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J Appl Physiol 97: 888-894, 2004; doi:10.1152/japplphysiol.01346.2003
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Strain differences in murine ventilatory behavior persist after urethane anesthesia

Iahn Gonsenhauser,1 Christopher G. Wilson,2 Fang Han,1 Kingman P. Strohl,1 and Thomas E. Dick1,3

1Division of Pulmonary and Critical Care Medicine, Department of Medicine, 2Division of Neonatology, Department of Pediatrics, and 3Department of Neurosciences, Case Western Reserve University, Cleveland, Ohio 44106-4941

Submitted 16 December 2003 ; accepted in final form 23 April 2004


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
Differences in breathing pattern between awake C57BL/6J (B6) and A/J mice are such that A/J mice breathe slower, deeper, and with greater variability than B6. We theorized that urethane anesthesia, by affecting cortical and subcortical function, would test the hypothesis that strain differences require a fully functional neuroaxis. We anesthetized B6 and A/J mice with urethane, placed them in a whole-body plethysmograph, and measured the durations of inspiration and expiration, respiratory frequency (FR), and peak amplitude during exposure to room air (21% O2), hyperoxia (5 min, 100% O2), hypoxia (5 min, 8% O2), and posthypoxic reoxygenation (5 min, 100% O2). Breathing variability was assessed by calculating the coefficient of variation (CV) and by applying spatial statistics to Poincaré plots constructed from the timing and amplitude data. Even though FR in anesthetized B6 and A/J mice was greater than that for unanesthetized animals, anesthetized A/J mice still breathed slower, deeper, and with greater variability than B6 mice at rest and during hyperoxia. During the fourth minute of hypoxia, FR and its CV were not significantly different between strains. Even though FR was similar between strains immediately after hypoxia, its CV was significantly greater for B6 than A/J mice. Posthypoxic FR was significantly less than baseline FR in B6 but not A/J mice, and the CV for posthypoxic FR was greater for B6 but less for AJ mice compared with baseline CV. This difference in patterning was confirmed by spatial statistical analysis. We conclude that strain-specific differences in respiratory pattern and its variability are robust genetic traits. The neural substrate for these differences, at least partially, exists within subcortical structures generating the breathing pattern.

respiratory control; genetic determinants of behavior; nonlinear dynamics

RESPIRATORY PATTERN IS AN inherited, phenotypic trait. We and others report that A/J animals breathe slower, deeper, and with greater variability than C57BL/6J (B6) mice (10–12, 21, 22, 24–26). Mechanics of the respiratory system do not differ substantially in B6 and A/J mice, so the fundamental strain difference is assumed to involve neural mechanisms controlling ventilation (12). Such strain-specific differences in the respiratory pattern were observed only in conscious animals; thus the underlying neural mechanisms for these differences could include cortical function and proprioceptive feedback.

Similarly, the ventilatory response to hypoxia and the breathing pattern after hypoxia are influenced by genetic background in awake, unanesthetized mice (10–12, 21, 22, 24–26). In B6 but not in A/J mice, breathing slows and can become quasi-periodic in the first 60 s after a 5-min exposure to 8% O2 (10–12). We suspect that an increase in variability in the breathing pattern after brief hypoxia may reflect instability in pattern formation, which is found in clinical conditions of sleep apnea (3, 7, 8, 23, 29). Thus a better definition of strain-specific differences in ventilatory stability and the effect of hypoxia on respiratory behavior will provide insight into these mechanisms. Anesthesia minimizes cortical function and its role in determining ventilatory behavior; however, anesthesia does not eliminate the ventilatory response to hypoxia (13, 18, 19, 27, 28). Thus differences in ventilatory behavior in anesthetized animals could begin to define the neural substrates underlying strain differences.

The approach that we used tested both peripheral and central regulatory mechanisms for breathing. A fundamental "controller" exists to generate the breathing pattern and to incorporate environmental changes as relayed to it through "sensors." The fact that anesthetized animals ventilate spontaneously and react to hypoxia indicates that these control and sensory mechanisms function, but it is a reasonable assumption that these mechanisms would be affected by anesthesia.

