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Br J Pharmacol. Dec 2002; 137(8): 1339–1345.
Published online Nov 27, 2002. doi:  10.1038/sj.bjp.0704991
PMCID: PMC1573615

Pharmacological evidence for a novel cysteinyl-leukotriene receptor subtype in human pulmonary artery smooth muscle

Abstract

  1. To characterize the cysteinyl-leukotriene receptors (CysLT receptors) in isolated human pulmonary arteries, ring preparations were contracted with leukotriene C4 (LTC4) and leukotriene D4 (LTD4) in either the absence or presence of the selective CysLT1 receptor antagonists, ICI 198615, MK 571 or the dual CysLT1/CysLT2 receptor antagonist, BAY u9773.
  2. Since the contractions induced by the cysteinyl-leukotrienes (cysLTs) in intact preparations failed to attain a plateau response over the concentration range studied, the endothelium was removed and the tissue treated continuously with indomethacin (Rubbed+INDO). In these latter preparations, the pEC50 for LTC4 and LTD4 were not significantly different (7.61±0.07, n=20 and 7.96±0.09, n=22, respectively). However, the LTC4 and LTD4 contractions were markedly potentiated when compared with data from intact tissues.
  3. Leukotriene E4 (LTE4) did not contract human isolated pulmonary arterial preparations. In addition, treatment of preparations with LTE4 (1 μM; 30 min) did not modify either the LTC4 or LTD4 contractions.
  4. Treatment of preparations with the S-conjugated glutathione (S-hexyl-GSH; 100 μM, 30 min), an inhibitor of the metabolism of LTC4 to LTD4, did not modify LTC4 contractions.
  5. The pEC50 values for LTC4 were significantly reduced by treatment of the preparations with either ICI 198615, MK 571 or BAY u9773 and the pKB values were: 7.20, 7.02 and 6.26, respectively. In contrast, these antagonists did not modify the LTD4 pEC50 values.
  6. These findings suggest the presence of two CysLT receptors on human pulmonary arterial vascular smooth muscle. A CysLT1 receptor with a low affinity for CysLT1 antagonists and a novel CysLT receptor subtype, both responsible for vasoconstriction. Activation of this latter receptor by LTC4 and LTD4 induced a contractile response which was resistant to the selective CysLT1 antagonists (ICI 198615 and MK 571) as well as the non-selective (CysLT1/CysLT2) antagonist, BAY u9773.
Keywords: Human pulmonary arteries, leukotrienes, contraction, CysLT receptors, ICI 198615, MK 571, BAY u9773

Introduction

Cysteinyl-leukotrienes (cysLTs), products of the 5-lipoxygenase enzymatic pathway, are metabolites of arachidonic acid and are potent constrictor agents in a number of vascular beds (Dahlén et al., 1982; Smedegard et al., 1982; Berkowitz et al., 1984; Piper et al., 1985). Unfortunately, the characterization and identification of the CysLT receptors responsible for the vasoconstriction in a number of vascular beds has received little attention.

Presently, there is evidence for two functional CysLT receptor subtypes in the human lung, a CysLT1 (Buckner et al., 1986) and CysLT2 (Labat et al., 1992). The former is antagonized by a number of classical selective antagonist while the latter is resistant to all of these compounds except for BAY u9773 which is not a selective antagonist (Gorenne et al., 1996). Recently, a cDNA encoding a CysLT1 receptor was cloned (Lynch et al., 1999; Sarau et al., 1999) and subsequently the clonage of the CysLT2 receptor was also reported (Takasaki et al., 2000; Heise et al., 2000; Nothacker et al., 2000). These molecular studies have confirmed the initial observations that two CysLT receptors exist (Drazen et al., 1980; Krell et al., 1981; Fleisch et al., 1982; Buckner et al., 1986; Labat et al., 1992). However, evidence from functional (Tudhope et al., 1994; Bäck et al., 2000a, b) and radioligand binding studies (Ravasi et al., 2000) as well as molecular investigations (Mellor et al., 2001) demonstrated that another CysLT receptor may also exist.

