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. 2000 Aug;130(8):1793–1798. doi: 10.1038/sj.bjp.0703488

Modulation of cholinergic airway reactivity and nitric oxide production by endogenous arginase activity

Herman Meurs 1,*, Marco A M Hamer 1, Stephanie Pethe 2, Sandrine Vadon-Le Goff 2, Jean-Luc Boucher 2, Johan Zaagsma 1
PMCID: PMC1572255  PMID: 10952667

Abstract

  1. Cholinergic airway constriction is functionally antagonized by agonist-induced constitutive nitric oxide synthase (cNOS)-derived nitric oxide (NO). Since cNOS and arginase, which hydrolyzes L-arginine to L-ornithine and urea, use L-arginine as a common substrate, competition between both enzymes for the substrate could be involved in the regulation of cholinergic airway reactivity. Using a perfused guinea-pig tracheal tube preparation, we investigated the modulation of methacholine-induced airway constriction by the recently developed, potent and specific arginase inhibitor NΩ-hydroxy-nor-L-arginine (nor-NOHA).

  2. Intraluminal (IL) administration of nor-NOHA caused a concentration-dependent inhibition of the maximal effect (Emax) in response to IL methacholine, which was maximal in the presence of 5 μM nor-NOHA (Emax=31.2±1.6% of extraluminal (EL) 40 mM KCl-induced constriction versus 51.6±2.1% in controls, P<0.001). In addition, the pEC50 (−log10 EC50) was slightly but significantly reduced in the presence of 5 μM nor-NOHA.

  3. The inhibition of Emax by 5 μM nor-NOHA was concentration-dependently reversed by the NOS inhibitor NΩ-nitro-L-arginine methyl ester (L-NAME), reaching an Emax of 89.4±7.7% in the presence of 0.5 mM L-NAME (P<0.01). A similar Emax in the presence of 0.5 mM L-NAME was obtained in control preparations (85.2±9.7%, n.s.).

  4. In the presence of excess of exogenously applied L-arginine (5 mM), 5 μM nor-NOHA was ineffective (Emax=33.1±5.8 versus 31.1±7.5% in controls, n.s.).

  5. The results indicate that endogenous arginase activity potentiates methacholine-induced airway constriction by inhibition of NO production, presumably by competition with cNOS for the common substrate, L-arginine. This finding may represent an important novel regulation mechanism of airway reactivity.

Keywords: Arginase, constitutive nitric oxide synthase, nitric oxide, L-arginine, Nω-hydroxy-nor-L-arginine, Nω-nitro-L-arginine-methyl ester, cholinergic, airway hyperreactivity, tracheal perfusion, guinea-pig

Introduction

It is now well established that nitric oxide (NO) is importantly involved in the regulation of airway tone as well as in asthmatic inflammation (Barnes & Belvisi, 1993; Gaston et al., 1994; Barnes & Liew, 1995). Thus, NO causes bronchodilation by inducing airway smooth muscle relaxation (Gruetter et al., 1989; Dupuy et al., 1992), is an important immunomodulator by promoting selective proliferation of Th2 lymphocytes (Barnes & Liew, 1995), and, at high concentrations, has deleterious effects in the airways by causing mucosal swelling, infiltration of inflammatory cells, epithelial damage and airway hyperreactivity (AHR) (Kuo et al., 1992; Flak & Goldman, 1996; Schuiling et al., 1998a).

NO is synthesized from the semi-essential amino acid L-arginine by the enzyme NO synthase (NOS), of which different isoforms have been identified in the airways. Constitutive NOS (cNOS) isoforms are mainly expressed in inhibitory nonadrenergic noncholinergic nerves (neuronal NOS or nNOS), endothelial cells (endothelial NOS or eNOS) and epithelial cells (nNOS and eNOS) of the airways (Fischer et al., 1993; Kobzik et al., 1993; Asano et al., 1994), and are thought to be primarily involved in the regulation of airway and vascular tone by local production of small amounts of NO in response to neurogenic and non-neurogenic stimuli (Barnes & Belvisi, 1993; Gaston et al., 1994). Inducible NOS (iNOS), producing large amounts of NO, is induced by proinflammatory cytokines during airway inflammation, and may be present in macrophages and epithelial cells (Barnes & Belvisi, 1993; Hamid et al., 1993; Asano et al., 1994). In addition to bronchodilation, high concentrations of iNOS-derived NO may be involved in the detrimental effects described above (Schuiling et al., 1998a).

