Chemical Senses

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Chem. Senses 28: 595-601, 2003
© Oxford University Press 2003

Real-time Monitoring of Nasal Mucosal pH During Carbon Dioxide Stimulation: Implications for Stimulus Dynamics

D. Shusterman¹ and P.C. Avila²

¹ Division of Occupational and Environmental Medicine ² Division of Allergy and Immunology, University of California, San Francisco, CA, USA

Correspondence to be sent to: Dennis Shusterman, Upper Airway Biology Laboratory, University of California, San Francisco, 1301 S. 46th Street, Bldg. 112, Richmond, CA 94804, USA. e-mail: dennis{at}itsa.ucsf.edu

	Abstract

Top Abstract Introduction Materials and methods Results Discussion Acknowledgments References

 
Carbon dioxide is a commonly employed irritant test compound in nasal chemesthetic studies because it is essentially free of olfactory stimulus properties. CO₂ is thought to act via hydration to H₂CO₃ and dissociation to H⁺ in nasal mucus, with resulting activation of acid sensors. However, transient changes in nasal mucosal pH have not been documented during CO₂ stimulation in humans. We placed a small pH probe on the floor of the right anterior nasal cavity during CO₂ stimulation in eight human subjects with historically high (>30%) and low (20%) CO₂ detection thresholds. Three second pulses of CO₂ (15–45% v/v) paired with air in random order (12–15 s inter-stimulus interval; 60 s inter-trial interval) were administered by nasal cannula at 5 l/min. in an ascending series. For each subject, both a CO₂ detection threshold and suprathreshold psychophysical ratings [; labeled magnitude scale] were generated. All subjects showed phasic drops in pH associated with CO₂ stimulation (pH). For all subjects combined, a positive correlation was apparent between applied [CO₂] and both pH and , as well as between pH and themselves (P < 0.0001 for each comparison). Subjects with historically low CO₂ thresholds showed steeper dose-response curves for as a function of both applied [CO₂] and pH, but not for pH as a function of applied [CO₂]. For the six of eight subjects with measurable pH changes at threshold, pH was positively related to log [CO₂ threshold] (P < 0.01). These data imply that variability in CO₂ detection thresholds and suprathreshold rating may derive from intrinsic differences in neural sensitivity, rather than differences in stimulus activation to hydrogen ion.

Key words: carbon dioxide, nasal mucosal pH, psychophysical testing, sensory irritation

	Introduction

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Phasic changes in mucosal pH have been presumed to underlie the effectiveness of carbon dioxide (CO₂) as a chemosensory stimulus (irritant) in the upper airway and oral cavity. This presumption is based upon the known chemistry of CO₂’s interaction with water, particularly in the presence of the enzyme carbonic anhydrase (Bryant, 2000). Empirical evidence derives from both animal and human experiments in which pharmacological inhibition of carbonic anhydrase results in decreased electrophysiological or psychophysical responses (Dessirier et al., 2000; Alimohammadi and Silver, 2001). In humans, static measurements of nasal mucosal pH have been carried out for the evaluation of various disease states and therapeutic interventions, but have not, to our knowledge, been applied to chemosensory studies (Cavaliere et al., 1988; England et al., 1999; Hehar et al., 1999; Selimoglu et al., 1999; Washington et al., 2000). Here, we determined whether CO₂-induced nasal sensory irritation reflects transient stimulus-related changes in nasal mucosal pH. To address this question, we studied this phenomenon by combining real-time nasal mucosal pH measurements with structured psychophysical testing, including both threshold determination and suprathreshold rating.

	Materials and methods

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In order to maximize contrasts (i.e. to maximize our statistical power to test hypotheses relating psychophysical to physiological measures), subjects with historically high (>30%) or low (20%) CO₂ detection thresholds were studied.

