-perfused lung caused an increase in capillary pressure due to pulmonary venoconstriction without significant changes in vascular permeability. These data suggest that allergen may activate inflammatory cells to release mediators in the lung and that these mediators may alter the vascular tone. However, these effects may be species dependent.

Alexander and coworkers (26) showed that bovine pulmonary arteries from sensitized calves contracted on stimulation with antigen. Hand and coworkers (27) demonstrated cumulative antigen concentration response in guinea pig pulmonary arteries, as well as in guinea pig airways. The antigen- induced contractile responses were dependent on the release of histamine and cysteinyl-leukotrienes. However, isolated human pulmonary arteries do not contract when challenged with antigen (30). Kelly and coworkers (31) demonstrated that in airways and pulmonary arteries from the guinea pig SKF-104353 (leukotriene antagonist) abolished the residual contraction observed after histamine receptor blockade, suggesting that the antigen response in the pulmonary artery had activated a specific receptor. In addition, these investigators observed a striking difference between the kinetics of contraction. The arterial preparations exhibited an immediate and unsustained contraction in response to antigen stimulation, whereas the airways showed a more protracted and sustained response. One possible explanation for this kinetic difference may be that a functional antagonism exists owing to the release of relaxing factors derived from the endothelium.

	CYSTEINYL-LEUKOTRIENE PARADOXICAL EFFECTS IN VASCULAR PREPARATIONS

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Contraction

In an attempt to understand the effects of cysteinyl-leukotrienes on pulmonary vessels, Hanna and coworkers (32) reported that cysteinyl-leukotrienes contracted not only isolated human bronchial preparations but also pulmonary veins, while the effect on pulmonary arteries was smaller. These observations were confirmed by Schellenberg and Foster (33), who demonstrated that FPL-55712 blocked the contractions in both the bronchial and venous preparations. Bourdillat and coworkers (34) reported that the LTD₄-induced contraction of pulmonary venous preparations was also antagonized by FPL-55712. Furthermore, a number of other studies have shown that FPL-55712 antagonized the cysteinyl-leukotriene contractions in a variety of vascular preparations from different species. In the rabbit renal vein, LTC₄ and LTD₄ induced contractions (35), whereas only small or no contractile responses were observed in pulmonary and portal veins. Berkowitz and coworkers (15) studied a number of vascular preparations from several species (rat, rabbit, and guinea pig). These investigators observed only weak contractions in guinea pig pulmonary veins, inferior vena cava, and jugular vein. The effects of LTC₄ were not examined. Gleason and coworkers (36) demonstrated that LTD₄ contracted the guinea pig isolated pulmonary artery; this effect was antagonized by 2-nor-leukotriene (analog of LTD₄), suggesting that the response was mediated by activation of a cysteinyl-leukotriene receptor. In addition to these results from a variety of animal species, Allen and coworkers (37) demonstrated that in human isolated saphenous veins, there was a pronounced constriction of these preparations by LTC₄ and LTD₄. These agonists were reported to be equipotent and no exploration of the types of receptors involved in the contractile response was undertaken.

Relaxation

Secrest and coworkers (38) reported that, in canine renal arteries where tone had been induced by a contractile agonist, LTD₄ induced relaxations. These endothelium-dependent relaxations were produced by stimulation of a specific receptor since the response was attenuated by FPL-55712. These investigators further showed that LTD₄ also increased cGMP accumulation in canine vessels (39). Together these observations indicated the presence of cysteinyl-leukotriene receptors on the endothelium and suggested that the relaxations may be via the liberation of nitric oxide (NO). Sakuma and coworkers (40, 41) demonstrated that pulmonary arteries from the guinea pig relaxed when challenged with either LTC₄ or LTD₄. These authors observed that the relaxations induced by LTC₄ and LTD₄ in the isolated guinea pig thoracic aorta were antagonized by ICI-198615 (leukotriene antagonist), suggesting that both agonists activate a single receptor. This antagonism was also observed in the pulmonary artery. In addition, the LTD₄ relaxations were unaffected by treatment of the tissues with indomethacin, but methylene blue markedly altered the relaxant effects. These data suggested that activation of a receptor on the endothelium of the guinea pig thoracic and pulmonary arteries relaxed the vascular smooth muscle via the release of NO. Data derived from isolated human pulmonary arteries and veins indicate that stimulation of the endothelium by LTD₄ induced relaxations via the NO pathway (30). In contrast, LTD₄ and LTC₄ relaxations of isolated human saphenous veins (36) are dependent on both the NO and cyclooxygenase pathways.

Receptors

Two categories of receptors for the cysteinyl-leukotrienes have been proposed (42). One subtype is characterized by the ability of a number of antagonists to block the effects of cysteinyl-leukotrienes in a variety of smooth muscle preparations. This receptor is referred to as CysLT₁. The effects associated with activation of the second receptor (CysLT₂) are not blocked by these antagonists. In vascular preparations, Nishiye and coworkers (43) showed that FPL-55712 and ONO-RS-411 blocked LTD₄ contractions in the guinea pig basilar artery, implicating activation of a CysLT₁ receptor. The use of a number of selective CysLT₁ antagonists (44) demonstrated that the contractions induced by cysteinyl-leukotrienes in human pulmonary veins were not affected by these antagonists (45). This receptor on the human pulmonary veins is therefore a CysLT₂ (Figure 1). In contrast, Rinkema and co-workers (46) demonstrated that LTD₄ contractions in the guinea pig inferior vena cava were blocked by LY-171883 and WY-48252 (CysLT₁ antagonists). However, the contractions induced by LTC₄ were blocked in a biphasic fashion by these two CysLT₁ antagonists, that is, the low concentrations of LTC₄ were not affected by the antagonists, suggesting two LTC₄ receptor subtypes. Therefore in some species, such as the guinea pig, vascular preparations may contain either one or several subtypes of cysteinyl-leukotriene receptors. Whether these receptors in the human pulmonary veins, which are resistant to the classic antagonists, are the same as the receptors in the guinea pig pulmonary artery, which are activated by LTC₄, remains to be established.