Since Bäck et al. (2000a) have suggested the presence of another CysLT receptor in human isolated pulmonary arterial preparations, the aim of this investigation was to further characterize the CysLT receptor in this tissue and to provide pharmacological evidence of those CysLT receptors responsible for vasoconstriction in the human pulmonary vascular bed.

Methods

Tissue preparation

The lung samples were obtained from patients (23 male and two female) who had undergone surgery for lung carcinoma. The mean age was 64±2 years. Intrapulmonary arteries and veins were removed, dissected free from surrounding tissue and cut into rings with a length of 3–5 mm and an inner diameter of approximately 2–4 mm. The rings were then set up in 10 ml organ baths containing Tyrode's solution (composition, mM: NaCl, 149.2; KCl, 2.7; NaHCO3, 11.9; CaCl2, 1.8 MgCl2, 0.5; NaH2PO4, 0.4 and glucose 5.5) and gassed with 5% CO2 in O2 at 37°C. Experiments were performed on preparations with an endothelium present (Intact) and on rings where the endothelium was mechanically removed by gently rubbing the luminal surface with a metal forceps. These latter preparations were continuously exposed to indomethacin (1.7 μM; Rubbed+INDO). Changes in force were recorded using isometric force displacement transducers (Narco F-60) connected to Linseis physiographs. The responses were monitored with an EMKA IOX data acquisition system. The preparations were placed in 10 ml organ baths under an initial load of 1.5 g and allowed to equilibrate for 90 min with washes every 10 min.

Contractions

Subsequent to the equilibration period, the intact arterial preparations were incubated 30 min with Tyrode's solution and cysLT concentration-effect curves were produced. The preparations (Rubbed+INDO), were exposed to either Tyrode's solution or Tyrode's solution containing a CysLT antagonist (ICI 198615 at 1 μM; MK 571 at 1 μM or BAY u9773 at 3 μM; 30 min) or S-hexyl-GSH (100 μM; 30 min). In addition, LTC4 concentration-effect curves were produced in rings (Rubbed+INDO) treated with ICI 198615 (3 μM; five preparations from two lung samples). When the cysLT contraction induced by the highest concentration had attained a plateau, the preparations were challenged with norepinephrine (10 μM). The response to norepinephrine (10 μM) in intact preparations was: 2.45±0.40 g (n=20). In preparations (Rubbed+INDO), the contraction induced by norepinephrine (10 μM) was: 2.65±0.32 g (n=22).

In a limited number of experiments BAY u9773 (3 μM; n=3) was added to isolated intact human pulmonary arteries and veins at resting tone.

Data analysis

The contractions are expressed as increased tension in grams or as per cent of the norepinephrine response. The maximal contraction (Emax value) produced with the highest concentration of the agonist and the half-maximal effective concentration value (EC50 value) were interpolated from the individual concentration-effect curves. The pEC50 values were calculated as the negative log of the EC50 values. When the pEC50 values obtained in the presence and absence of the antagonist were significantly different, the equilibrium dissociation constant for the antagonist (KB value) was calculated. The following equation was used: KB=[B]/(DR−1), where [B] is the concentration of the antagonist and DR (dose ratio) is the ratio of the EC50 of agonist in the presence and absence of antagonist. The pKB values were calculated as the negative log of the KB values. All data are expressed as means±s.e.means. Statistical evaluation was performed using a Student's t-test for paired or unpaired data, a P-value of less than 0.05 was considered significant.