The involvement of endogenous NO in the regulation of airway tone is indicated by observations that NOS inhibitors such as Nω-nitro-L-arginine methyl ester (L-NAME) and NG-monomethyl-L-arginine (L-NMMA) enhanced muscarinic agonist-, histamine- and substance P-induced constriction of intact perfused guinea-pig tracheal tube preparations in vitro (Nijkamp et al., 1993; De Boer et al., 1996; Figini et al., 1997) as well as bronchoconstriction in response to allergen, methacholine, histamine and bradykinin in guinea-pigs and/or asthmatic patients in vivo (Persson et al., 1993; Nijkamp et al., 1993; Ricciardolo et al., 1994; 1996; Mehta et al., 1997a, 1997b; Schuiling et al., 1998b).

In many cells throughout the body, including the lung (Que et al., 1998), L-arginine is also metabolized by arginase to ornithine and urea. Two isoforms of mammalian arginase have been identified (Jenkinson et al., 1996). Type I arginase (arginase I) is a cytosolic enzyme, mainly expressed in liver as a component of the urea cycle, whereas type II arginase (arginase II) is a mitochondrial enzyme only expressed in extrahepatic tissue. Because extrahepatic tissues do not possess a complete urea cycle, the biological function of arginase in these tissues is presently unclear. One function of extrahepatic arginase might be the production of L-ornithine, a precursor of polyamines and proline, which are important in cell growth and tissue repair (Jenkinson et al., 1996). In addition, since arginase and NOS use L-arginine as a common substrate, it has been suggested that arginase may be important in the regulation of NO production by limiting the availability of intracellular L-arginine. Evidence for this hypothesis has particularly been obtained in activated macrophages or macrophage-like cells, which express high levels of arginase and iNOS (Wang et al., 1995; Modolell et al., 1995; Hey et al., 1997; Morris et al., 1998; Chang et al., 1998; Boucher et al., 1999). Moreover, evidence for reciprocal regulation of arginase and cNOS has recently also been obtained (Baggio et al., 1999; Cox et al., 1999).

Recent immunohistochemical studies in rat lung have indicated that both arginase I and arginase II are constitutively expressed in the airways, particularly in the bronchial epithelium and in peribronchial connective tissue fibroblasts (Que et al., 1998). The expression of both isotypes in the airways was upregulated during hyperoxic lung injury and recovery, and associated with reduced NO production in the lung, which may indicate a role for arginase in inflammatory tissue repair (Que et al., 1998).

The role of arginase with respect to airway function is presently unknown. Since both arginase and cNOS are constitutively expressed in the airway epithelium, and activation of cNOS in the airway epithelium by contractile agonists appears to dampen airway constriction in response to these agonists (Nijkamp et al., 1993), we hypothesized that competition between both enzymes for their common substrate may be involved in the modulation of cholinergic airway reactivity. Therefore, using a perfused guinea-pig tracheal tube preparation, we investigated the modulation of methacholine-induced airway constriction by the recently developed highly potent and specific arginase inhibitor Nω-hydroxy-nor-L-arginine (nor-NOHA) (Custot et al., 1997; Tenu et al., 1999). Nor-NOHA is a new analogue of the endogenous intermediate in NO synthesis and arginase inhibitor Nω-hydroxy-L-arginine (NOHA), bearing a shorter lateral side chain with one CH2, group less (Custot et al., 1997).

Methods

Tracheal perfusion

Specified pathogen-free Dunkin Hartley guinea-pigs (Harlan, Heathfield, UK), weighing 600–800 g, were used in this study. The animals were killed by a sharp blow on the head and exsanguinated. The tracheas were rapidly removed and placed in Krebs-Henseleit (KH) solution (37°C) of the following composition (mM): NaCl 117.5, KCl 5.60, MgSO4 1.18, CaCl2 2.50, NaH2PO4 1.28, NaHCO3 25.0, D-glucose 5.50; gassed with 5% CO2 and 95% O2; pH 7.4.

