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Department of Medicine, Case Western Reserve University, Cleveland Veterans Affairs Medical Center, Cleveland, Ohio 44106
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Nitric oxide (NO) is a
regulating factor in respiration. The question was whether NO synthase
(NOS) blockade would affect posthypoxic ventilatory behavior similarly
in two rat strains with known differences in steady-state hypoxic and
hypercapnic responses and in posthypoxic ventilatory behavior.
Ventilatory behavior [respiratory frequency (f) and minute ventilation
(
E)] was measured by body plethysmography on
unanesthetized, unrestrained adult male Sprague-Dawley (SD; n
= 8) and Brown Norway rats (BN; n = 8) at baseline
and 1 min after rapid transition to 100% O2 after 5 min of
isocapnic hypoxia (10% O2-3% CO2-balance
N2). Testing was performed 30 min after intraperitoneal
injection of either saline (vehicle) or 100 mg/kg of
NG-nitro-L-arginine methyl ester
(L-NAME). Resting f and E increased after L-NAME in both strains, more markedly in SD compared
with BN (77 vs. 47% for f, and 42 vs. 16% for E,
respectively; P < 0.05). With vehicle, posthypoxic f
and E decline (Dejours phenomenon) was present only
in BN and was absent in SD. With L-NAME, the Dejours
phenomena were still present in BN but also were apparent in SD (f:
95.3 vs. 134.4 beats/min at baseline; E: 66.3 vs.
88.8 ml/min at baseline; P < 0.05). Thus NOS
blockade results in a strain-specific alteration in resting ventilation and uncovers the Dejours phenomenon in the SD strain.
hyperoxia; hypoxia; nitric oxide; NG-nitro-L-arginine methyl ester
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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NITRIC OXIDE (NO) IS A MESSENGER MOLECULE that acts as a mediator of many fundamental biological processes, including respiration (15, 17). NO synthase (NOS) catalyzes the formation of NO from the terminal guanido nitrogen of arginine, with the stoichiometric production of citrulline. Homologous but distinctly expressed NOS genes are differentially expressed in neuronal and endothelial tissues and presumably account for variations in NO-specific functions (15, 16). Endothelial NOS (eNOS) plays a key role in maintaining basal vascular tone and regulation of regional blood flow, as well as mediating vasodilatation in response to various stimuli. Neuronal NOS (nNOS) has widespread cellular localizations, a short half-life, and unique diffusion properties that have led to speculation that it plays a key role in nervous system morphogenesis and synaptic plasticity. In regard to control of respiratory frequency (f) and tidal volume (VT; ventilatory behavior), studies have demonstrated the presence of NOS in the nerve plexuses of the carotid body (18, 28). Reduced NADP diaphorase, a marker of NOS, is present in neurons within several pontomedullary regions that are known to mediate integrative functions of cardiorespiratory regulation in the rat (27). This topographic distribution of NOS indicates that NO influences the physiology of chemosensitivity in the intact animal.
Studies in rats suggest that NOS activity exerts excitatory influences on respiration, accompanied by a sustained vasomotor tone and temperature fall, during hypoxia (9, 10, 20). However, mutant mice deficient in nNOS exhibit augmented responses to hypoxia (14), whereas those deficient in eNOS had blunted hypoxic ventilatory responses (HVRs) (13). Surprisingly, mutant nNOS-deficient mice as well as mice treated with an antagonist to nNOS had attenuated short-term potentiation and long-term facilitation despite an augmented acute response (12). Thus NO in the mouse appears to play a modulator role in respiratory control, with differing and opposing functions when derived from eNOS or nNOS.
Our laboratory has previously described two strains of rats, Sprague-Dawley (SD) and Brown Norway (BN), with markedly different ventilatory responses to steady-state hypoxia and hypercapnia (23). Differences are present in the ventilatory response to rapid reoxygenation after brief hypoxic exposure, i.e., Dejours phenomenon (25). SD exhibit a tendency for short-term potentiation, whereas, in the BN, a tendency for posthypoxic frequency declines (PHFD). These observations are consistent with the concept that inherited factors determine such differences. Indeed, for steady-state responses, an intercross of SD and BN results in second-generation progeny with a wider range of ventilatory chemosensitivity than is present in either parental strain (24). This information indicates that, in the rat, naturally occurring NOS polymorphisms may shape such differences; however, direct evidence of this is lacking. A physiological approach to this issue is to determine the effects of a NOS inhibitor in the two strains (11). Administration of a broad NOS inhibitor to unanesthetized SD and BN would address the overall influence of NOS on differences in the ventilatory responses that inheritance currently provides in these two rat strains.