The anesthetic agents used in most respiratory studies performed with mice were isoflurane or a mixture of urethane and {alpha}-chloralose. Low concentrations of volatile anesthetics significantly reduce the response to hypoxia and hypercapnia (27, 28). We chose urethane not only for its long-lasting effect but also for its ability to anesthetize with minimal effect on variables related to respiratory mechanics, unlike isoflurane, which has been shown to dilate airways (4, 9). These animals breathed spontaneously and without intubation, making upper airway constriction a factor to be considered. Thus, even though urethane anesthesia may affect the magnitude of the strain differences in the breathing pattern and the respiratory response to hypoxia, our hypothesis, that strain differences depend on an intact neuroaxis, will be rejected if strain-specific differences are present after anesthesia.

To better understand the hypoxic ventilatory response as well as the complex behavior of the central pattern generator, spatial statistical analyses were utilized to quantify the differences in breath-to-breath variability between strains and conditions. Skewness of the data distribution was used as a preliminary assessment of normality and periodicity. Poincaré plots were generated to assess whether patterns appeared to be deterministic. Deterministic patterns have discernable shapes visible in the Poincaré mapping because state-dependent changes exhibit reproducible topography. Multimodal and quasi-periodic patterns of breathing can appear as seemingly random or spatially grouped (2). To assess the strain differences in the dynamic behavior of the respiratory system, we used spatial statistics to quantify the distribution patterns of the Poincaré plots.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
Animals.   Experiments were performed on adult, male A/J (n = 9; 25.2 ± 6.6 g, mean ± SD) and B6 (n = 5; 31.2 ± 1.0 g) mice. Animals were obtained from Jackson Laboratory, Bar Harbor, ME, and were housed in the Case Western Reserve University Animal Resource Center for at least 3 wk before investigation (food and water ad libitum; 7 AM–7 PM and 7 PM–7 AM light-dark cycle). Experimental protocols used were approved by the Case Western Reserve University School of Medicine Institutional Animal Care and Use Committee and were in agreement with the National Institutes of Health Guide for the Care and Use of Laboratory Animals.

Protocol.   Animals were tested between 10:00 AM and 2:00 PM to minimize circadian variation (20). Animals were weighed and then anesthetized with urethane (1.2 g/kg body wt ip). We assessed anesthetic level from the absence or presence of corneal and withdrawal reflexes; in a fully anesthetized animal, these reflexes are absent. Once these reflexes were absent, we measured rectal temperature and placed the animals in a plethysmographic chamber equilibrated with room air.

Animals were exposed to room air (21% O2), hyperoxia (100% O2), and hypoxia (8% O2-92% N2). Each gas was administered for 5 min in the following order: room air, hyperoxia, room air, hypoxia, hyperoxia, and then room air. At the end of each exposure, the chamber was flushed rapidly with the replacement gas for 10 s. During the initial 5-min room-air exposure (baseline), gas exiting the chamber was analyzed for O2 and CO2 (Beckman OM-11 and LB-2 analyzers; Beckman Instruments, Pittsburgh, PA) to determine O2 consumption (O2) and CO2 production (CO2) as an index of metabolic activity, respiratory exchange ratio (RER).

Measurement of ventilatory behavior.   A flow-through whole body plethysmograph was used to measure ventilatory behavior in the anesthetized mice (10–12, 21, 22). Briefly, this chamber was a Lucite cylinder (600 ml) with sealed ends. Test gases were administered through a baffled inlet port. The outlet port was connected to a vacuum that produced a constant flow of 0.3 l/min through the chamber. At the end of a 5-min sampling test period, gases were flushed from the chamber at 15 l/min for 10 s. The animal's chamber was connected through a high-impedance, small-diameter tube to a reference chamber. The pressure difference between the animal and reference chamber was measured with a pressure transducer (Validyne DP45, Validyne Engineering). The high-impedance connection minimized slow direct current pressure shifts in the test chamber but allowed the high-frequency pressure differences to be measured. The plethysmograph was not calibrated for volumetric measurement in this study. Animals were recorded under comparable conditions including time of day (20). Environmental variables (room temperature, humidity, and barometric pressure) were monitored, and three animals were tested during each session. The laboratory was a climate-controlled environment, with minimal differences in room temperature, humidity, and barometric pressure over the experimental period.

