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(Chest. 1999;115:1678-1683.)
© 1999 American College of Chest Physicians

Is ß-Adrenergic-Mediated Airway Relaxation of Salmeterol Antagonized by Its Solvent Xinafoic Acid?*

Harald Groeben , MD and Charles Emala , MD

* From Abteilung für Anaesthesiologie & Intensivmedizin (Dr. Groeben), Universität Essen, Germany; and the Department of Anesthesiology and Environmental Health Sciences (Dr. Emala), The Johns Hopkins Medical Institutions, Baltimore, MD.


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Study objective: Isolated case reports of asthmatic fatalities accompanied by the use of salmeterol have raised the question whether a paradoxical effect of salmeterol or its vehicle on the airways might contribute to these fatalities. We questioned whether salmeterol's solvent, xinafoic acid, has detrimental effects on the tone of airways or on ß-adrenoceptor binding.

Materials and methods: Basenji-greyhound dogs were anesthetized and their peripheral airways challenged with xinafoic acid via a wedged bronchoscope technique. Radioligand binding assays were performed in lung membranes prepared from these dogs.

Results: In contrast to a methacholine control, xinafoic acid (0.001 to 1.0 mg/mL) aerosolized into the peripheral airways of anesthetized dogs did not increase airway resistance. Xinafoate alone had no significant effect on the specific binding of 125I-cyanopindolol to lung membranes and did not affect the affinity of salmeterol for the ß-adrenoceptor in the absence or presence of xinafoate, respectively (-log concentration that inhibits 50% [IC50] of the high-affinity site, 7.7 ± 0.15 and 7.9 ± 0.27; -log IC50 of the low-affinity site = 5.6 ± 0.44 and 5.3 ± 0.28 [n = 4]).

Conclusion: These findings suggest that xinafoic acid, the solvent for salmeterol, does not have direct airway irritant effects, does not bind to ß-adrenoceptors, and does not impair the binding of salmeterol to ß-adrenoceptors. Thus, xinafoate is unlikely to contribute to the worsening of airway symptoms in asthmatics using salmeterol xinafoate.

Key Words: ß-adrenoceptor • airways • bronchoconstriction • bronchodilation • salmeterol


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Salmeterol is a member of a new generation of ß-sympathomimetic compounds that is characterized by a prolonged bronchodilatory effect.1 2 3 Salmeterol is administered as a salt of xinafoic acid. While the beneficial effects of salmeterol have been well described, the direct effects of its solvent, xinafoic acid, are unknown.4 5 6 Although additives and solvents are supposed to improve or augment the pharmacologic properties of the active compound, there are additives that are known to cause adverse effects,7 8 such as Na-ethylenediaminetetraacetic acid (EDTA), previously used as an additive in metered-dose inhalers (MDIs).9 10 The fact that xinafoic acid has a chemical structure similar to several bifunctional organic acids associated with occupational asthma suggests that it might cause adverse effects when inhaled by asthmatics.11 12 13

There are several reports of serious acute respiratory events, including fatalities, in patients using a salmeterol MDI, which were suggested to be due to inappropriate use of salmeterol xinafoate.14 15 16 Most of these reports describe the use of salmeterol xinafoate in acute emergency situations, which is not a proper indication for salmeterol xinafoate, but instead for short-acting ß-sympathomimetic substances.3 15 16 In light of these fatal events associated with the use of salmeterol xinafoate, we questioned whether xinafoate contributed to these fatalities.