The tracheas were prepared free of serosal connective tissue and cut into two halves of approximately 17 mm before mounting in a perfusion setup, as described previously (De Boer et al., 1996). To this aim, the tracheal preparations were attached at each side to stainless steel perfusion tubes fixed in a Delrin perfusion holder. The holder with the trachea was then placed in a water-jacketed organ bath (37°C) containing 20 ml of gassed KH (the serosal or extraluminal (EL) compartment). The lumen was perfused with recirculating gassed KH from a separate 20 ml bath (mucosal or IL compartment) at a constant flow rate of 18 ml min−1. Two axially centred side-hole catheters connected with pressure transducers (TC-XX,Viggo-Spectramed B.V., Bilthoven, The Netherlands) were situated at the distal and proximal ends of the trachealis to measure hydrostatic pressures (Poutlet and Pinlet, respectively). The signals were fed into a differential amplifier to obtain the difference between the two pressures (ΔP=Pinlet−Poutlet), which was plotted on a flatbed chart recorder. ΔP reflects the resistance of the tracheal segment to perfusion and is a function of the mean diameter of the trachea between the pressure taps (Munakata et al., 1989). The transmural pressure in the trachea was set at 0 cmH2O.

After a 45 min equilibration period with three washes with fresh KH (both IL and EL), 1 μM isoprenaline was added to the EL compartment for maximal smooth muscle relaxation to assess basal tone. After three washes during at least 30 min, the trachea was exposed to EL 40 mM KCl in KH to obtain a receptor-independent reference response. Subsequently, the preparation was washed four times with KH during 45 min and a cumulative concentration response curve was made with IL methacholine. When used, L-NAME (0.1, 0.5 or 1 mM) and nor-NOHA (1, 5 or 10 μM) were applied to the IL reservoir, 40 min prior to agonist-addition. L-arginine (0.3, 1.0 or 5.0 mM) was added to the EL reservoir, 30 min prior to agonist addition.

Data analysis

To compensate for differences in ΔP due to variation in resting internal diameter of the preparations used, IL responses of the tracheal tube preparations to methacholine were expressed as a percentage of the response induced by EL administration of 40 mM KCl. The contractile effect of 10 mM methacholine (highest concentration) was defined as Emax (De Boer et al., 1996). Using this Emax, the sensitivity to methacholine was evaluated as pEC50 (−log10EC50) value. Data are expressed as means±s.e.mean. Statistical analysis was performed using the Student's t-test for unpaired observations. Differences were considered statistically significant at P<0.05.

Chemicals

Methacholine chloride, L-arginine hydrochloride, Nω-nitro-L-arginine methyl ester and L-norvaline were obtained from Sigma Chemical Co. (St. Louis, MO, U.S.A.). Nω-hydroxy-nor-L-arginine was synthesized as described previously (Custot et al., 1997).

Results

IL perfusion of the tracheae with the arginase inhibitor nor-NOHA caused a concentration-dependent decrease in methacholine-induced airway constriction (Figure 1, Table 1). In the presence of 5 μM nor-NOHA, the Emax to methacholine was maximally reduced to approximately 60% of control (P<0.001). In addition, the pEC50 value for the agonist was slightly reduced in the presence of the arginase inhibitor (Table 1). In the presence of 10 mM of the specific, but less potent arginase inhibitor L-norvaline (Chang et al., 1998), an inhibition of methacholine-induced airway constriction was also observed, which was virtually identical to that obtained by 10 μM nor-NOHA (Figure 2).

Figure 1.

Figure 1

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Effect of 1.0, 5.0 and 10.0 μM nor-NOHA (IL) on methacholine (MeCh; IL)-induced constriction of intact perfused guinea-pig tracheae. Results are means±s.e.mean of 3–10 experiments.

Table 1.

Effects of (combinations of) nor-NOHA, L-norvaline, L-NAME and L-arginine on the responsiveness to methacholine of intact perfused guinea-pig tracheae

graphic file with name 130-0703488t1.jpg

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Figure 2.

Figure 2

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Effect of 10.0 mM L-norvaline (IL) and 10.0 μM nor-NOHA (IL) on methacholine (MeCh; IL)-induced constriction of intact perfused guinea-pig tracheae. Results are means±s.e.mean of 3–10 experiments.