Data analysis.   Data were recorded continuously during testing by use of LabView data-acquisition software (I.C.E., Cleveland, OH). Variables measured included peak amplitude (PK; millivolts indicating change in inspiratory tidal volume), respiratory frequency (FR; breaths/min), inspiratory time (TI), expiratory time (TE), O2, CO2, and RER. Breathing pattern measurements were the mean of at least 30 uninterrupted breaths. Augmented breaths, sighs, and gasps were excluded from the analysis. We arbitrarily defined augmented breaths as isolated inspirations that exceeded mean PK by >150%. Measurements were made during the fourth to fifth minute during exposure to hyperoxia and hypoxia and within the first minute of reoxygenation after hypoxia. A two-way repeated-measures ANOVA was used to test for significance of differences between strains. Specific differences were identified by Student-Newman-Keuls test. Results are expressed as means ± SD.

Breath-to-breath variabilities of TI, TE, FR, and PK were assessed by calculating the coefficient of variation [(standard deviation/mean) x 100] and by graphing Poincaré plots in which the values for breath n + 1 are plotted against n (Fig. 6). The distribution of points was assessed via spatial statistics and cluster analysis (Software-R, MatLab). We compared the distribution pattern of the Poincaré plots generated by the experimental data with those generated after shuffling the data. For these shuffled data sets (n = 100), a geometric reference point was determined by averaging all x-coordinates and all y-coordinates. The distance (radius) from the weighted center of the distribution to each point in the shuffled and experimental data sets was measured. These distances were sorted into 10 bins each one-tenth of the greatest distance from center. The number of points per bin was counted and plotted as a histogram. The experimental data had a significant nondeterministic quality if its point was beyond the range of those from the shuffled data.



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  		Fig. 6. A: Poincaré plots of n vs. n + 1 for FR (top), TI (middle), and TE (bottom) for each breath in the 5-min recording period in room air (baseline; left) and posthypoxic reoxygenation (post-hypoxia; right). B: histograms of average real ({circ} and bold hatch marks) vs. shuffled radii from center data. The variability pattern of FR for the B6 animal during posthypoxia appears similar to that of the AJ at baseline in that points deviate from the line of identity horizontally and vertically, indicating that short breaths can be followed by long breaths. This is in contrast to the other plots, which show the distribution of points along the line of identity indicating that short breaths are followed by short breaths and long breaths are followed by long breaths. Real data falling outside of the shuffled distributions indicate a significant hole. Open circles indicate real data outside of the shuffled distribution, whereas large hatch marks indicate data within the range of the shuffled data.

 

   RESULTS
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 METHODS
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DISCUSSION
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 REFERENCES
 
Urethane-anesthetized adult male mice from two strains (A/J and B6) were exposed to a sequence of gases with different partial pressures of oxygen to test the hypothesis that phenotypic respiratory response patterns did not depend on consciousness. Body temperature, CO2, O2, and RER were not significantly different between A/J and B6 mice (Table 1).


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  		Table 1. Respiratory exchange ratio

 
Phenotypic differences between murine strains after anesthesia.   With urethane anesthesia, FR was greater than that reported previously for unanesthetized animals (Fig. 1, Table 2). However, FR was significantly lower for anesthetized A/J than B6 animals while animals breathed room air (Table 2, 196 ± 37 vs. 260 ± 43 breaths/min). A difference in the variability of the breathing pattern was also apparent between strains (Fig. 2). The coefficients of variation (CVs) for TI, TE, and FR were significantly greater for A/J compared with B6 mice (Fig. 2, Table 2). Spatial statistics also showed the baseline breathing pattern for A/J to be more variable than that for B6 animals in that the Poincaré plots for A/J had more points beyond the range defined by the shuffled data than the B6 animals (see Fig. 6).



