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J Appl Physiol 98: 1630-1638, 2005. First published January 20, 2005; doi:10.1152/japplphysiol.01148.2004
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Genetic determinants on rat chromosome 6 modulate variation in the hypercapnic ventilatory response using consomic strains

M. R. Dwinell,1 H. V. Forster,1 J. Petersen,1 A. Rider,1 M. P. Kunert,1 A. W. Cowley, Jr.,1 and H. J. Jacob1,2

1Department of Physiology, 2Human and Molecular Genetics Center, Medical College of Wisconsin, Milwaukee, Wisconsin

Submitted 12 October 2004 ; accepted in final form 14 December 2004


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
To understand the genetic basis of pathways involved in the control of breathing, a large scale, high-throughput study using chromosomal substitution strains of rats is underway. Eight new consomic rat stains (SS-2BN, SS-4BN, SS-6BN, SS-7BN, SS-8BN, SS-11BN, SS-12BN, SS-14BN, SS-YBN), containing one homozygous BN/NHsdMcwi (BN) chromosome on a background of SS/JrHsdMcwi (SS), were created by PhysGen (http://pga.mcw.edu) Program for Genomic Applications. Male and female rats were studied using standard plethysmography under control conditions and during acute hypoxia (inspired oxygen fraction = 0.12) and hypercapnia (inspired CO2 fraction = 0.07). The rats were also studied during treadmill exercise. Both male and female BN rats had a significantly lower ventilatory response during 7% CO2 compared with SS rats of the same gender. SS-6BN female rats had a significantly reduced ventilatory response, similar to BN rats due primarily to a reduced tidal volume. Male SS-6BN rats had a significantly reduced tidal volume response to hypercapnia but a slightly increased frequency response during hypercapnia. Gene(s) on the Y chromosome may play a role in this increased frequency response in the male rats because the SS-YBN hypercapnic ventilatory response involves a significantly increased frequency response. Several chromosomal substitutions slightly altered the ventilatory responses to hypoxia and exercise. However, genes on chromosomes 6 and Y of those studied are of primary importance in aspects of ventilatory control currently studied.

control of breathing; chromosomal substitution; hypoxia; hypercapnia; exercise

IT IS BECOMING EVIDENT THAT responses to ordinary physiological stimuli vary greatly not only between species (13, 15) but also among different strains or substrains of the same species (i.e., rats) (7, 8, 12, 13, 18). The use of inbred strains of rats reduces the complexity of the effects of both genetics and environment on these responses. Studies of ventilatory control using inbred mouse strains have clearly demonstrated that traits involved in the control of breathing can be linked to genomic regions on different chromosomes (20–24), furthering the concept that genetic mechanisms play an important role in determining eupneic breathing as well as during stressed conditions.

To begin to dissect the mechanisms involved with changes in overall pulmonary ventilation or timing and pattern of breathing during various respiratory stimuli, the comparison of rat strains or substrains has been a common approach. Strain differences in the acute response to hypoxia (11, 25), hypercapnia (12, 18), episodic hypoxia (3), and the posthypoxic frequency response (2, 19) have been reported suggestive of a genetic component to these responses. Several studies involving the control of breathing in inbred strains of mice have identified regions on mouse chromosomes 1, 3, 5, and 9 to which specific breathing phenotypes can be linked (17, 20, 22, 23). Additional studies have used knockout mice models to understand the role of targeted genes in ventilatory responses to various stimuli (10, 14). Despite these reports, the ability to narrow the field of candidate genes involved in these strain differences has been challenging.

To gain insight into the genetic basis of pathways involved in the control of breathing, we have studied consomic (chromosomal substitution) strains of rats. A single chromosome from one inbred rat strain (donor) is introgressed onto the background of another inbred rat strain (parental), while all other chromosomes remain identical to the parental inbred strain. If the consomic rat retains the parental phenotype, then the genes underlying that phenotype are on a chromosome other than the introgressed chromosome. A robust difference in the ventilatory response to hypercapnia has been found between our two parental strains with a significantly attenuated response in Brown Norway (BN; chromosome donor) compared with the Dahl salt-sensitive (SS; chromosome recipient) in both male and female rats (9, 12). However, the first five chromosomal substitutions did not alter the hypercapnic ventilatory response compared with the parental SS rat. This demonstrated that not every chromosomal substitution has a huge effect on ventilatory control. However, because of the large difference in hypercapnic sensitivity of the two parental strains, we hypothesized that it was highly likely that one of the nine new consomic strains would acquire the reduced sensitivity of the parental BN strain. The current manuscript reports the results from nine new consomic rat strains.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
A total of 391 (10–12 wk old) male (n = 234) and female (n = 157) rats were produced and housed at the Medical College of Wisconsin Animal Resource Transgenic Barrier Facility. The rats were maintained on a low-salt diet from weaning until the completion of the studies. All protocols were reviewed and approved by the Medical College of Wisconsin Animal Care Committee.