The contribution of xinafoic acid to these fatalities cannot be excluded from the available data. Xinafoate could antagonize the beneficial effect of salmeterol by direct irritation of the airways, by direct effect on smooth muscle cells, or via interference with the ß-adrenoceptor binding of salmeterol. Salmeterol has a significantly longer onset of action than its short-acting relatives. This might allow time for xinafoate to produce an initial irritation. Such irritation might conceivably be outweighed by the initiation of bronchodilation and finally overcome and outlasted by the bronchodilatory effect of the ß-sympathomimetic aerosol. Furthermore, xinafoate could interfere with the ß-adrenoceptor binding of salmeterol or cause a bronchoconstrictive effect by directly acting on smooth muscle cells, as has been described for Na-EDTA.10 17

We performed ß-adrenoceptor binding studies of xinafoic acid with and without salmeterol and evaluated the effect of aerosolized xinafoic acid and salmeterol on canine peripheral airways.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Peripheral Airway Resistance
These studies were approved by the Animal Use and Care Committee of the Johns Hopkins School of Public Health. Six basenji-greyhound dogs (weight range, 15 to 24 kg) with well-characterized nonspecific airway hyperresponsiveness18 were anesthetized with a bolus of thiopental sodium (range, 15 to 20 mg/kg IV), followed by a continuous infusion (range, 5 to 10 mg/kg/h), and the tracheas were intubated. For measurements of peripheral airway resistance, supplemental doses of fentanyl citrate (range, 25 to 50 µg) were administered every 10 to 30 min as needed. The lungs were ventilated with room air using a constant-volume ventilator (Harvard Apparatus Co; Millis, MA) to maintain an end-tidal CO2 at 4.5%.

The ECG was monitored continuously, and BP was measured with an automatic BP cuff every 3 min. Arterial oxygen saturation was continuously monitored by pulse oximetry with a clip attached to the tongue. Rectal temperature was monitored, and body temperature was maintained by a warming mattress. Depth of anesthesia was assessed by canthal reflex, heart rate, BP, and the presence of spontaneous movements or breathing.

Measurement of Peripheral Airway Resistance
A fiberoptic bronchoscope (outer diameter, 5.5 mm) was inserted through the endotracheal tube and visually guided to a wedge position in a sublobar bronchus. A double-lumen catheter was threaded through the suction port of the bronchoscope. Through one lumen, a constant flow of room air with 5% CO2 (200 mL/min = coll) was delivered to the wedged segment. The other lumen, connected to a transducer, served to measure the pressure at the bronchoscope tip (Pb). At functional residual capacity, peripheral airway resistance (Rp) was determined when the Pb reached a plateau, and the pressure in the surrounding unobstructed lung (the term Pao in the following equation) equaled zero. Rp (cm H2O/mL/s) was calculated as follows: Rp = (Pb - Pao)/coll. The percent increase in Rp was calculated as: %Rp = (Rpa - Rpb)/Rpb/100, where Rpa is the peak Rp after a challenge and Rpb is the average of three measurements of Rp before a challenge. At the end of the experiment, the dogs were monitored continuously until they were fully awake.

Peripheral airways were challenged with ethanol, which served as the vehicle for xinafoic acid, salmeterol, and methacholine. Ethanol was always used prior to xinafoic acid or salmeterol in order to evaluate the possibility of a vehicle effect. Methacholine was used at the end of the xinafoic acid challenge in order to demonstrate that the bronchoscope was correctly wedged and that the technique was performed properly and would detect airway constriction, if present.

Aerosols
1-Hydroxy-2-naphthoic-acid (xinafoic acid), salmeterol, and methacholine were dissolved in ethanol. Beginning with a concentration of 1 mg/mL, xinafoic acid was diluted in ethanol to 0.1, 0.01, and 0.001 mg/mL. The beginning solution of salmeterol had a concentration of 0.2 mg/mL and was subsequently diluted in ethanol to 0.02 and 0.002 mg/mL. Methacholine was diluted in ethanol at a concentration of 2.0 mg/mL. The aerosol generated by an ultrasonic nebulizer was driven by a flow of 200 mL/min through the working channel of the bronchoscope. This resulted in a total dose of 35 ± 9 µL of aerosol being delivered through the bronchoscope. All solutions were prepared fresh daily prior to each experiment.