Subject recruitment

Eight non-smoking, non-asthmatic subjects between the ages of 21 and 56 years (including six males and four allergic rhinitics) participated. All were previous participants in chemosensory studies who had demonstrated either consistently high (>30%) or low (20%) CO₂ detection thresholds on two previous testing sessions at least 2 months apart, utilizing the testing protocol described below (four in each subgroup; Table 1). Subjects’ allergy status was confirmed by matching questionnaire responses with results of skin prick testing with a panel of 16 common aeroallergens/mixes; seasonal allergic rhinitic subjects were studied outside of their relevant aeroallergen season. Subjects signed a written informed consent approved by the Committee on Human Research of the University of California, San Francisco prior to testing. Subjects refrained from eating, drinking or exercising for at least 1 h prior to testing, and also refrained from using scented products during the day of testing. Testing took place in a 950 ft³ climate-controlled chamber maintained at 22 ± 1°C and 40 ± 3% relative humidity.

View this table: [in this window] [in a new window]   Table 1 Characteristics of subjects

 
pH recording

Nasal mucosal pH was measured using a 3 mm diameter flexible glass-tipped probe medically approved for monitoring esophageal pH (Probe M3, Medical Instruments Corporation, Solothurn, Switzerland). After daily calibration (at pH 4.0 and 7.0), the probe was introduced 4 cm along the floor of the right nasal cavity and maintained in position using paper tape applied to the nose and forehead. The probe, in turn, was connected to a direct-reading pH meter with analog output (Model 6171, Jenco Instruments, San Diego, CA). Output from the pH meter was digitized using an analog-to-digital convertor board (DI-195B, DataQ Instruments, Akron, OH) and signal conditioning input module (SCM5B41–01, ±1V, Dataforth Corp., Tucson, AZ) on a Windows-compatible laptop computer (Dell Computers, Roundrock, TX). Data were logged utilizing commercial software (WinDaq, DATAQ Instruments) with a sampling rate of 10 Hz.

CO₂ stimulation

On a single testing date, nasal pH was measured in the right anterior nasal cavity during CO₂ stimulation. The stimulus delivery apparatus and testing protocol have been described in detail previously (Shusterman and Balmes, 1997; Shusterman et al., 2001). Briefly stated, 3 s stimulus pulses, paired with 3 s air pulses in random order (12–15 s inter-stimulus interval; 60 s inter-trial interval) were administered dichorhinically in a single-blinded fashion by cannula (no. 1606; Salter Labs, Arvin, CA) at 5 l/min, synchronized with inspiration. CO₂ stimuli followed an ascending concentration series (beginning with 0% or ‘sham’, and progressing to 15, 20, 25, 30, 35, 40 and 45%), with five trials per CO₂ concentration. For each trial, subjects were asked to identify the more irritating of the two pulses, and in addition, to rate the more irritating pulse using a computer-based version of the labeled magnitude scale with the index terms ‘none’, ‘barely detectable’, ‘weak’, ‘moderate’, ‘strong’, ‘very strong’ and ‘strongest imaginable’ (Green et al., 1996). The CO₂ detection threshold was defined as the lowest concentration at which a subject identified all five CO₂ stimuli as being more irritating than the paired air pulses. Psychophysical ratings of nasal irritation (, 0–100) were also recorded directly to computer file using commercial data acquisition software (LabView, National Instruments, Austin, TX).

Data abstraction and analysis

Delta pH (pH) was defined as any phasic (transient) pH change (exceeding baseline oscillatory fluctuations) registered within 30 s following the onset of a stimulus pulse, and was measured using the ‘data calipers’ (graphical scaling tool) feature of WinDaq. In addition to noting pH, time latency to maximum pH deviation was recorded, and note was made, when possible, of the mean pH measurable at a particular subjects’ threshold CO₂ step. Data were analyzed on a Macintosh G4 computer (Apple Computers, Cupertino, CA) using JMP software (SAS Institute, Cary, NC). Prior to analysis, individual pH and psychophysical data were averaged for the five trials at a given stimulus concentration. Repeated-measures ANOVA was used to evaluate the stability of individual CO₂ detection thresholds over time. CO₂ detection thresholds with and without the pH probe were compared using Student’s t-test. Linear regression was applied to pooled data (and multivariate regression models examined the role of individual subject) for applied [CO₂] and measured pH, and . Analysis of covariance (ANCOVA) was used to evaluate the effect of historical CO₂ threshold (‘high’ vs. ‘low’) on the relationship of [CO₂] to both pH and . Based upon theoretical considerations (Gescheider, 1985), the [natural] log of CO₂ detection thresholds was used to examine the relationship between CO₂ detection threshold and pH at threshold.