View larger version (26K): [in this window] [in a new window]   Figure 1.   Cysteinyl-leukotriene receptors in isolated human pulmonary vascular preparations (48). A single receptor is present on the endothelium of pulmonary arteries (CysLT2) whereas on the endothelium of pulmonary veins, two receptors are present (CysLT1 and CysLT2). Activation of CysLT2 induced the release of NO and activation of CysLT1 induced the release of a contractile factor. However, on the vascular smooth muscle, activation of a CysLT2 receptor in the veins produced contractions. Presently, the receptor associated with the contractions in arteries has not been identified.

On the endothelium of guinea pig arterial preparations, a single receptor is present (40, 41) and is associated with relaxation. This is not the case in either canine renal arteries and veins (47) or in human pulmonary arteries and veins (48). In canine preparations the renal veins relaxed in response to LTD₄ but veins were approximately 100-fold more sensitive to this mediator when compared with the arteries. This difference in agonist potency suggests that different receptors may be present on the endothelium of these vascular preparations. LTC₄ was not examined in these tissues. In canine splanchnic venous capacitance vessels the receptors associated with the relaxations have not been identified.

	SUMMARY

TOP INTRODUCTION ALLERGEN CHALLENGE IN THE... CYSTEINYL-LEUKOTRIENES AND THE... CYSTEINYL-LEUKOTRIENE... CYSTEINYL-LEUKOTRIENE... SUMMARY REFERENCES

The paradoxical effects of cysteinyl-leukotrienes, namely contraction and relaxation, are now well documented in a number of vascular preparations from various species. The vascular smooth muscle contractions are associated with activation of a single receptor subtype (44) and in some vascular smooth muscles with activation of two receptor subtypes (46). However, the receptors implicated in the contraction of vessels such as pig pulmonary arteries and veins (18), dog inferior vena cava, and dog splenic and mesenteric veins (49) remain to be established.

There are sufficient data concerning some vascular tissues to suggest that relaxations induced by cysteinyl-leukotrienes are via the stimulation of specific receptors present on the endothelium. The endothelium in human pulmonary arteries has one receptor (CysLT₂) and activation induced the release of NO. However, in isolated human pulmonary veins two receptors are present, CysLT₁ and CysLT₂ (Figure 1). Activation of the former induced the release of a contractile factor whereas activation of the CysLT₂ receptor released NO. In guinea pig pulmonary artery and guinea pig thoracic aorta, one receptor has been demonstrated since the relaxations are blocked by ICI-198615. These data suggest the presence of a CysLT₁ receptor. Activation of this receptor leads to the release of a relaxant factor, namely, nitric oxide. In contrast, in human pulmonary arteries and veins activation of a receptor that is resistant to ICI-198615 is associated with NO release. These results suggest that there may be species differences even when analogous vascular preparations are examined.

While the cysteinyl-leukotrienes are known to relax vascular smooth muscle in a variety of preparations from different species, there are presently two pathways known to be involved in this response. One involves the metabolites of arachidonic acid via the cyclooxygenase enzymatic pathway and the other implicates products of the L-arginine enzymatic pathway. Although both pathways may be present and active in the endothelium of the vascular preparations only one of these enzymatic pathways may be dominant and responsible for the relaxations observed. Ortiz and coworkers (48) have demonstrated that in pulmonary veins the dominant pathway for cysteinyl-leukotriene relaxations is the NO pathway. There are some reports from animal studies that support a dominant role for NO in pulmonary veins (50). In contrast, Allen and co-workers (37) demonstrated that the LTC₄-induced relaxations in isolated human saphenous veins were not modified by treatment of tissues with an NO inhibitor but were significantly enhanced after treatment with indomethacin. These authors suggested that a contracting factor derived from the arachidonic acid pathway was released in preparations challenged with LTC₄. In addition, these investigators demonstrated that the NO inhibitor had no effect on the LTC₄ relaxations. Together, these results suggest that cysteinyl-leukotriene effects in human pulmonary veins are dominated by the NO pathway whereas in human systemic veins these mediator effects are modified by metabolites of the cyclooxygenase pathway. Unfortunately, most studies involving the actions of cysteinyl-leukotrienes on vessels have been performed in the presence of indomethacin, making interpretation of the relative contribution of the cyclooxygenase and NO pathways difficult. In any event, the cysteinyl-leukotrienes may have a prominent role in the activation of these pathways and the receptors involved have not been clearly established.

	Footnotes

Correspondence and requests for reprints should be addressed to Charles Brink, Ph.D., Centre Chirurgical Marie Lannelongue, CNRS ESA 8078, 133 avenue de la Résistance, 92350 Le Plessis Robinson, France. E-mail: brink{at}wanadoo.fr

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