The generation of the consomic rats has been previously described in detail (4, 9). In brief, parental inbred strains (SS and BN) were crossed. F1 offspring were backcrossed with the parental SS. Marker-assisted selection was used to select offspring with target chromosomes from the BN. Eight to ten additional backcrosses were necessary to obtain heterozygosity at the target chromosome and SS homozygosity at all other chromosomes. The SS-8BN and SS-12BN are actually congenic rats since only a majority, rather than the entire chromosome from the BN, was transferred to the SS background. The segment of chromosome 8 that carries the BN DNA extends from D8rat163 to D8rat81. The segment of chromosome 12 that carries the BN DNA extends from D12arb13 to D12rat79.

Surgery.   Rats were anesthetized with ketamine (100 mg/kg im), xylazine (20 mg/ml im), and acepromazine (10 mg/ml im) in a 7:2:1 ratio. With the use of an aseptic technique, catheters were implanted in the femoral artery, exteriorized at the shoulders, and passed through a spring secured to the skin near the shoulders. To maintain catheter patency, the catheters were flushed and filled with a heparin-saline solution.

Protocols.   To familiarize the rats with the plethysmographs, 4 days of adaptation were done before the first study. On the first adaptation day, the rats were placed in the plethysmographs for 20 min under control (normoxic) conditions. During the second day of adaptation, after 10 min of normoxia, the rats were exposed to hypoxia [inspired oxygen fraction (FIO2) = 0.12] for 10 min by injecting 4.5 liters of N2 into the plethysmograph. The third adaptation day was used to expose the rats to hypercapnia (inspired CO2 fraction = 0.07) by injecting 650 ml of CO2 into the plethysmograph. The final adaptation repeated the exposure to hypoxia (FIO2 = 0.12) for 10 min.

On the day of the hypoxia protocol, the rat was placed into the plethysmograph and the arterial catheter was connected to the pressure transducer. The rat was allowed 20 min to adapt to the plethysmograph before data collection. The plethysmograph was sealed and calibrated for 30 s using a 0.3-ml pulse at a frequency of 2 Hz. Control data were collected for 5 min under eupnic conditions. An arterial blood sample (0.4 ml) was drawn at 3 min. Then, 4.5 liters of 100% N2 were injected into the plethysmograph to create an FIO2 of 0.12. One minute was allowed for equilibration. Ventilation, arterial blood pressure, and heart rate were measured continuously for 10 min. An arterial blood sample (0.4 ml) was drawn at minute 7 of hypoxia. A final calibration was done at the end of the 10-min hypoxic period. Rectal temperature was measured before being placed in the plethysmograph and immediately on removal from the plethysmograph. Air temperature and relative humidity were continuously monitored inside the plethysmograph using a calibrated Omega RX-93 temperature and relative humidity probe. Arterial PCO2, PO2, and pH were measured using a Chiron Rapidlab model 840 blood gas analyzer.

The following day, the hypercapnic protocol was completed. The protocol was identical to the hypoxia protocol other than the exposure to hypercapnia (inspired CO2 fraction of 0.07, injecting 650 ml of 100% CO2), and no arterial blood samples were drawn.

To assess the ventilatory response to exercise, the rats were familiarized with a four-lane rodent treadmill (Columbus Instruments) two times before surgery and two times after surgery before study. On the day of the exercise test, the rat was placed into one lane of the treadmill and the arterial catheter was connected to a pressure transducer. The rat was allowed to rest on the treadmill for 20 min. During the final 5 min of the rest period, blood pressure and heart rate were monitored continuously. An arterial blood sample (0.4 ml) was taken at the end of the rest period. The treadmill speed was increased to 0.8 m/min with a 5% grade. The rats walked for 5 min while blood pressure and heart rate were monitored. An arterial blood sample (0.4 ml) was drawn at the end of the 5-min walk period. Because we were unable to directly measure breathing while on the treadmill, we assessed the ventilatory response to exercise as the change in arterial PCO2 between rest and exercise (as in past studies).