Compounds

Norepinephrine, indomethacin (INDO), and S-hexyl glutathione (S-hexyl GSH) were obtained from Sigma (St. Louis, MO, U.S.A.). LTC4, LTD4, and BAY u9773 (6(R)-(4′-carboxyphenylthio) - 5(S)-hydroxy - 7(E),9(E),11(Z)14(Z)-eicosatetrenoic acid) were from Cayman Chemicals (Reading, U.K.). ICI 198615 {[1-[[2-methoxy-4-[[(phenyl-sulfonyl)amino]carbonyl]-phenyl]methyl]-1H-indazol-6-yl]-carbamic acid cyclopentyl ester} was from Zeneca (Wilmington, DE, U.S.A.) and MK 571 ((3-(2(7-chloro-2-quinolinyl)ethenyl)phenyl)(3-(dimethylamino-3-oxopropyl)thio)methyl)thio propanoic acid) was from Bayer (U.K.).

Solutions of cysLTs and BAY u9773 were obtained by diluting stock solutions at concentrations of 1 mM (LTC4 and LTE4), 0.5 mM (LTD4) and 10 mM (BAY u9773) into Tyrode's solution. INDO was dissolved in 1% ethanol in Tyrode's solution, ICI 198615 in dimethyl sulphoxide (DMSO; the final bath concentration of the solvents being less than 0.1%). Norepinephrine was dissolved in Tyrode's solution.solution.

Table 1
Effects of cysteinyl-leukotrienes in human isolated pulmonary arterial preparations

Results

Intact human isolated pulmonary arterial preparations contracted when challenged with cysLT. However, the concentration-effect curves did not attain a plateau response over the concentration range studied (Figure 1). In contrast, the results presented in Figure 1 show that the contractile response to LTC4 and LTD4 were markedly increased in human pulmonary arterial preparations where the endothelium had been removed and the tissues treated with indomethacin (Rubbed+INDO). Under these latter conditions LTE4 did not contract human pulmonary arterial preparations. In addition, the LTC4 concentration effect curves were not altered by S-hexyl GSH (inhibitor of LTC4 metabolism; Figure 2).

Figure 1
Cysteinyl-leukotriene concentration-effect curves produced in human isolated pulmonary arterial preparations. The results are derived from intact tissues (endothelium present, solid circle) and tissues devoid of an endothelium and treated with indomethacin ...
Figure 2
The effects of S hexyl glutathione (S-hexyl-GSH) on LTC4 concentration effect curves in human isolated pulmonary vascular preparations devoid of an endothelium and treated with indomethacin (Rubbed+INDO). Control and results obtained in tissues treated ...

The antagonist BAY u9773 (3 μM) was examined on basal tone in intact pulmonary arterial and venous preparations (Figure 3). An increase in basal tone was observed in human pulmonary veins whereas in arteries no contractions were observed. The data presented in Figure 4 show that the classical CysLT1 antagonists, ICI 198615 (1 μM), MK 571 (1 μM) and the non-selective dual antagonist (CysLT1/CysLT2), BAY u9773 (3 μM) shifted the LTC4 curves to the right and the pEC50 values were significantly different (Table 2). However, a higher concentration of ICI 198615 (3 μM; five preparations two different lung samples) did not cause a further displacement of the LTC4 curves (data not shown). In contrast, these same antagonists failed to block the contractions induced by LTD4 (Figure 5). The pKB values for the three antagonists are presented in Table 2. However, MK 571 (1 μM) significantly reduced the LTD4 contractions at the highest agonist concentrations (0.1 and 1 μM) but did not modify the pEC50 values (Table 2). In addition, exposure of human pulmonary arterial preparations to LTE4 (1 μM; 30 min; n=4) did not significantly modify either the LTC4 or LTD4 response (Figure 6). The pEC50 values for LTC4 (7.66±0.33) and LTD4 (7.72±0.07) were not altered subsequent to this LTE4 treatment in paired lung samples (LTC4, 7.55±0.18 and LTD4, 7.44±0.12).