ß-Adrenoceptor Binding
Preparation of Lung Membranes: Adult basenji-greyhound dogs were killed by exsanguination after induction of anesthesia with barbiturates. The lungs and trachea were removed en bloc following a thoracotomy. The most peripheral 2 cm of the lung parenchyma was dissected from all lobes and was resuspended in membrane buffer (Tris, 50 mM, pH 7.4; EDTA, 1 mM; leupeptin, 5 µg/mL; dithiothreitol, 1 mM; aprotinin, 5 µg/mL; benzamidine, 16 µg/mL; and trypsin inhibitors, 10 µg/mL). The lung parenchyma was finely minced with a razor blade, then homogenized on ice (Tissuemizer; Tekmar Co; Cincinnati, OH; setting 10 for 6 s). The tissue suspension was then filtered through two layers of gauze and homogenized with 30 strokes in a homogenizer (Potter-Elvejhem; Wheaton Scientific; Millville, NY). The crude homogenate was centrifuged at 400g for 15 min at 4°C, thus removing intact cells and nuclei. The supernatant was collected and centrifuged at 48,000g for 30 min at 4°C, and the pellet was collected and washed twice in membrane buffer. The final membrane pellet was resuspended in membrane buffer without the EDTA at a protein concentration of 4 to 8 mg/mL and stored frozen at -70°C until used for radioligand binding studies.

Inhibition of125I-cyanopindolol-Specific Binding by Salmeterol: Thirty to 60 µg of lung membranes prepared from five separate dogs were incubated in triplicate tubes in binding buffer (12 mM Tris, pH 7.9; 0.5 mM ascorbic acid; 4 mg/mL bovine serum albumin; 60 mM NaCl; 9 mM MgCl2; 1.8 mM EDTA), containing 80 pM nonselective ß-adrenoceptor antagonist 125I-cyanopindolol (125ICYP; 2,200 Ci/mmol). Salmeterol was included at 21 different concentrations (100 mM to 10 pM) in the presence or absence of 0.5 mg/mL (1.2 mM) xinafoate. Salmeterol and xinafoate were dissolved in 100% ethanol at 100x stock solutions, resulting in a final concentration of ethanol of 1 to 2% in binding reactions. This amount of ethanol did not affect the 125ICYP binding in preliminary studies. All incubations were performed in a final volume of 250 µL and were incubated for 45 min at 37°C, conditions found to achieve equilibration of specific binding in preliminary experiments. Binding assays were terminated by filtration through GF/C glass fiber filters using a cell harvester (Brandel; Gaithersburg, MD) and washed three times with 5 mL cold 0.9% NaCl. Filters were counted in a {gamma}-emission counter (5000 series; Hewlett Packard; Palo Alto, CA) with an efficiency of 73%. The displacement of 125ICYP by salmeterol in the presence or absence of xinafoate was analyzed by nonlinear regression and fit to a one-site and two-site equation for displacement of 125ICYP binding using appropriate computer software (Inplot 4.0; GraphPad Software; San Diego, CA). An F test was performed using the sum of squares and degrees of freedom to determine whether the more complex two-site model fit the data significantly better than the simpler, one-site model. The software was used to calculate the percent of receptors in the high- or low-affinity state for the agonist salmeterol. Because salmeterol binds in a noncompetitive manner, values for the inhibition constant were not calculated using the equation of Cheng and Prusoff,19 since this is appropriate only for competitive inhibitors. The values for the concentration that inhibits 50% for the two affinity sites identified by the displacement of 125ICYP by salmeterol were presented.

Protein Determination: Protein was assayed with a protein assay reagent (BCA; Pierce Chemical Co; Rockford, IL). Bovine serum albumin was used as a standard.

Materials: Salmeterol powder was donated (Glaxo Wellcome; Middlesex, UK). Xinafoic acid (hydroxy-naphthoic-acid) was purchased (Sigma Chemical Co; St. Louis, MO), and 125ICYP (2,200 Ci/mmol) was also purchased (New England Nuclear; Boston, MA).