Data acquisition and analysis.   Minute ventilation (E; ml/min), breathing frequency (f; breaths/min), tidal volume (VT; ml), inspiratory time (in s), expiratory time (in s), mean arterial blood pressure (MAP; mmHg), and heart rate (beats/min) were collected using data acquisition software (Dataq Instruments Windaq) at a sample rate of 100 samples/s. Additionally, relative humidity and temperature inside the plethysmograph were collected continuously. The ventilatory and blood pressure data were analyzed during control and 1–3 and 7–9 min of hypoxia and hypercapnia. Each segment of data was between 30 and 60 s of continuous breathing without sniffs, sighs, or movement. A computer software program (Windaq) was used to find peaks, valleys, and timing to calculate ventilation, heart rate, and blood pressure. VT was calculated using standard plethysmographic methods (6), factoring in body temperature, plethysmograph temperature, and relative humidity and atmospheric pressure into the VT calculations. E and VT during eupnea were corrected for body weight and expressed as milliliters per 100 grams of body weight. The ventilatory (E, f, VT) responses during hypoxia and hypercapnia were expressed as a percent of control values.

Statistics.   Data are expressed as means ± SE. A one-way ANOVA with Dunnett's post hoc test was used to compare parental and consomic strains. Unpaired t-tests were used to determine whether significant differences between male and female phenotypes (e.g., body weight) existed. A P value of <0.05 was considered statistically significant.


   RESULTS
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 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 GRANTS
 REFERENCES
 
Gender differences within strains were found in many phenotypes, primarily due to a significantly lower body weight in female vs. male rats found in all strains (P < 0.001) (large t-test table comparing male and female rats available at http://pga.mcw.edu).

Control room air conditions.   Control room air E, f, and VT were not significantly different between the parental SS and BN strains for both male and female rats. Total pulmonary ventilation was not different among consomic and parental strains, although some differences in f among strains were found. Tables 1 and 2 summarize the variation between parental and consomic strains and between male and female rats for values obtained during room air, resting conditions for ventilation (body weight corrected), arterial blood gases, MAP, heart rate, and body temperature.


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  		Table 1. Male rat group mean and SE of traits while breathing room air

 

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  		Table 2. Female rat group mean and SE of traits while breathing room air

 
Ventilatory response to hypercapnia.   E, f, and VT were increased from eupnea in all strains during hypercapnia (inspired CO2 fraction = 0.07). As previously reported, the ventilatory response to CO2 was significantly lower in male and female BN rats compared with SS rats of the same gender (P < 0.05). E and VT were also significantly reduced in female SS-6BN rats compared with female SS rats during the CO2 challenge (Fig. 1, A and B). Male SS-6BN rats had a significantly lower VT response to hypercapnia compared with male SS rats (Fig. 1E). However, f increased significantly in male SS-6BN rats compared with male SS rats, resulting in an overall ventilatory response to hypercapnia similar to male parental SS rats. SS-YBN rats (male) had a significantly increased frequency response to hypercapnia compared with male parental SS rats (Fig. 1F). Female SS-7BN had a significant increase in frequency during hypercapnia compared with female parental SS rat (Fig. 1C), although the overall ventilatory response was not significantly different from female SS rats. Other than these differences, the remaining consomic strains did not differ from each other or from the SS parental strain in any ventilatory variables.



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  		Fig. 1. Pulmonary ventilation (E; A and D), tidal volume (VT; B and E), and breathing frequency (f; C and F) expressed as a percentage of room air breathing during minutes 7–9 of hypercapnia (inspired CO2 fraction = 0.07) in male (D–F) and female (A–C) rats. Values are means ± SE. The broken line represents the average of the SS rats. BN, Brown Norway rats; SS, Dahl salt-sensitive rats. *Significantly different from the SS rats of the same gender (P < 0.05).