Figure 3
The effects of BAY u9773 on basal tone in intact human isolated pulmonary vascular preparations. Results of a representative experiment are shown (n=3 lung samples).
Figure 4
LTC4 concentration-effect curves produced in human isolated pulmonary arterial preparations devoid of an endothelium and treated with indomethacin (Rubbed+INDO). Control and results obtained in tissues treated with (a) ICI 198615 (1 μM, 30 min), ...
Figure 5
LTD4 concentration-effect curves produced in human isolated pulmonary arterial preparations devoid of an endothelium and treated with indomethacin (Rubbed+INDO). Control and results obtained in tissues treated with (a) ICI 198615 (1 μM, 30 min), ...
Figure 6
LTC4 and LTD4 concentration-effect curves produced in human isolated pulmonary arterial preparations devoid of an endothelium and treated with indomethacin (Rubbed+INDO). Control and results obtained in tissues treated with LTE4 (1 μM, 30 min). ...
Table 2
Effects of antagonists on cysteinyl-leukotriene contractions in human isolated pulmonary arterial preparations

Discussion

Bäck et al. (2000a) observed that the LTC4 contractions in human pulmonary arteries were not blocked by either the CysLT1 antagonist, MK 571, or the non-selective CysLT1/CysLT2 antagonist, BAY u9773. These preliminary data suggested that the CysLT receptor responsible for the contractions did not fit the classical CysLT receptor profile since the responses were resistant to the known CysLT antagonists. The data (present report) provide further information on this CysLT receptor. However, the results suggest that the cysLT contractions of human isolated pulmonary arteries are more complex than what was initially proposed. The evidence demonstrates that there are factors released from both the endothelium as well as the vascular smooth muscle which modify the cysLTs contractions. In the present investigation the production of cysLT concentration-effect curves was established by treatment of the human pulmonary arterial preparations devoid of an endothelium with indomethacin. Under these experimental conditions, pEC50 values were calculated and established that LTC4 and LTD4 were equipotent contractile agonists in human isolated pulmonary arterial preparations whereas LTE4 did not contract these tissues.

Previous reports (Hanna et al., 1981; Schellenberg & Foster, 1984; Bourdillat et al., 1987) have demonstrated that human isolated pulmonary arteries exhibited only a small response when stimulated by cysLTs. These observations were recently confirmed by Bäck et al. (2000a) using LTC4. The present report indirectly suggests that the reason why cysLT concentration-effect curves were not produced in these previous reports was related to the release of endogenous relaxant factors which modulate the vascular responses (Figure 1). The results (present report) demonstrate that both LTC4 and LTD4 contractions were enhanced when the endothelium was removed and the preparations were treated with indomethacin. These observations suggest that the failure to produce a concentration-effect curve in intact human pulmonary arterial preparations (endothelium present) over the concentration ranged used was due to the release of endothelium derived relaxant factors. However, the relaxant factors released from the human isolated pulmonary artery may, in part, also originate from the vascular smooth muscle since either indomethacin treatment or removal of endothelium previously has been shown to only partially modify the contractions (Bäck et al., 2000a), whereas the combination of indomethacin treatment and removal of the endothelium unmasked the full cysLTs concentration-effect curves in these tissues (present report). While the nature and origin of the relaxant factor remains to be elucidated the data indirectly suggest that a cyclo-oxygenase metabolite may be involved. Previous reports have demonstrated that prostacyclin (PGI2) may be released from the endothelium in arterial preparations (Moncada et al., 1977) but there is little information concerning release of this metabolite from vascular smooth muscle. However, in a recent report Soler et al. (2000) have shown that human vascular smooth muscle cells in culture express prostaglandin E synthase and demonstrated that PGE2 and prostacyclin were produced, during basal, and enhanced after stimulation with a variety of agonists. Although these results were derived from the human popliteral artery, other investigators (Jourdan et al., 1997) had already shown that human pulmonary artery vascular smooth muscle cells in culture produced these metabolites and these observations have been confirmed by Shaul et al. (1999). Together these results suggest that the vascular smooth muscle may be responsible for the release of cyclooxygenase metabolites which may modify the vascular contractions (Mugridge et al., 1984; Qian et al., 1994; Walch et al., 1999, 2001).