The hypotheses to be tested included: (1) pulsed CO₂, but not air, will produce negative phasic changes in nasal pH (pH); (2) the magnitude of pH will be proportional to the CO₂ concentration administered;(3) psychophysical ratings of nasal irritation () for individual stimuli will be proportional to the magnitude of pH; (4) The relationship of pH to applied [CO₂] will be constant across subjects; (5) The relationship of to pH will be constant across subjects; (6) pH measured at threshold will be constant across subjects.

	Results

Top Abstract Introduction Materials and methods Results Discussion Acknowledgments References

 
Characteristics of participating subjects appear in Table 1. The eight subjects ranged in age from 21 to 56 years (mean 39.4), and included six males and an equal number of allergic rhinitics and non-rhinitics. Mean CO₂ detection thresholds differed between the historically high- and low-CO₂ threshold subgroups in an ANCOVA model including historical testing times 1 and 2 (mean of two determinations each) and at time 3 (single determination along with pH measurement; P < 0.001). In terms of stability of measures, there was a downward trend in mean CO₂ detection threshold in the high-threshold group indicative of a possible training effect (P = 0.17 in repeated measures subanalysis). However, this effect was overshadowed by measured stability grouping by either historical CO₂ threshold or individual subject (P < 0.0001).

Subjects adapted quickly to the presence of the pH probe and tolerated the procedure well. Mean (±SEM) CO₂ detection thresholds with the probe in place did not differ significantly from the immediately previous measurement (25.0 ± 3.8 vs. 27.2 ± 4.6% respectively; P = 0.72). With regard to CO₂ detection thresholds, the pH probe was equally unobtrusive in the historically high- and low-threshold subgroups (data not shown). All subjects showed phasic drops in pH associated with CO2—but not air—stimulation (see Figure 1 for representative tracings). Averaged by trial, latencies to peak deviation varied from 2.8 to 12.9 s (mean 7.3; median 6.7), and pH ranged up to 0.26 pH units. Baseline nasal mucosal pH (recorded between stimulus trials) ranged between approximately 7.04 and 7.70 (i.e. physiologically neutral), and did not vary significantly by subjects’ CO₂ threshold or rating behavior.

View larger version (23K): [in this window] [in a new window]   Figure 1 Example of real-time recording of nasal mucosal pH during pulsed stimulation with CO2 (rectangular waves with arrows) and air (rectangular waves without arrows). Pulses are 5 l/min., 3.0 s duration, synchronized with inspiration, and delivered dichorhinically by nasal cannula. The first series of pulses were all control (0% CO2) stimuli; vertical arrows in series 2 and 3 indicate CO2 stimuli. Note baseline shift (as distinguished from phasic change) during control series (probably due to movement artifact). Subject is a 29 year old female.

 
Applying linear regression to data from all subjects combined, a positive relationship was apparent between applied CO₂ concentration and pH (P < 0.0001; Figure 2a). Stratified by historical CO₂ sensitivity, the regression lines for the high- and low- threshold groups were parallel (0.0029 pH units/%CO₂) and not significantly displaced from one another (P = 0.25; Figure 2b). A multivariate model confirmed that subjects did not differ in their acidification of nasal mucus in response to CO₂ (P = 0.79)

View larger version (11K): [in this window] [in a new window]   Figure 2 (a) Individual mean values of pH (inverted scale) as a function of applied [CO2], all subjects combined (P < 0.0001). (b) Stratified by historical CO2 threshold, there was no significant difference in regression lines between low-threshold and high-threshold subjects. Each dot represents the mean of five observations, within individual and stimulus series.