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  		Fig. 1. Respiratory pattern in 2 different murine strains breathing room air (21% O2): comparison of awake (A) and anesthetized (B) A/J and C57BL/6J (B6) mice. A and B: raw plethysmographic traces for A/J (top trace) and B6 (bottom trace). C: mean and SD of breathing frequency (FR). In both awake (A and C) and anesthetized (B and C) states, A/J mice breathed slower and deeper than B6 mice. These differences between strains were evident in anesthetized animals even though anesthetizing the mice increased their FR.

 

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  		Table 2. Ventilation during resting breathing

 


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  		Fig. 2. Distribution of respiratory pattern variables. Left: breath-by-breath values of inspiratory duration (TI), expiratory duration (TE), and FR are plotted sequentially for an A/J and B6 animal. Right: mean ± SD and the distribution of values >75th and <25th percentile for FR in each A/J (top) and B6 (bottom) mouse. These plots of data from the initial 5-min room-air exposure show that breath-to-breath variability, which is greater for the A/J mice, has a bimodal distribution of values for A/J mice, whereas values are clustered around a local mean for the B6 animal.

 
Strain differences in the breathing pattern remained during hyperoxia in both awake (Table 3) and anesthetized animals (Table 4). During hyperoxia, FR tended to decrease in both strains so that FR remained significantly lower for A/J than B6 mice (Table 4, Fig. 3). In particular, TI was significantly greater in A/J than B6 animals (Table 4). The CVs for TI, TE, and FR also remained significantly greater in A/J than in B6 animals.


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  		Table 3. Unanesthetized ventilatory responses in A/J and C57BL/6J mice

 

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  		Table 4. Anesthetized ventilatory responses during room air, hypoxia, and posthypoxia in A/J and C57BL/6J mice

 


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  		Fig. 3. Breathing pattern during room air (A), hyperoxia (B), hypoxia (C), and hyperoxia after hypoxia (D). Tracings are from 2nd–5th minute of room air; 4th minute of hyperoxia (100% O2); 4th minute of hypoxia (8% O2); and 1st 30 s of reoxygenation (100% O2). In these examples, the A/J mouse (left) had a slow, irregular pattern on room air that became slower and less variable during hyperoxia, then faster and less variable during hypoxia and slower but less variable after hypoxia. In contrast, the B6 mouse (right) displayed a stable pattern that was similar during room air and hyperoxia that slowed at the end of hypoxia, but with reoxygenation the pattern became irregular.

 
Strain differences diminished during steady-state hypoxia.   During the fourth minute of hypoxia, strain differences were not apparent in the breathing pattern. Ventilation tended to be greater than baseline in A/J but less than baseline in B6 mice (Table 4). Furthermore, variability of pattern decreased from baseline in A/J but increased from baseline in B6 mice (Table 4, Fig. 4). Consequently, FR and its CV were not significantly different between A/J and B6 mice during the fourth minute of hypoxia.



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  		Fig. 4. Means ± SD and the distribution of values >75th and <25th percentile for TI (top), TE (middle), and FR (bottom) for each animal during each exposure. Breathing pattern changes were consistent with illustrative examples.

 
Strain differences during first minute after reoxygenation.   In the first minute after hypoxia, FR and the CVs for TI, TE, FR, and PK were not significantly different between strains. For the A/J strain, the pattern of breathing in the first minute after hypoxia was not significantly different from that during baseline. However, the CV for TE, FR, and PK tended to be less than baseline in all nine animals (Table 4, Fig. 3). In contrast, in the B6 mice, posthypoxic FR was significantly less than that at baseline (201 ± 59 vs. 239 ± 22). Furthermore, variability of the breathing pattern tended to be greater than that at baseline, with the CV for TE being significantly greater than that at baseline.

Strain differences were evident in the relative changes of posthypoxic CVs from baseline (Fig. 5). The percent difference from baseline for posthypoxic CV of FR, TI, TE, and PK was negative for AJ but positive for B6 mice (Fig. 5). The changes in CV in the first minute after hypoxia were significant between strains.