Statistics
Data were presented as mean ± SEM. Differences in airway resistance measurements are analyzed by a two-way analysis of variance with Bonferroni posttest comparisons. Analysis of salmeterol displacement radioligand assays was first plotted by nonlinear regression analysis using a four-parameter logistic equation or sigmoid curve equation (log scale) with the slope factor set to -1. This analysis was carried out as a one-site or two-site competition curve, and then an F test was used to compare the goodness of fit. To compare differences in affinity sites in the absence or presence of xinafoic acid, unpaired, two-tailed Student's t tests were performed.


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Peripheral Airway Resistance
Effects of Aerosolized Ethanol:
The nebulization of ethanol as the vehicle for subsequent nebulization of xinafoic acid or methacholine into the peripheral airways via the wedged bronchoscope did not signifi- cantly change peripheral airway resistance compared to baseline (0.23 ± 0.05 cm H2O/mL/s). The peak response 30 s after ethanol nebulization was 0.26 ± 0.04 cm H2O/mL/s and decreased to 0.22 ± 0.04 cm H2O/mL/s 15 to 25 min after challenge (n = 6, p > 0.05) (Fig 1 , top left, A).



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  		Figure 1. Rp before and after 30 s of airway challenge (vertical bar) with ethanol (vehicle control; top left, A), increasing concentrations of xinafoic acid (0.001 to 1.0 mg/mL; top right, B, to bottom left, E), and methacholine (2.0 mg/mL; bottom right, F). All challenges were performed subsequently in the same sublobar segment. Data represent mean ± SEM for six basenji-greyhound dogs. None of the four concentrations of xinafoic acid led to a significant change compared to the vehicle control. The methacholine challenge at the end of each experiment demonstrated correct positioning of the bronchoscope and intact reactivity of airways.

 
Effects of Nebulized Xinafoic Acid:
The response to nebulization of xinafoic acid dissolved in ethanol in concentrations of 0.001, 0.01, 0.1, and 1.0 mg/mL did not differ significantly from the response to the vehicle alone (p > 0.05). Peak responses were 0.31 ± 0.08, 0.32 ± 0.09, 0.32 ± 0.09, and 0.33 ± 0.09 cm H2O/mL/s 30 s after challenge with a nonsignificant baseline shift between 0.22 and 0.24 cm H2O/mL/s 15 to 25 min after challenge (n = 6 for each dose) (Fig 1 , top right, B, to bottom left, E).

Effects of Nebulized Methacholine:
At the end of the xinafoic acid nebulizations, the challenge with methacholine 2.0 mg/mL dissolved in ethanol led to a peak increase in peripheral airway resistance of 2.49 ± 0.34 cm H2O/mL/s (p < 0.001). Following the methacholine challenge, peripheral airway resistance did not return to the baseline within 25 min (n = 6)(Fig 1 , bottom right, F).

Effects of Nebulized Salmeterol:
The response to nebulization of salmeterol dissolved in ethanol in concentrations of 0.002, 0.02, and 0.2 mg/mL (0.33 ± 0.14, 0.31 ± 0.14, and 0.37 ± 0.15 cm H2O/mL/s) did not differ significantly from the response to the vehicle alone (0.33 ± 0.13 cm H2O/mL/s). The baseline shifted nonsignificantly (p > 0.05) between 0.27 and 0.32 cm H2O/mL/s 15 to 25 min after the challenge (n = 6) (Fig 2 ).



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  		Figure 2. Rp before and after 30 s of airway challenge (vertical bar) with ethanol (vehicle control) and increasing concentrations of salmeterol (0.001 to 1.0 mg). All challenges were performed subsequently in the same sublobar segment. Data represent mean ± SEM of six basenji-greyhound dogs. None of the three concentrations of salmeterol led to a significant change compared to the vehicle control in these dogs with unconstricted airways.