 
MAP increased significantly in male BN rats compared with male SS rats during the 10-min exposure to hypercapnia (Fig. 2C). The change in MAP from room air conditions to 7% CO2 in male BN rats was also significantly different than the response in SS-6BN, SS-8BN, and SS-YBN rats (Fig. 2C). The change in MAP from room air to hypercapnia followed the same trend in female BN compared with female SS rats, although the change was not significantly different. Both male and female SS-6BN rats had a significant decrease in blood pressure during hypercapnia compared with male and female BN rats (Fig. 2, A and C). Heart rate decreased in all strains during hypercapnia, with a significant difference only between the female BN and female SS-14BN rats (Fig. 2B).



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  		Fig. 2. Change in mean arterial blood pressure (mmHg; A and C) and heart rate (beats/min; B and D) from room air to minute 8 of hypercapnia (inspired CO2 fraction = 0.07) in male (C and D) and female (A and B) rats. *Significantly different from SS rats of the same gender (P < 0.05). #Significantly different from BN rats of the same gender (P < 0.05).

 
Ventilatory response to hypoxia.   E, f, and VT were increased from eupnea in all strains during the first 3 min of hypoxia (FIO2 = 0.12) (Fig. 3; Table 3). Both parental and all consomic male rats had a significantly increased ventilatory response to hypoxia, but no differences existed between strains (Fig. 3D). All female rats significantly increased ventilation in response to hypoxia, with SS-7BN female rats having a significantly greater response compared with female SS rats (Fig. 3A). During the final 7–9 min of hypoxia, the ventilatory response decreased in all strains (roll-off, hypoxic ventilatory depression) with a greater reduction in male and female BN rats compared with parental SS rats of the same gender (Fig. 4, A and E). This decline in ventilation is due primarily to a decrease in VT in all strains (Fig. 4, C and G). Additionally, body temperature declined after the 10-min exposure to hypoxia more in BN rats than in SS rats. The decline in body temperature was present in both male and female rats, although it was only significantly lower in female BN compared with female SS rats (–1.6 ± 0.9°C in female BN rats vs. –0.3 ± 0.4°C in female SS rats).



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  		Fig. 3. Pulmonary E, VT, and f expressed as a percentage of room air breathing during minutes 7–9 of hypoxia (inspired O2 fraction = 0.12) in male (D–F) and female (A–C) rats. Values are means ± SE. The broken line represents the average of the SS rats. *Significantly different from SS rats of the same gender (P < 0.05).

 

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  		Table 3. Arterial PO2, PCO2, and pH during control, room air, and after 7–9 min of hypoxia (FIo2 0.12) for male and female rats

 


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  		Fig. 4. Hypoxic ventilatory decline during hypoxia, expressed as the change in E (A and E), f (B and F), and VT (C and G) from 2–3 min of hypoxia (inspired O2 fraction = 0.12) to 7–9 min of hypoxia in male (E–G) and female (A–C) rats. The change in arterial PCO2 (PaCO2) from normoxia to hypoxia in male (H) and female (D) rats follows the change in ventilation from room air to hypoxia.

 
MAP decreased slightly in all strains other than the SS-4BN rats (Fig. 5, A and C) during 10 min of poikilocapnic hypoxia. Heart rate did not change much during hypoxia in most strains of rats compared with the change observed during the hypercapnic ventilatory response. The change in heart rate in male BN rats was significantly greater compared with male SS, SS-2BN, SS-4BN, and SS-YBN rats (Fig. 5D). Arterial PCO2 decreased during hypoxia to a similar degree in the eight consomic strains reported. The change in arterial PCO2 from normoxia to hypoxia matched the ventilatory responses in the parental and consomic strains (Fig. 4, D and H).



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  		Fig. 5. Change in mean arterial blood pressure (mmHg; A and C) and heart rate (beats/min; B and D) from room air to minute 8 of hypoxia (inspired O2 fraction = 0.12) in male (C and D) and female (A and B) rats. *Significantly different from SS rats of the same gender (P < 0.05).

 
Ventilatory response to exercise.   As was previously reported for the parental (SS, BN) and first five consomic strains of rats, all strains of rats hyperventilated while resting on the treadmill compared with the results obtained during room air conditions in the plethysmograph (Table 4). Relative to rest, all strains of rats hyperventilated while walking on the treadmill (Fig. 6) with the largest change in arterial PCO2 being from rest to exercise in BN rats.