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  		Fig. 5. Variability of the breathing pattern decreases in A/J but increases in B6 mice immediately after hypoxia compared with baseline. Differences in the posthypoxic coefficient of variation (CV) of TI, TE, FR, and peak amplitude (PK) as a percentage of baseline CV. The CV for parameters of the breathing pattern is more variable at baseline than during posthypoxic period for A/J but not for B6 mice.

 
Ventilatory arrhythmia after hypoxia.   Neither strain displayed apneas during exposures to the test gases. Even though variability increased in B6 mice during posthypoxic reoxygenation, apneic periods did not occur (Fig. 3). However, B6 mice exhibited periods of distinct waxing and waning of FR and PK as well as periods of oscillation between two distinctly different FR. These different FR patterns of breath-to-breath variabilities were evident in Poincaré plots (Fig. 6).

In a waxing and waning pattern, breaths have a tendency to be followed by slightly longer or shorter breaths and points become distributed parallel to the line of identity (e.g., posthypoxic FR for A/J and baseline FR for B6, Fig. 6). In a pattern containing abrupt changes in FR, breaths of distinctly different cycle lengths follow one another. In this case, points are displaced from the line of identity (e.g., baseline FR for A/J and posthypoxic FR for B6, Fig. 6).

Spatial statistics also indicated that the variability of the breathing pattern for A/J and B6 mice reversed after hypoxia such that the Poincaré plots for B6 had more points beyond the range defined by the shuffled data than the A/J animals (Fig. 6).


   DISCUSSION
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 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
The respiratory pattern as a phenotypic behavior in adult, conscious animals remained after anesthesia, despite urethane suppression of cortical as well as subcortical activity and metabolism, minimizing these effects on pattern formation. Thus brain stem neural and remaining reflex mechanisms were the primary determinants of the pattern. A subcortical mechanism may explain the strain-specific difference evident in the change of breathing pattern variability after hypoxia. Immediately after hypoxia and on reoxygenation, breathing became more variable and, perhaps, less stable in B6 mice, whereas breathing was less variable compared with baseline in AJ mice. Our data indicate that fundamental differences exist between strains in the basic elements controlling breathing, e.g., the central pattern generator and integration of afferent information, and suggest that cortical and metabolic effects are not responsible for differences between A/J and B6 strains. Whereas RER values are <1.0, values >1.0 may have resulted from measurement error due either to an imbalance between the magnitude of the changes in partial pressure of O2 and CO2 and the sensitivity of the instruments or to sampling during a non-steady-state period. Even though we sampled over a 5-min period, the animals may not have been in a steady state because the anesthetics concomitantly affected ventilatory pattern, thermogenesis, and body temperature as well as release and sensitivity to metabolic hormones (16, 17). Regarding the ventilatory pattern, respiratory rate increased with the induction of anesthesia, which may cause hyperventilation and an abnormally high RER.

Strain differences.   In awake, steady-state normoxic conditions, the A/J animals breathe slower and deeper than the B6 animals, but B6 animals breathe more regularly than A/J animals (10–12, 21, 22, 24–26). In anesthetized animals under normoxic conditions, the A/J animals breathed slower but not deeper, and the B6 animals remained more variable. When breathing hyperoxic gas mixtures, both strains reduced ventilation by slowing FR and decreasing PK. The pattern remained less variable in B6 than A/J animals during hyperoxia.

In steady-state hypoxia measured in the fourth minute of the exposure, the pattern and its variability were not significantly different than baseline. The peak response to hypoxia occurs in the first minute of the exposure in both awake and anesthetized mice (10, 11, 13, 14, 18). In our animals, the peak FR did occur during the first minute in seven of nine A/J, as well as in all B6 animals. Peak FR increased from baseline in six of nine A/J and decreased in four of five B6 animals, so these data are consistent with those obtained in awake animals (10–12). In animals that showed the greatest increase in FR, peak FR occurred early during the exposure, indeed as early as the 10th breath during hypoxia. However, the magnitude of these changes was less than that of awake animals because of the effect of anesthesia (14). We focused on the fourth minute of hypoxia and the first minute of reoxygenation to capture the response to reoxygenation, in particular the posthypoxic ventilatory decline.