We hypothesized that NOS blockade would produce different effects on ventilatory behavior in these two rat strains in the unanesthetized state. If the null hypothesis is rejected by evidence showing differences, then one could reason that the genetic background of the animals plays a role in the pharmacological effect.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Adult male SD (SD/Harlan; n = 8) and BN (BN-SSN/Harlan; n = 8) between the ages of 12 and 16 wk were obtained from Harlan (Indianapolis, IN), housed in our animal facility, and fed rat chow and water ad libitum. The animals were tested 8-10 wk after arrival. The study protocol was approved by the Louis Stokes Veterans Affairs Medical Center Institutional Animal Care and Use Committee and was in agreement with the National Institutes of Health Guide for the Care and Use of Laboratory Animals.
Ventilation and metabolism were assessed by whole body plethysmography
via the open-circuit method, as previously described (23).
The chamber consisted of a 14-cm-diameter Plexiglas cylinder of
8.4-liter volume, with air intake and output ports to allow for
different gas mixtures to be flushed through the chamber at a rate of
30 l/min and a low continuous flow of the gas to be drawn through the
chamber during the testing period at a rate of 600 ml/min, which our
laboratory has previously found to be sufficient in studies of adult
rats to keep CO2 levels below 0.03% and to maintain a
constant chamber temperature and humidity at or near ambient room
temperature and humidity, yet prevent excessive chamber noise
(23). Flow rates lower than ~550 ml/min over time produce CO2 buildup that is accompanied by a fall in oxygen
consumption; higher flow rates increase chamber noise and possibly heat
loss through evaporation, as well as prevent the accuracy of
measurement of metabolic parameters. A small opening in the top of the
chamber permitted sampling of chamber air for assessment of oxygen and carbon dioxide concentration within the chamber. Ventilatory parameters included minute ventilation (E), VT, f,
and metabolic parameters: oxygen consumption and carbon dioxide
production. Two setups allowed two animals to be tested at a time.
Protocol.
Testing was done between 10:00 AM and 1:00 PM to limit circadian
effects. Animals were brought to the laboratory at 9 AM and allowed 45 min to acclimatize to the testing chamber. Baseline resting ventilation
and carbon dioxide and oxygen concentrations were continuously recorded
during this acclimatization. At the end of the acclimatization period,
animals were injected intraperitoneally with 2 ml of vehicle (saline),
and five measurements were taken over a 15-min period to provide
resting values for ventilation and metabolism. Animals were then
exposed to a 5-min presentation of the test gases in the following
order: 10% O2-3% CO2-balance N2
followed rapidly by reoxygenation with 100% O2. During the challenges, ventilatory parameters were continuously recorded. Representative values of f, VT, and E
were obtained at baseline on room air and at the following time points:
end of minute 5 of hypoxia and, after the switch to
hyperoxia, at the end of the minute 1. Animals were returned
to room air and observed until values for ventilation returned to
within 5% of baseline values. Approximately 20 min later, animals were
exposed to 7% CO2-93% O2 (hypercapnia), and
similar measurements were made after minute 5 of exposure.
This was followed by a 30-min recovery period. Afterward, 100 mg/kg of
NG-nitro-L-arginine methyl ester
(L-NAME) dissolved in 2 ml of vehicle were injected
intraperitoneally in each animal. Metabolic values were again measured,
and the protocol using test gases was repeated in an identical manner
(baseline followed by 5 min of hypoxia, hyperoxia, and, after a 20-min
period, hypercapnia).
Data analysis.
Values for ventilatory behavior were obtained by using computer scoring
of breaths (BGPLOT). Sniffing and sighs were not included in the
calculations of VT and f. A mean value of 10 breaths at each time point was entered for each animal. Values are reported as the
mean and standard deviation. VT measurements were not
corrected for the temperature of the animal. Chamber temperature did
not systematically vary according to the protocol or strain. At the end
of testing, the animal was removed from the chamber, and body weights
and body length were obtained. HVR and hypercapnic ventilatory response
(HCVR) was defined as percent change in f, VT, and
E from air to the end of minute 5 of gas
challenge. Dejours phenomenon was defined as change in f,
VT, and E from baseline to 50-60 s
after the switch to breathing 100% O2.
E and carbon dioxide
production). A P value of <0.05 was considered significant.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Mean values for age (24 ± 4 wk in BN vs. 23 ± 3 wk in SD; P > 0.05) were similar in the two strains. Chamber temperature during the studies of BN was 24.4 ± 1.0°C and, during the SD studies, was 24.9 ± 1.0°C (P > 0.05); corresponding barometric pressures were 754 ± 9 and 754 ± 8 Torr, respectively (P > 0.05).
Mean values for temperature before and after vehicle were similar among
strains and temperature (37.8 ± 0.4°C in BN and 38.0 ± 0.3°C in SD; P > 0.05). Baseline values for resting
ventilation and ventilation after vehicle for the two strains are shown
in Table 1. Values for oxygen consumption
and carbon dioxide production were significantly different between
strains (Table 1). SD rats were significantly heavier (482 ± 50 g for SD vs. 300 ± 41 g for BN; P < 0.0001), but the values of carbon dioxide production corrected for body
weight were not significantly different between the two strains.