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  		Table 4. Arterial PO2, PCO2, and pH during rest and during 5 min of exercise (walk, 0.8 m/min, 5% grade) for male and female parental and consomic rats

 


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  		Fig. 6. Change in arterial PCO2 from rest to walking on the treadmill (0.8 m/min, 5% grade). The broken line represents the average of the SS strain. *Hyperventilation during walking was significantly different than that in SS rats (P < 0.05). #Significantly different from BN rats of the same gender (P < 0.05).

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
The results described herein are part of a large rat phenome project designed to screen the contribution of genes on each chromosome on the physiology of the heart, lung, and blood systems. This protocol was designed to use the chromosomal substitution strategy to begin to dissect genetic influences on pathways involved in the ventilatory responses to acute stimuli. These results demonstrate that the ventilatory responses to hypoxia, hypercapnia, and exercise are complex, involving more than one gene or chromosome. Not only are several genes involved in these responses, but gender differences exist in the ventilatory response to acute hypoxia and hypercapnia.

To date we have studied consomic rats for 13 of the 20 autosomal chromosomes and the Y chromosome. The introgression of the BN chromosome 6 onto the SS background had a significant effect on the ventilatory response to hypercpania. One or more genes on rat chromosome 6 are involved in the reduced VT during hypercapnia observed in male and female BN rats compared with parental SS rats. Similarly, in humans, much of the variability in the VT response to CO2 can be attributed to genetic factors (1). In contrast, gene(s) on the Y chromosome may impact the frequency response in male rats, resulting in a hypercapnic ventilatory response similar to the parental male SS rat. This example provides support that several genes are involved in the hypercapnic ventilatory response and that gene-gene interactions may also play a critical role in ventilatory responses to stressors. The ventilatory responses to hypoxia and hypercapnia in the remaining 12 consomic strains studied thus far, in both male and female rats, are not greatly different from the responses in the parental SS rat, providing additional validation that this approach is a reliable way to identify genes important in determining the level of ventilatory response to a given stimulus. However, it is not unexpected that more genes on more than one chromosome have effects on these ventilatory responses. It is rather unlikely that a single gene could be entirely responsible for the ventilatory responses to hypoxia, hypercapnia, or exercise.

The use of consomic strains allows one to map traits to single chromosomes. To narrow the list of candidate genes, narrow congenic strains can be developed rapidly from consomic strains. Approximately 260 genes have been mapped to chromosome 6 in the rat (16) with predicted syntenic regions to mouse chromosomes 12 and 17 and human chromosomes 2, 7, and 14. Additional strategies are needed to narrow the list of potential genes involved in the reduced hypercapnic ventilatory response. However, candidate genes on chromosome 6 that could possibly be involved in the attenuation of the hypercapnic ventilatory response include calmodulin 1, calmodulin 2, Cpg1 (candidate plasticity gene 1), Foxo1 (forkhead box O1), Bxw2 (basic leucine zipper and W2 domains), Hif1a, Ifrd1 (interferon-related developmental regulator 1), Kcnf1, Kcng3, Kcnh5, Kcnk10, Kcnk3 (potassium channel genes), Nrxn3 (neurexin 3), Ptprn2 (protein tyrosine phosphatase receptor), Sstr1 (somatostatin receptor 1), Vipr2 (vasopressin intestinal peptide receptor 2), and Ywhaq (tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activitation protein).

One advantage to this consomic rat approach is that traits can be assigned to chromosomes with confidence since these rats have fixed genetic backgrounds. As a single chromosome from one inbred rat strain (donor) is introgressed onto the background of another inbred rat strain (parental), all other chromosomes remain identical to the parental inbred strain. From the consomic rat strains, congenic strains can be rapidly generated to narrow the region of interest on a particular chromosome. As the region of interest is narrowed with congenic strains, the list of potential genes is also reduced. Additionally, multiple chromosomal substitution models can be used to study gene-gene interactions involved with complex traits (5).

In addition, the effect of BN chromosome 6 introgression must be specific to CO2 chemoreception. The ventilatory responses to hypoxia and exercise in consomic SS-6BN were not different from those of the SS parental rat, whereas the ventilatory response to hypercapnia was attenuated like that of the BN rats. The cardiovascular response to hypercapnia was also altered in the SS-6BN rats. Heart rate, in both male and female rats, declined significantly during the 10-min exposure to hypercapnia compared with both SS and BN parental rats. In contrast, the heart rate response during hypoxia in the SS-6BN rats did not differ from the SS and BN parental rats.