The reduced responsiveness to methacholine in the presence of 5 μM nor-NOHA was concentration-dependently reversed by the NOS inhibitor L-NAME (Figure 3, Table 1). In the presence of 0.1 mM L-NAME (IL), the methacholine response in the norNOHA-treated airways was normalized to the control response, while a further, maximal increase in responsiveness to about 1.7-fold control was obtained in the presence of 0.5 mM L-NAME (P<0.001). In control preparations, the responsiveness to methacholine was also significantly enhanced by the NOS inhibitor; however, the increase in Emax was already maximal in the presence of 0.1 mM L-NAME (1.8-fold; Figure 4, Table 1). The responsiveness of the norNOHA-treated airways in the presence of 0.5 mM L-NAME was very similar to that of the control preparations in the presence of 0.1 and 0.5 mM of the NOS inhibitor (Figures 3 and 4, Table 1).

Figure 3.

Figure 3

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Effect of 5.0 μM nor-NOHA (IL) in the absence and presence of 0.1, 0.5 and 1.0 mM L-NAME (IL) on methacholine (MeCh; IL)-induced constriction of intact perfused guinea-pig tracheae. Results are means±s.e.mean of 4–10 experiments.

Figure 4.

Figure 4

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Effect of 0.1 and 0.5 mM L-NAME (IL) on methacholine (MeCh; IL)-induced constriction of intact perfused guinea-pig tracheae. Results are means±s.e.mean of 4–10 experiments.

We have previously established that administration of exogenous arginine significantly suppressed the responsiveness to methacholine in a concentration-dependent manner (De Boer et al., 1999; Figure 5, Table 1). In the presence of an excess of 5 mM L-arginine, the Emax for methacholine was reduced to about 60% of control (P<0.01), as in the presence of 5 μM nor-NOHA (Figure 6, Table 1). In the presence of 5 mM L-arginine, 5 μM nor-NOHA had no further effect on the responsiveness to methacholine (Figure 6, Table 1).

Figure 5.

Figure 5

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Effect of 0.3, 1.0 and 5.0 mM L-arginine (EL) on methacholine (MeCh; IL)-induced constriction of intact perfused guinea-pig tracheae. Results are means±s.e.mean of 3–11 experiments. Taken from De Boer et al., 1999.

Figure 6.

Figure 6

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Effect of 5.0 μM nor-NOHA (IL), 5.0 mM L-arginine (EL) and 5.0 μM nor-NOHA (IL)+5.0 mM L-arginine (EL) on methacholine (MeCh; IL)-induced constriction of intact perfused guinea-pig trachea. Results are means±s.e.means of 3–10 experiments.

Nor-NOHA, L-NAME and L-arginine had no effect on basal airway tone (not shown).

Discussion

Using the recently developed, highly potent arginase inhibitor nor-NOHA, as well as the specific but less potent arginase inhibitor L-norvaline, we demonstrated that constitutive endogenous arginase activity is involved in the regulation of cholinergic airway reactivity. The Nω-hydroxy-L-α-aminoacid nor-NOHA is one of the most potent arginase inhibitors reported so far, inhibiting purified rat liver arginase activity and arginase contained in murine macrophages with IC50 values of 2 to 10 μM, respectively (Custot et al., 1997; Tenu et al., 1999). A maximal effect of the arginase inhibitor on airway reactivity was obtained in the presence of 5 μM nor-NOHA, which is well in the range of these IC50 values.

The reduced methacholine-induced airway constriction in the presence of 5 μM nor-NOHA was dose-dependently reversed by the non-selective NOS inhibitor L-NAME, indicating that the reduced airway responsiveness was caused by enhanced production of NO. Similar to previous studies (De Boer et al., 1996; 1998; 1999; Meurs et al., 1999), 0.1 mM L-NAME caused a 1.8-fold increase in the Emax to methacholine in the control airways, demonstrating that methacholine-induced constriction of guinea-pig tracheal tube preparations is functionally antagonized by agonist-induced (cNOS-derived) NO production. In these preparations Emax was not further increased by using higher concentrations of the NOS inhibitor. A similar maximal increase in Emax to methacholine by L-NAME (to 1.7-fold control) was observed in the nor-NOHA-treated airways. However, a higher concentration of the NOS inhibitor (0.5 mM) was required to obtain this effect, indicating that L-NAME had to compete with a higher concentration of endogenous L-arginine in these preparations. The higher availability of L-arginine in the nor-NOHA-treated airways and the subsequent NO-dependent reduction of methacholine-induced airway constriction in these preparations may well be explained by reduced metabolism of the substrate due to inhibition of arginase activity. This would imply that under basal conditions L-arginine is a limiting factor for NO production and that the functional antagonism of cholinergic airway tone by NO is governed by competition between arginase and cNOS for their common substrate. The latter hypothesis is strongly supported by the observation that administration of exogenous L-arginine significantly reduced the responsiveness to methacholine (Figure 4; De Boer et al., 1999), indicating that the production of agonist-induced NO is enhanced by suppletion of substrate, while, as expected, the nor-NOHA effect was abolished in the presence of a supramaximal concentration (5 mM) of L-arginine (Figure 6). Remarkably, the maximal reduction of airway reactivity induced by nor-NOHA was comparable to that observed in the presence of a maximally effective concentration of L-arginine, indicating that endogenous arginase activity is a major factor in the regulation of airway reactivity.