 
ß-Adrenoceptor Binding
Salmeterol Displacement of 125ICYP-Specific Binding:
Salmeterol displaced 125ICYP from ß-adrenoceptors in lung membranes prepared from five basenji-greyhound dogs. Nonlinear regression analysis of this displacement indicated that salmeterol exhibited two affinity sites for ß-adrenoceptors. Statistical analysis of competition displacement curves of salmeterol and 125ICYP in lung membranes from the dogs revealed a best fit of the data to a two-site model (p < 0.05), indicative of a low- and high-affinity site for salmeterol. This reflected either two receptor subtypes with differing affinities for salmeterol or a single predominating subtype with a high- and low-affinity site for salmeterol (Fig 3 ). The affinity of salmeterol for either the high- or low-affinity site was unaffected by the presence of 1.2 mM xinafoate in the binding assay. Salmeterol's affinity for the high-affinity site was (-log ) 7.7 ± 0.15 and 7.9 ± 0.27 in the absence or presence of xinafoate, respectively (n = 4; p = 0.95). The affinity of salmeterol to the low-affinity site was (-log ) 5.6 ± 0.44 and 5.3 ± 0.28 in the absence or presence of xinafoate, respectively (n = 4; p = 0.55). Xinafoate also had no effect on the percentage of receptor binding sites exhibiting a high vs low affinity for salmeterol (66 ± 6.2% and 77 ± 4.5% high-affinity sites for control and xinafoate, respectively (n = 4; p = 0.22).



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  		Figure 3. Salmeterol displaced 125ICYP from ß-adrenoceptors in basenji-greyhound dog lung membranes. Two affinity sites for salmeterol were present in lung membranes (p < 0.05). Xinafoic acid (0.5 mg/mL) had no significant effect on the affinity of salmeterol for either the high- or low-affinity site (n = 4).

 
The use of ethanol being used as the vehicle for all solutions did not significantly affect 125ICYP-specific binding up to a concentration of 2% (p = 0.18; n = 4). Similarly, xinafoate did not alter 125ICYP-specific binding (p = 0.62; n = 5).


   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The purpose of this study was to evaluate the inherent properties of xinafoic acid on peripheral airway resistance and ß-adrenoceptor binding. Xinafoic acid is used as a solvent for the ß-sympathomimetic bronchodilator salmeterol, although its inherent properties on airway tone and ß-adrenoceptors have not been previously described. These properties are of particular interest because of fatal outcomes related to the use of salmeterol MDIs.14 15 16 With the molecular structure including an organic ring system, two reactive side groups, and a molecular weight of 188, xinafoic acid is related to agents known to cause occupational asthma.11 12 13 However, the results of the current study demonstrate that neither the effects of xinafoic acid on peripheral airways nor its possible interference with ß-adrenoceptor binding could contribute to fatal outcomes in the use of salmeterol MDIs.

We did not address the question of sensitization to salmeterol or xinafoic acid and a subsequent allergic response. However, to our knowledge, there has not yet been any report of an allergic response to salmeterol xinafoate.

With the standard treatment of salmeterol, ie, two puffs bid, 50 µg salmeterol and 25 µg xinafoic acid are delivered by an MDI.20 With the consideration that <= 75% of the dose reaches the bronchial tree and that < 2% of the bronchial surface is wedged behind the bronchoscope, we assumed that <= 1 µg salmeterol and 0.5 µg xinafoic acid reaches this section of the bronchial tree. Therefore, the range of aerosolized doses used in the present study (7.0 to 0.07 µg salmeterol and 35.0 to 0.035 µg xinafoic acid through the bronchoscope) includes the clinically relevant range of both compounds. Similarly, the concentration of xinafoate (0.5 mg/mL) in the binding assay sufficiently covers the clinically relevant concentrations.

In the current study, we found no difference in the affinity of salmeterol for the ß-adrenoceptor in the presence or absence of xinafoic acid. This suggests that the deposition of xinafoic acid into the airways during the aerosol administration of salmeterol is unlikely to interfere directly with salmeterol's ability to stimulate the ß-adrenoceptor.