Although many of the ventilatory responses to these acute stimuli are not significantly different than the responses in the parental SS rats, the responses in the many of the consomics are either slightly greater or lesser than both the SS and BN parental responses. Each strain of rats is studied under identical conditions including age, diet, housing, conditioning to the plethysmograph and treadmill, and surgical preparation. Each strain of rats is studied as a group of 12 male, 12 female, and 2 male SS parental rats during a 2-wk period. It therefore seems unlikely that environmental or protocol differences account for these small changes. The consomic responses that are greater or lesser than either parental strain could be due to gene-gene interactions that are altered when a chromosome from one strain is introgressed onto a different background. Although the responses of both parental strains do not differ, the new interactions created by the chromosomal substitution may alter the responses from those of the parental strains. In the present study, for example, the gender difference in the hypercapnic ventilatory response in the SS-6BN rats may be due to the interaction or regulation of genes on different chromosomes. The SS-YBN rats have an increased f response during hypercapnia compared with male SS rats. This suggests that interactions between genes on chromosomes 6 and Y may be involved in the decreased VT and increased f during hypercapnia in the male SS-6BN rats. Subjecting the parental and consomic rats to different protocols may provide insight into subtle differences that are accentuated after chromosomal substitution or mechanistic pathways involved in the complex responses to respiratory stimuli.

Although 14 of the 22 consomic strains have been completed, we have found no sizeable changes with the ventilatory response to hypoxia and exercise and only one for the hypercapnic ventilatory response. On the treadmill, both male and female BN rats hyperventilate to a greater degree than SS or SSBN consomic rats, and all consomics studied to date are not significantly different than the SS rats. This could mean that, by chance, we have not yet studied the right consomic rats or we may not find a strain that responds like the BN rat (chromosome donor). An alternate explanation might be that the major regulatory genes are on select chromosomes not yet studied and/or that gene-gene interactions exist.

In conclusion, this chromosomal substitution strategy has provided evidence that genes on chromosome 6 are involved in the ventilatory response to CO2. Additional strategies are needed to further identify the gene(s) involved. The consomic strategy can also be used to differentiate age-dependent changes. Because genes are not knocked out, just switched from one strain to another strain, both the short- and long-term effects of the gene can be investigated. These approaches will aid in our understanding of many basic and complex physiological mechanisms.


   GRANTS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 GRANTS
REFERENCES
 
This study was supported by National Heart, Lung, and Blood Institute Grant PGA U01 HL-66579.


   FOOTNOTES
 

Address for reprint requests and other correspondence: M. R. Dwinell, 8701 Watertown Plank Rd., Milwaukee, WI 53226 (E-mail: mrdwinel{at}mcw.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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 DISCUSSION
 GRANTS
 REFERENCES
 