LTC4 is known to be metabolized to LTD4 as has been reported in other preparations (Krell et al., 1981; Jones et al., 1984; Bäck et al., 2001). Since LTC4 and LTD4 curves were similar in human isolated pulmonary arteries (Bäck et al., 2000a) one explanation may be that the LTC4 was metabolized to LTD4. However, S-hexyl-GSH did not modify the LTC4 concentration-effect curves in human pulmonary arterial preparations (Figure 4) suggesting that the contractile effects were directly dependent on LTC4. These data show that in human airways (Buckner et al., 1986) and human vascular smooth muscle preparations (Labat et al., 1992; present report) the cysLT contractions were not modified by the cysLT metabolic enzyme inhibitors suggesting that major differences in enzymatic activities may exist between species (Bäck et al., 2001). In addition, under the present experimental conditions (rubbed preparations treated with indomethacin), LTC4 and LTD4 were equipotent. These results suggest a major difference in the rank order potency of these contractile agonists between human airways (LTC4[gt-or-equal, slanted]LTD4[gt-or-equal, slanted]LTE4; Buckner et al., 1986; Labat et al., 1992) and human pulmonary veins (LTC4=LTD4>LTE4; Labat et al., 1992) when compared with the contractions obtained in human pulmonary arteries (LTC4=LTD4). Previous attempts to establish the cysLT potency in human isolated pulmonary arterial preparations have failed (Bourdillat et al., 1987) or provide, at best, only estimates (Schellenberg & Foster, 1984; Bäck et al., 2000a).

The observation that LTD4 contractions (present report) were not modified by either MK 571, ICI 198615 or BAY u9773 extend the observation of Bäck et al. (2000a) to include the equipotent ligand, LTD4. Thus LTD4 induced contractions are also resistant to the three cysLT antagonists, results which are similar to what had been previously reported for LTC4. Several reports (Labat et al., 1992; Ortiz et al., 1995) have demonstrated that LTC4 and LTD4 contractions produced in human isolated pulmonary veins were resistant to ICI 198615 and MK 571 but were antagonized by BAY u9773. These observations lead to the suggestion that a CysLT2 receptor was present in the human pulmonary veins and the existence of a CysLT2 receptor has recently been confirmed by molecular techniques (Nothacker et al., 2000; Heise et al., 2000; Takasaki et al., 2000). However, in human pulmonary arterial preparations, the LTD4 contractions were resistant not only to ICI 198615 and MK 571 but also to BAY u9773 suggesting that the receptor present in the pulmonary arterial vascular smooth muscle may be different from that in the pulmonary veins. Together these data support the notion that the ligands may be acting at the same CysLT receptor and that this receptor is not identical to that responsible for contraction of human airways (blocked by CysLT1 antagonists) nor the receptor associated with the contraction of human pulmonary veins (CysLT2). Therefore, the observation (present report) that LTD4 contractions were resistant to all three antagonists suggests the presence of another CysLT receptor subtype in the human lung.

Bäck et al. (2000a) previously demonstrated that LTC4-induced contractions were not modified by the antagonists, however, the results presented in Table 2 demonstrate that the three antagonists significantly modified the LTC4 pEC50 values. This apparent discrepancy between the initial publication (Bäck et al., 2000a) and the present work warrants an explanation. The experimental conditions were different. The optimal conditions to obtain cysLT concentration-effect curves is in tissues where the endothelium had been removed and the tissues treated with indomethacin (present report). Under these conditions a pharmacological assessment of the antagonists can be performed on the agonist concentration-effect curve. Thus inhibition of a cyclo-oxygenase metabolite at the level of the vascular smooth muscle which masks the cysLT contractions is a prerequisite for uncovering the CysLT1 receptor component in human isolated pulmonary arterial muscle preparations. Under the previous experimental conditions (Bäck et al., 2000a), namely, intact tissues, endothelium denuded tissues or intact tissues treated with indomethacin only the antagonist resistive contractile component is observed. Interestingly, the results obtained with the CysLT1 antagonists in human pulmonary arteries (Table 2) were at least one order of magnitude different from that observed in human airways (ICI 198615, pKB=8.3; MK 571, pKB=8.8; Gorenne et al., 1996) suggesting that the CysLT1 receptor in the human pulmonary artery may have a lower affinity than those present in the airways. Of considerable interest is the observation that LTC4 is blocked by the classical antagonists but not LTD4 suggesting again that the CysLT1 receptor activated by LTC4 does not fit the classical profile.