 
For all subjects combined, a positive relationship was apparent between applied CO₂ concentration and (P < 0.0001; Figure 3a). Stratifying by historical CO₂ sensitivity, the regression lines for the high- and low-threshold groups had significantly different slopes, with increasing by 0.94 units per %CO₂ in the low-threshold group and 0.48 units per %CO₂ in the high-threshold group (P < 0.01; Figure 3b). A multivariate model indicated that individuals differed significantly in their psychophysical response to increasing CO₂ concentrations (P < 0.0001).

View larger version (10K): [in this window] [in a new window]   Figure 3 (a) Individual mean values of (LMS scale) as a function of applied [CO2], all subjects combined (P < 0.0001). (b) Stratified by historical CO2 threshold, low-threshold subjects had a significantly steeper regression line than did high-threshold subjects (P < 0.01). Each dot represents the mean of five observations, within individual and stimulus series.

 
In addition to their individual relationships to applied CO₂ concentration, and pH, grouped by individual + trial, were themselves significantly correlated (P < 0.001; Figure 4a). Stratifying by historical CO₂ sensitivity, the regression lines for the high- and low-threshold groups had significantly different slopes, with increasing by 274 per pH unit in the low-threshold group and 61 per pH unit in the high-threshold group (P < 0.05; Figure 4b). Stratifying by historical CO₂ threshold, subjects in each subgroup responded similarly (P = 0.25)—but the subgroups themselves responded differently (P < 0.05)—to increasing CO₂ concentrations.

View larger version (11K): [in this window] [in a new window]   Figure 4 (a) Relationship between individual mean pH and , averaged by stimulus level, all subjects combined (P < 0.001). (b) Stratified by historical CO2 threshold, low-threshold subjects had a significantly steeper regression line than did high-threshold subjects (P < 0.05). Each dot represents the mean of five observations, within individual and stimulus series.

 
pH was also measurable at threshold for six of eight subjects, including three in the low-threshold group and three in the high-threshold group. Among these six subjects, there was a significant positive correlation between log-transformed [CO₂ threshold] and mean pH at threshold (Figure 5; P < 0.05). Stated differently, individuals who were ‘less sensitive’ to CO₂ (i.e. who had higher CO₂ detection thresholds) were responding to greater pH changes at threshold than were ‘more sensitive’ subjects (those with lower CO₂ detection thresholds).

View larger version (13K): [in this window] [in a new window]   Figure 5 Relationship between [log-transformed] CO2 detection threshold and pH at threshold for six of eight subjects in which measurable pH fluctuations were observed at that stimulus step. pH at threshold increased significantly with increasing [log-transformed] CO2 detection threshold (P < 0.05).

 
Latency to peak pH deviation significantly decreased with either applied [CO₂] or pH, with the strongest relationship being to the latter variable (P < 0.0001; Figure 6). The shortening of latency with increasing stimulus concentration is a consistent effect across subjects (P < 0.01).

View larger version (14K): [in this window] [in a new window]   Figure 6 Relationship of latency to peak pH deviation to pH on a trial-to-trial basis, all subjects combined. There is a significant negative correlation (P < 0.0001).

 

	Discussion

Top Abstract Introduction Materials and methods Results Discussion Acknowledgments References

 
CO₂ stimulation has widespread application in nasal chemosensory studies, including those involving detection thresholds (Stevens et al., 1982; Anton et al., 1992; Shusterman et al., 2001), thresholds for transient respiratory disruption (Cometto-Muniz and Cain, 1982; Dunn et al., 1982; Stevens et al., 1982), cortical evoked responses (Barz et al., 1997; Hummel and Kobal, 1992; Hummel et al., 1998), magnetoencephalography (Huttunen et al., 1986; Hari et al., 1997) and mucosal electrophysiologic responses (Kobal, 1985; Thurauf et al., 1991, 1993; Hummel et al., 1996). Notwithstanding this agent’s widespread use in this context, knowledge of its mechanism of action is largely indirect. The belief that CO₂ acts by hydration to H₂CO₃, dissociation to H⁺, and stimulation of acid-sensitive ion channels is based primarily on studies involving either: (i) inhibition of carbonic anhydrase, the enzyme facilitating CO₂’s hyration/ dissociation (Alimohammadi and Silver, 2001; Dessirier et al., 2000); or (ii) pharmacological inhibition of a subpopulation of acid-sensing receptors (in particular, VR1; Alimohammadi and Silver, 2002).