  1. Arkinstall WW, Nirmel K, Klissouras V, and Milic-Emili J. Genetic differences in the ventilatory response to inhaled CO2. J Appl Physiol 36: 6–11, 1974.[Free Full Text]
  2. Bach KB, Kinkead R, and Mitchell GS. Post hypoxic frequency decline in rats: sensitivity to repeated hypoxia and {alpha}2-adrenoreceptor antagonism. Brain Res 817: 25–33, 1999.[CrossRef][ISI][Medline]
  3. Bavis RW, Baker-Herman TL, Zabka AG, Golder FJ, Fuller DD, Behan M, and Mitchell GS. Respiratory long-term facilitation differs among inbred rat strains (Abstract). FASEB J 18: 559.5, 2003.
  4. Cowley AW Jr, Roman RJ, and Jacob HJ. Application of chromosomal substitution techniques in gene-function discovery. J Physiol 554: 46–55, 2004.[Abstract/Free Full Text]
  5. Cowley AW Jr, Roman RJ, Kaldunski ML, Duman P, Dickhout JG, Greene AS, and Jacob HJ. Brown Norway chromosome 13 confers protection from high salt to consomic Dahl S rat. Hypertension 37: 456–461, 2001.[Abstract/Free Full Text]
  6. Drorbaugh JE and Fenn WO. A barometric method for measuring ventilation in newborn infants. Pediatrics 16: 81–86, 1955.[Abstract/Free Full Text]
  7. Fuller DD, Bach KB, Baker TL, Kinkead R, and Mitchell GS. Long term facilitation of phrenic motor output. Respir Physiol 121: 135–146, 2000.[CrossRef][ISI][Medline]
  8. Fuller DD, Baker TL, Behan M, and Mitchell GS. Expression of hypoglossal long-term facilitation differs between substrains of Sprague-Dawley rat. Physiol Genomics 4: 175–181, 2001.[Abstract/Free Full Text]
  9. Forster HV, Dwinell MR, Hodges MR, Brozoski D, and Hogan GE. Do genes on rat chromosomes 9, 13, 16, 18, and 20 contribute to regulation of breathing? Respir Physiol Neurobiol 135: 247–261, 2003.[CrossRef][ISI][Medline]
  10. Gaultier C, Dauger S, Simonneau M, and Gallego J. Genes modulating chemical breathing control: lessons from mutant animals. Respir Physiol Neurobiol 136: 105–114, 2003.[CrossRef][ISI][Medline]
  11. Golder FJ, Zabka AG, Bavis RW, Baker-Hermann TL, Fuller DD, and Mitchell GS. Differences in time-dependent hypoxic phrenic responses among inbred rat strains. J Appl Physiol. 98: 838–844, 2005.[Abstract/Free Full Text]
  12. Hodges MR, Forster HV, Papenek PE, Dwinell MR, and Hogan GE. Ventilatory phenotypes among four strains of adult rats. J Appl Physiol 93: 974–983, 2002.[Abstract/Free Full Text]
  13. Mitchell GS and Johnson SM. Neuroplasticity in respiratory motor control. J Appl Physiol 94: 358–374, 2003.[Abstract/Free Full Text]
  14. Powell FL. Functional genomics and the comparative physiology of hypoxia. Annu Rev Physiol 65: 203–230, 2003.[CrossRef][ISI][Medline]
  15. Powell FL, Dwinell MR, and Aaron EA. Measuring ventilatory acclimatization to hypoxia: comparative aspects. Respir Physiol 122: 271–284, 2000.[CrossRef][ISI][Medline]
  16. Rat Genome Database. Milwaukee, WI: Medical College of Wisconsin, 2004. http://rgd.mcw.edu/
  17. Schneider H, Patil SP, Canisius S, Gladmon EA, Schwartz AR, O'Donnell CP, Smith PL, and Tankersley CG. Hypercapnic duty cycle is an intermediate physiological phenotype linked to mouse chromosome 5. J Appl Physiol 95: 11–19, 2003.[Abstract/Free Full Text]
  18. 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]
  19. Subramanian S, Erokwu B, Han F, Dick TE, and Strohl KP. L-NAME differentially alters ventilatory behavior in Sprague-Dawley and Brown Norway rats. J Appl Physiol 93: 984–989, 2002.[Abstract/Free Full Text]
  20. Tankersley CG. Selected contribution: variation in acute hypoxic ventilatory response is linked to mouse chromosome 9. J Appl Physiol 90: 1615–1622, 2001.[Abstract/Free Full Text]
  21. Tankersley CG. Genetic aspects of breathing: on interactions between hypercapnia and hypoxia. Respir Physiol Neurobiol 135: 167–178, 2003.[CrossRef][ISI][Medline]
  22. Tankersley CG and Broman KW. Interactions in hypoxic and hypercapnic breathing are genetically linked to mouse chromosomes 1 and 5. J Appl Physiol 97: 77–84, 2004.[Abstract/Free Full Text]
  23. Tankersley CG, DiSilvestre DA, Jedlicka AE, Wilkins HM, and Zhang L. Diffferential inspiratory timing is genetically linked to mouse chromosome 3. J Appl Physiol 85: 360–365, 1998.[Abstract/Free Full Text]
  24. Tankersley CG, Elston RC, and Schnell AH. Genetic determinants of acute hypoxic ventilation: patterns of inheritance in mice. J Appl Physiol 88: 2310–2318, 2000.[Abstract/Free Full Text]
  25. Weil JV, Stevens T, Pickett CK, Tatsumi K, Dickinson MG, Jacoby CR, and Rodman DM. Strain-associated differences in hypoxic chemosensitivity of the carotid boy in rats. Am J Physiol Lung Cell Mol Physiol 274: L767–L774, 1998.[Abstract/Free Full Text]



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