Immediately after hypoxia, FR decreased below baseline and variability increased above baseline in B6 but not A/J mice. The breathing pattern variability during baseline and then during posthypoxia changed inversely for these two strains.

In animals with very different breathing patterns at rest, we found that these strain-specific respiratory pattern differences remained after urethane administration; however, the magnitudes of these differences were less than those in conscious animals. Even though FR increased in anesthetized A/J and B6 mice, the relative difference remained at baseline and hyperoxia. The respiratory pattern was most variable during baseline for A/J mice but during posthypoxia for B6. Variability in TE and FR decreased significantly for A/J mice with the increase in respiratory drive during hypoxia.

The differences and changes in variability were reflected in the Poincaré plots. In Poincaré plots, the next value is plotted against the previous value. In a random system, the distribution of points is formless, but in a system like breathing where the next breath depends on the previous one the distribution often has a form (6). Low variability in the breathing pattern was associated with a clustered distribution or a distribution along the line of identity, whereas variable patterns had a scattered distribution or even points distributed perpendicularly to the line of identity. Even though these "perpendicularly distributed" points were few, they were not random but indicated that long cycles were followed by short cycles, thus termed a "bistable" pattern. In contrast, points distributed along the line of identity indicated that long breaths were followed by long breaths. The bistable patterns were expressed in A/J animals under baseline conditions and in B6 animals during the reoxygenation period after hypoxia. Correspondingly, the spatial statistical analysis indicated that the point distribution for the Poincaré plots of the A/J's breathing pattern at baseline exhibited a significantly nonrandom distribution. For FR, TI, TE, and PK, the distribution of points for the actual data were beyond the limits of the shuffled data set, indicating a hole, or quasi-periodicity in the breathing pattern. For the B6 animal, a quasi-periodic pattern was present during reoxygenation. Quasi-periodicity can arise when an oscillatory process is modulated by additional oscillatory processes (at a different frequency) causing destabilization (6). A quasi-periodic pattern was evident in unanesthetized B6 animals with reoxygenation after hypoxia (11, 12). Han et al. reported that a periodic pattern with apneas followed hypoxia (12). Our data indicate that A/J animals may have a quasi-periodic pattern in the resting state that becomes stabilized after hypoxia.

The neural mechanisms and physiological consequences of breathing pattern differences are unknown, but the fact that strain differences persist in reduced preparations will allow further study regarding their mechanism and the consequences of repeated exposures to hypoxia.

Limitations of the technique.   Plethysmographic data were a continuous and amplified voltage signal from a pressure transducer that reflected pressure changes in the chamber. Changes in pressure were generated by the animal heating the inspired gas. False positives can be generated by animal movement, but movement was absent in these animals anesthetized to a surgical plane. Furthermore, we eliminated sighs and/or augmented breaths from the analysis. Measurements of FR were determined by counting the number of apexes in the voltage signal over a specified period of time. In contrast to FR, PK was derived by calibrating the voltage signal from the transducer. The plethysmograph was not calibrated for volumetric measurement in this study. However, the changes in PK relative to baseline appeared during the different gas exposures to be consistent with previous publications (11).

Frequency increased with anesthetic.   Volatile anesthetics, like isoflurane, have been shown to significantly reduce the response to hypoxia and hypercapnia (27, 28). We chose urethane not only for its fast acting, long-lasting effect but also for its ability to anesthetize without altering airway diameter, thus minimizing effects on respiratory variables (4, 15). Generally, one assumes that breathing pattern slows with anesthesia. However, in previous studies using urethane rather than barbiturate anesthesia, animals had an increased heart rate and decreased arterial CO2 and bicarbonate levels (1). These physiological effects may be common to anesthetics that affect muscarinic receptors, specifically M2 autoreceptors (5). Douglas and coworkers (5) reported that an increase in FR of adult B6 mice was associated with an increased release of ACh in prefrontal cortex.

In support of an effect due to the anesthetic agent, FR increased shortly after anesthetic administration, without an apparent change in body temperature or metabolism. Onset was associated with the anesthetic effect. Although cortical suppression could contribute to this response, an increase in FR has not been generally associated with decorticate preparations, so it can be assumed that it is a product of the anesthetic and not of cortical suppression. Consequently, during urethane anesthesia, either strain-specific activation of bulbar circuitry controlling respiration or strain differences in the bulbar pattern generator would lead to these results.