We directly examined this model of stimulus dynamics by applying a novel mucosal monitoring technique to CO₂-induced trigeminal irritation. A small-diameter pH probe introduced into the floor of one nostril during CO₂ stimulation yielded real-time pH measurements during psychophysical testing, measurements which then could be compared with both stimulus [CO₂] and response (threshold and suprathreshold scaling) data (hypothesis 1). Averaging across subjects, a significant dose–response relationship was observed between applied stimulus concentration [CO₂] and both and pH (hypothesis 2). In addition, mean and pH were significantly interrelated (hypothesis 3). In a stratified analysis, historically high- and low-CO₂ threshold groups differed with regard to the relationship between and both [CO₂] and , but not the relationship between [CO₂] and pH, with low-threshold (‘sensitive’) individuals showing steeper dose–response curves (hypotheses 4 + 5). For the six of eight subjects in whom phasic pH changes were apparent at their CO₂ detection threshold step, pH was greater at threshold in those having higher [log-transformed] CO₂ thresholds (hypothesis 6). Finally, latency to peak pH deviation decreased with increasing stimulus concentration, possibly reflecting buffering kinetics in nasal mucus.

Our results show that a widely used psychophysical model can be broken into compartments (Figure 7). Measurement of pH in nasal mucus accesses an intermediate step in CO₂ stimulus dynamics. Despite the robust associations observed, however, further dissection of the process may be instructive. Specifically, it is unclear to what degree pH changes in nasal mucus represent parallel pH changes within the epithelial or subepithelial cell layers (i.e. in the vicinity of trigeminal nerve endings). Animal studies utilizing pH microelectrodes and/or supravital dyes could potentially provide this information.

View larger version (19K): [in this window] [in a new window]   Figure 7 Theoretical framework for studies relating applied stimulus concentration [CO2], pH, CO2 detection threshold, and suprathreshold rating of sensory irritation . Other abbreviations: CA, carbonic anhydrase enzyme activity; ASIC, acid-sensitive ion channel; VR1, vanilloid (capsaicin/H+/heat) receptor (also referred to as TRPV1); Cr. N. V, fifth (trigeminal) cranial nerve.

 
An important aspect of our CO₂ nasal chemosensory work concerns inter-individual variability. Numerous studies have documented differences in CO₂ chemosensitivity by age, gender, smoking status, rhinitis status, and olfactory function (for review, see Shusterman, 2002). The biological basis for these differences is speculative at this time, but possibilities include: (i) interindividual differences in CO₂ activation (i.e. carbonic anhydrase enzymatic activity); (ii) differences in mucus buffering; and (iii) differences in nociceptor sensitivity. Based on the dose–response relationships observed, our data suggest that historically high- and low-threshold individuals differ in their threshold and suprathreshold response to a given pH excursion, rather than in their activation or buffering of CO₂ pulses. This implies that intrinsic differences in neural sensitivity to H⁺ may play a role in chemesthetic variability. Notwithstanding this finding, complementary studies in our laboratory are currently addressing stimulus activation by documenting interindividual differences in carbonic anhydrase gene expression in the human nasal mucosa (Tarun et al., 2003).

To our knowledge, these data provide the first direct evidence that CO₂-induced nasal sensory irritation reflects short-term decreases in nasal mucosal pH. This technique provides an initial view of pH dynamics with acidic air pollutants and, in theory, could be applied to basic compounds (e.g. ammonia vapor, sodium carbonate dust) as well. Unexplored aspects of the CO₂/pH/ relationship include potential stimulus duration effects and further exploration of anatomical subcompartments (see above). However, the current study provides an important first step in understanding mucosal stimulus dynamics involving rapid pH changes.

	Acknowledgments

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We thank David Glidden, PhD for his advice regarding the statistical analysis. Work supported by NIEHS grant R01 ES10424 (D.S.) and NIAID grant P01 AI50694 (P.A.).

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Top Abstract Introduction Materials and methods Results Discussion Acknowledgments References

 
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Accepted July 7, 2003

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