Salmeterol was found in the present study to exhibit two affinity sites for the ß-adrenoceptor in lung membranes, consistent with previous studies of salmeterol with ß-adrenoceptors.21 This is expected of an agonist for G-protein coupled receptors. These two affinity sites represent either salmeterol interacting with a single ß-adrenoceptor subtype that is coupled to its G protein (high affinity) or is disassociated from its G protein (low affinity). Alternatively, these two affinity sites may represent salmeterol's affinity for two subtypes of ß-adrenoceptors with different affinities for the agonist. We have previously shown in lung membranes of dogs that both ß1- and ß2-adrenoceptors exist, but the predominant subtype (82%) is the ß2-subtype.22 Thus the two affinity sites identified in the present study likely represent salmeterol's affinity states for the ß2-adrenoceptor. The receptor affinities identified in the present study are similar to those reported in guinea pig bronchi.23 The addition of xinafoic acid to the binding assays had no effect on salmeterol binding to either affinity site. Salmeterol has been shown to bind to ß-adrenoceptors in a noncompetitive manner.23 Therefore, the values were not converted to values for the inhbition constant by the equation of Cheng and Prusoff,19 which requires competitive inhibition of binding.

Na-EDTA and benzalkonium chloride have been used as additives in ipratropium bromide MDIs. It has been shown in animal and human studies that these additives could elicit bronchoconstriction and lead to paradoxical effects in the use of ipratropium bromide MDIs.24 25 26 These adverse effects were demonstrated most clearly in the airway periphery using the wedged bronchoscope technique.10 17 To exclude the effect on the peripheral airway by the additive xinafoate, we evaluated the effect of xinafoic acid using the wedged bronchoscope technique. Over the range of concentrations used, no bronchoconstrictive properties of the additive could be detected. The responses to the different doses were similar to the response to the vehicle (ethanol) alone. To exclude the possibility that the lack of response was due to insufficient delivery of the aerosols or a malposition of the bronchoscope, we routinely induced bronchoconstriction with methacholine at the end of each experiment. Therefore, we feel justified in excluding airway irritation or a direct constricting effect on the bronchial smooth muscle by xinafoic acid in clinically relevant doses.

The finding that no dilation of the peripheral airways could be detected after salmeterol nebulization is probably due to the fact that the measurements started with nonpreconstricted airways with a low resting tone. The low baseline resistance makes it difficult to detect any further dilation. Furthermore, the late onset of salmeterol bronchodilation contributes to the difficulty to show bronchodilation in the time frame of this study. However, the bronchodilatory effect of salmeterol has been well described and was not the main subject of this study.

In conclusion, with a slow onset of bronchodilation, a long-lasting effect, and a low rate of side effects in the range of the recommended doses,27 salmeterol xinafoate has excellent pharmacologic properties for long-term therapy on a regular basis, particularly in blocking nocturnal asthma.4 28 29 With all the limitations in mind when transferring results from an animal model to humans, we conclude that the vehicle solvent of salmeterol, xinafoic acid, has no direct bronchoconstricting effect in vivo and does not interfere with ß-adrenoceptor binding in vitro. Thus, xinafoic acid does not have detrimental effects on the bronchodilatory properties of salmeterol and likely has no role in the rare fatalities associated with salmeterol use. The use of salmeterol xinafoate can be considered a safe and beneficial medication in the armamentarium of antiobstructive airway therapy.


   Acknowledgements
 
ACKNOWLEDGMENT: We are grateful to Dr. Carol Hirshman and Dr. Carl Lawyer for useful discussions concerning this study.


   Footnotes
 
Correspondence to: Harald Groeben, MD, Department of Anesthesiology and Critical Care Medicine, University of Essen, Hufelandstrasse 55, 45122 Essen, Germany; e-mail: harald.groeben@uni-essen.de

Abbreviations: EDTA = ethylenediaminetetraacetic acid; 125ICYP = 125I-cyanopindolol; MDI = metered-dose inhaler; Pb = pressure at the bronchoscope tip; Rp = peripheral airway resistance

Received for publication June 17, 1998. Accepted for publication December 9, 1998.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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