   GRANTS
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 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 GRANTS
ACKNOWLEDGMENTS
 REFERENCES
 
We acknowledge the support of National Institutes of Health funding through NS-46062, HL-25830, and HL-64278 and of the Veterans Affairs Research Service.


   ACKNOWLEDGMENTS
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REFERENCES
 
We gratefully acknowledge the assistance of Marwan Jabar in the programming for the spatial statistical analysis.


   FOOTNOTES
 

Address for reprint requests and other correspondence: T. E. Dick, Division of Pulmonary and Critical Care Medicine, Dept. of Medicine, Case Western Reserve University, Biomedical Research Bldg. BRB B55, 10900 Euclid Ave., Cleveland, OH 44106-4941 (E-mail: ted3{at}po.cwru.edu).

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


   REFERENCES
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 REFERENCES
 

  1. Buelke-Sam J, Holson JF, Bazare JJ, and Young JF. Comparative stability of physiological parameters during sustained anesthesia in rats. Lab Anim Sci 28: 157–162, 1978.[ISI][Medline]
  2. Del Negro CA, Wilson CG, Butera RJ, Rigatto H, and Smith JC. Periodicity, mixed-mode oscillations, and quasiperiodicity in a rhythm-generating neural network. Biophys J 8: 206–214, 2002.
  3. Dempsey JA, Smith CA, Harms CA, Chow C, and Saupe KW. Sleep-induced breathing instability. Sleep 19: 236–247, 1996.[ISI][Medline]
  4. Dikmen Y, Eminoglu E, Salihoglu Z, and Demiroluk S. Pulmonary mechanics during isoflurane, sevoflurane and desflurane anaesthesia. Anaesthesia 58: 745–748, 2003.[CrossRef][ISI][Medline]
  5. Douglas CL, Baghdoyan HA, and Lydic R. M2 muscarinic autoreceptors modulate acetylcholine release in prefrontal cortex of C57BL/6J mouse. J Pharmacol Exp Ther 299: 960–966, 2001.[Abstract/Free Full Text]
  6. Garfinkel A, Chen PS, Walter DO, Karagueuzian HS, Kogan B, Evans SJ, Karpoukhin M, Hwang C, Uchida T, Gotoh M, Nwasokwa O, and Sager P. Quasiperiodicity and chaos in cardiac fibrillation. J Clin Invest 99: 305–314, 1997.[ISI][Medline]
  7. Georgopoulos D, Bshouty Z, Younes M, and Anthonisen NR. Hypoxic exposure and activation of the afterdischarge mechanism in conscious humans. J Appl Physiol 69: 1159–1164, 1990.[Abstract/Free Full Text]
  8. Gleeson K and Sweer LW. Ventilatory pattern after hypoxic stimulation during wakefulness and NREM sleep. J Appl Physiol 75: 397–404, 1993.[Abstract/Free Full Text]
  9. Hamelmann E, Schwarze J, Takeda K, Oshiba A, Larsen GL, Irvin CG, and Gelfand EW. Noninvasive measurement of airway responsiveness in allergic mice using barometric plethysmography. Am J Respir Crit Care Med 156: 766–775, 1997.[Abstract/Free Full Text]
  10. Han F and Strohl KP. Inheritance of ventilatory behavior in rodent models. Respir Physiol 121: 247–256, 2000.[CrossRef][ISI][Medline]
  11. Han F, Subramanian S, Dick TE, Dreshaj IA, and Strohl KP. Ventilatory behavior after hypoxia in C57BL/6J and A/J mice. J Appl Physiol 91: 1962–1970, 2001.[Abstract/Free Full Text]
  12. Han F, Subramanian S, Price ER, Nadeau J, and Strohl KP. Periodic breathing in the mouse. J Appl Physiol 92: 1133–1140, 2002.[Abstract/Free Full Text]