Recently, BAY u9773 has been reported to be a partial agonist in cells containing the CysLT2 cloned receptor (HPN321; Nothacker et al., 2000). In addition, in human pulmonary veins BAY u9773 has partial agonist contractile activities at the CysLT2 receptor (Labat et al., 1992). However, the observations concerning the effects of BAY u9773 on basal tone in intact pulmonary arterial preparations showed that this compound did not constrict these vascular preparations. The differential effects in arteries and veins observed with the analogue of LTE4 (BAY u9773) were also observed with LTE4. Thus in human pulmonary arteries no contractile activity was observed with either of these compounds, providing evidence for the lack of CysLT2 receptors in arterial preparations. Furthermore, LTE4 did not block the cysLT contractions in human isolated arterial preparations. In contrast, BAY u9773 significantly reduced the LTC4 pEC50 values without altering the LTD4 contractions. These results are markedly different from the LTE4 and BAY u9773 antagonism observed in human airways and in human pulmonary veins (Labat et al.,1992). These observations provide further support for the existence of another CysLT receptor subtype in the human lung since there was antagonist divergence at the CysLT receptor in the human isolated pulmonary arteries.

Tudhope et al. (1994) provided initial evidence for the presence of another functional CysLT receptor and this observation has received support from a number of recent functional studies (Bäck et al., 2000a, b) and provide further evidence for a CysLT receptor which does not fit the classical CysLT receptor profile (Coleman et al., 1995). Of considerable interest is the report in human mast cells (Mellor et al., 2001) which demonstrated a partial antagonist effect of BAY u9773 on LTC4 but not on LTD4-mediated calcium flux. In addition, data from radioligand binding studies have also suggested the existence of another CysLT receptor (Ravasi et al., 2000) since BAY u9773 blocked the binding of LTC4 but not that of LTD4. These reports suggest a discriminative effect of LTC4 and LTD4 on a CysLT1 receptor, evidence which is also provided by the present report.

In summary, the evidence presented in this report suggest the existence of several CysLT receptor subtypes in human pulmonary arteries which are responsible for vasoconstriction. While Bäck et al. (2000b) provided the initial observation for a different CysLT receptor subtype in the human pulmonary artery, the present report extend these data and provide pertinent evidence that this novel CysLT receptor subtype is activated by LTC4 and LTD4 and is resistant to both the selective and non selective CysLT receptor antagonists. This profile is different from the CysLT1 and CysLT2 receptors previously described in human airways (Buckner et al., 1986) and pulmonary veins (Labat et al., 1992). In addition, the results also suggest the presence of a CysLT1 low affinity receptor present in the vascular muscle layer which is activated by LTC4. This preliminary and indirect evidence is schematically presented in Figure 7. An exploration of these observations either using ligand binding, cloning and sequencing of the receptor mRNA or transfection of a functional protein will clearly establish the existence of other receptor subtypes.

Figure 7
A schematic presentation of the CysLT receptors present in human pulmonary arterial vascular smooth muscle. LTC4 activates two receptors in arterial preparations. One receptor has a low affinity for the selective CysLT1 antagonists (ICI 198615 and MK ...

Abbreviations

LTC4
leukotriene C4
LTD4
leukotriene D4
LTE4
leukotriene E4
Emax
maximal contraction
cysLTs
cysteinyl-leukotrienes
CysLT receptors
cysteinyl-leukotriene receptors
INDO
indomethacin

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