Although the source of NO in our perfused tracheal tube preparations was not assessed, L-NAME only increased the agonist-induced constriction and not basal tone, both in control and nor-NOHA-treated airways, indicating that the NO was most likely produced by cNOS. In addition, in control preparations, we previously demonstrated that L-NAME also had no effect on airway constriction induced by KCl, when administered in the EL compartment (i.e. directly activating airway smooth muscle), indicating the absence of functional iNOS activity in these preparations (De Boer et al., 1996). It has recently been demonstrated that nor-NOHA is not a substrate for nNOS and iNOS (Moali et al., 1998), indicating that metabolism of the arginase inhibitor to NO is unlikely to have contributed to the observed effects on airway reactivity. This is also indicated by the observation that L-norvaline, which cannot be a substrate for NOS due to the absence of a guanidino group, caused a similar inhibition of methacholine-induced airway constriction compared to nor-NOHA.

Using a guinea-pig model of allergic asthma, characterized by allergen-induced early and late asthmatic reactions, airway inflammation and AHR to methacholine and histamine after both reactions (Santing et al., 1994; 1995), we have recently established both ex vivo (De Boer et al., 1996) and in vivo (Schuiling et al., 1998a, 1998b) that a deficiency of cNOS-derived NO contributes to the AHR observed after the early asthmatic reaction (EAR). A deficiency of cNOS-derived NO modulating airway reactivity was also observed in patients with severe asthma (Ricciardolo et al., 1997), which may similarly be induced by allergen challenge (Ricciardolo et al., 1999). In perfused tracheal preparations obtained from sensitized guinea-pigs at 6 h after allergen challenge, we subsequently demonstrated that the deficiency of NO after the EAR is due to limitation of L-arginine as substrate for cNOS (De Boer et al., 1999). Since it has been reported that the expression of arginase may be enhanced by prostaglandin E2 and TH2 lymphocyte-derived cytokines (Corraliza et al., 1995; Modolell et al., 1995; Waddington et al., 1998), which are important mediators of allergic airway inflammation, it is tempting to speculate that induction of arginase after allergen challenge is involved in the development of AHR after the EAR. However, the role of arginase in the modulation of NOS activity, inflammation and airway reactivity in allergic asthma remains to be established.

In conclusion, the present study indicates that endogenous arginase activity potentiates cholinergic airway constriction by inhibition of NO production, presumably by competition with cNOS for the common substrate, L-arginine. This finding represents an important novel regulation mechanism of airway reactivity, which might be disturbed in allergic asthma.

Acknowledgments

The authors wish to thank Mr H. Maarsingh for expert technical assistance.

Abbreviations

AHR

airway hyperreactivity

cNOS

constitutive nitric oxide synthase

EAR

early asthmatic reaction

EL

extraluminal

Emax

maximal effect

eNOS

endothelial nitric oxide synthase

IL

intraluminal

iNOS

inducible nitric oxide synthase

KH

Krebs-Henseleit

L-NAME

Nω-nitro-L-arginine methyl ester

L-NMMA

NG-monomethyl-L-arginine

nNOS

neuronal nitric oxide synthase

NO

nitric oxide

nor-NOHA

Nω-hydroxy-nor-L-arginine

Pinlet

(hydrostatic) pressure at the inlet

Poutlet

(hydrostatic) pressure at the outlet

pEC50

−log10 of the concentration causing 50% of the effect

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