  13. Hayashi F, Coles SK, Bach KB, Mitchell GS, and McCrimmon DR. Time-dependent phrenic nerve responses to carotid afferent activation: intact vs. decerebellate rats. Am J Physiol Regul Integr Comp Physiol 265: R811–R819, 1993.[Abstract/Free Full Text]
  14. Huey KA, Low MJ, Kelly MA, Juarez R, Szewczak JM, and Powell FL. Ventilatory responses to acute and chronic hypoxia in mice: effects of dopamine D2 receptors. J Appl Physiol 89: 1142–1150, 2000.[Abstract/Free Full Text]
  15. Hunter JD, McLeod JZ, and Milsom WK. Cortical activation states in sleep and anesthesia. II: respiratory reflexes. Respir Physiol 112: 83–94, 1998.[CrossRef][ISI][Medline]
  16. Ohlson KB, Lindahl SG, Cannon B, and Nedergaard J. Thermogenesis inhibition in brown adipocytes is a specific property of volatile anesthetics. Anesthesiology 98: 437–448, 2003.[CrossRef][ISI][Medline]
  17. Pashkov VN and Hemmings HC Jr. The effects of general anesthetics on norepinephrine release from isolated rat cortical nerve terminals. Anesth Analg 95: 1274–1281, 2002.[Abstract/Free Full Text]
  18. Powell FL, Milsom WK, and Mitchell GS. Time domains of the hypoxic ventilatory response. Respir Physiol 112: 123–134, 1998.[CrossRef][ISI][Medline]
  19. Richter DW, Schmidt-Garcon P, Pierrefiche O, Bischoff AM, and Lalley PM. Neurotransmitters and neuromodulators controlling the hypoxic respiratory response in anaesthetized cats. J Physiol 514: 567–578, 1999.[Abstract/Free Full Text]
  20. Spengler CM, Czeisler CA, and Shea SA. An endogenous circadian rhythm of respiratory control in humans. J Physiol 526: 683–694, 2000.[Abstract/Free Full Text]
  21. Strohl KP, Thomas AJ, St. Jean P, Schlenker EH, Koletsky RJ, and Schork NJ. Ventilation and metabolism among rat strains. J Appl Physiol 82: 317–323, 1997.[Abstract/Free Full Text]
  22. Subramanian S, Han F, Erokwu BO, Dick TE, and Strohl KP. Do genetic factors influence the Dejours phenomenon? Adv Exp Med Biol 499: 209–214, 2001.[ISI][Medline]
  23. Tagaito Y, Polotsky VY, Campen MJ, Wilson JA, Balbir A, Smith PL, Schwartz AR, and O'Donnell CP. A model of sleep disordered breathing in the C57BL/6J mouse. J Appl Physiol 91: 2758–2766, 2001.[Abstract/Free Full Text]
  24. Tankersley CG. Genetic control of ventilation: what are we learning from murine models? Curr Opin Pulm Med 5: 344–348, 1999.[CrossRef][Medline]
  25. Tankersley CG. Variation in acute hypoxic ventilatory response is linked to mouse chromosome 9. J Appl Physiol 90: 1615–1622, 2001.[Abstract/Free Full Text]
  26. Tankersley CG, Fitzgerald RS, and Kleeberger SR. Differential control of ventilation among inbred strains of mice. Am J Physiol Regul Integr Comp Physiol 267: R1371–R1377, 1994.[Abstract/Free Full Text]
  27. Van den Elsen M, Dahan A, Berkenbosch A, DeGoede J, van Kleef JW, and Olievier IC. Does subanesthetic isoflurane affect the ventilatory response to acute hypoxia in healthy volunteers? Anesthesiology 81: 860–867, 1994.[CrossRef][ISI][Medline]
  28. Van den Elsen M, Sarton E, Teppema L, Berkenbosch A, and Dahan A. Influence of 0.1 minimum alveolar concentration of sevoflurane, desflurane and isoflurane on dynamic ventilatory response to hypercapnia in humans. Br J Anaesth 80: 174–182, 1998.[Abstract/Free Full Text]
  29. Younes M. The physiological basis of central apnea and periodic breathing. Curr Pulm 10: 265–326, 1989.



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