Although the values for f, VT, and E
were significantly higher in SD than in BN, there were no significant
strain differences in E corrected for body weight or
in E corrected for carbon dioxide production. In
response to 100% O2, a significant depression in f [PHFD
(5)] and E (Dejours phenomenon) was
present in BN but not consistently observed in SD (Table
2, Fig.
1). There were differences in hypoxic
and hypercapnic responses between the two strains for f,
VT, and E after administration of
vehicle, with SD showing more brisk hypoxic and hypercapnic ventilatory drive, consistent with previous studies (data not shown)
(25).
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After administration of L-NAME, there occurred a fall in
temperature of 1.7 ± 0.2°C in BN (P = 0.011)
and a 0.7 ± 0.2°C fall in SD (P < 0.05); the
difference between strains was 1.1 ± 0.09°C (P < 0.01). As shown in Table 1, a significant reduction in oxygen consumption occurred in both strains, and carbon dioxide production decreased significantly only in BN (Fig.
2, Table 1). After L-NAME, there was an increase in baseline f and E that was
significantly greater in SD compared with BN (Fig. 2, Table 1).
Changes in values for E corrected for carbon dioxide
production showed no differences between the two strains (Fig. 1). In
the posthypoxic period, a significant decline in f and
E, i.e., Dejours phenomenon, was now observed in SD
as well as in BN (Table 2, Fig. 1).
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With vehicle and after L-NAME, animals were given ~20 min
to recover before hypercapnic testing; values for ventilation were not
significantly different from baseline values obtained before hypoxic
and hyperoxic challenges. There were no significant differences between
strains in values (f, VT, and E) for
HVRs and HCVRs expressed as percent difference between vehicle and
L-NAME (Fig. 3).
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In a protocol to control for the time effect of the second injection, three SD underwent testing after vehicle and then with a second vehicle injection rather than L-NAME, and there were no significant differences in body temperature, metabolism, or ventilation after the second sham injection.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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NOS blockade with L-NAME alters both metabolism and ventilation in these rat strains. With L-NAME, there occurred some fall in body temperature, which was greater in magnitude in BN than in SD. Nevertheless, ventilation while breathing room air was increased in both strains, primarily because of an increase in f; this effect was more pronounced in SD. The Dejours phenomenon, not consistently seen in SD after vehicle, was present after NOS blockade, whereas the phenomenon was still present in BN.
Effects on metabolism. The literature involving inhibition of endogenous generation of NO have yielded mixed results. Shen et al. (19) studied conscious dogs and showed that administration of a specific NOS inhibitor, N-nitro-L-arginine, increased whole body oxygen consumption. However, Crystal and Zhou (6) administered L-NAME to anesthetized dogs and found no effect on oxygen consumption. Kline et al. (14) found that hypoxia induced a decrease in oxygen consumption that was greater in a NOS-3 knockout mutant mouse compared with a wild-type mouse. Barros and Branco (2) showed that administration of a nonspecific NOS blocker, NG-nitro-L-arginine, to awake unrestrained Wistar rats produced a significant drop in oxygen consumption and body temperature. Our results indicate a drop in temperature and a reduction in the production of carbon dioxide that differs quantitatively between SD and BN. In aggregate, the studies in unrestrained rodents lend support for a role of NOS in maintenance of whole body metabolism.
Whether this is an effect mediated through the central nervous system or through a direct effect on cellular metabolism was not identified in this study. It is reasonable to suspect that it would be a central mechanism, given the literature on the central role of NO in determining the set point of body temperature and mitigating the fall in temperature with hypoxia (9, 21).Effects on resting ventilation.
Compared with vehicle, L-NAME increased resting ventilation
in both strains primarily because of an increase in f and was much
greater in SD. Gozal et al. (10) also showed that there was a marked increase in E response to
L-NAME in rats, primarily because of an increase in f, and
this was accompanied by a decrease in VT. Barros and Branco
(2) describe a similar increase in resting
E, but, in contrast to Gozal et al.
(10), this was primarily due to an increase in
VT. The increase in f and E was more in
SD than in BN, suggesting that there may be a more tonic inhibitory
effect of NOS under resting conditions in SD. In the study by Gozal et
al. (10), an increase in E did not occur with a selective nNOS blocker. In the present study, there were
no differences between strains in the increase in E
corrected for carbon dioxide production. This would suggest that the
greater increase in E in SD is not due to
differential effects of NOS blockade on the pulmonary circulation
and/or dead space fraction in the two strains. Taken together, these
data support the hypothesis that there is a strong tonic NOS-mediated
modulation of resting ventilation in the rat. The strain differences
may be attributable to qualitative and quantitative differences in this modulation.
Effects on ventilatory behavior with hypoxia-reoxygenation. We have previously reported that BN exhibits posthypoxic frequency decline and SD shows posthypoxic potentiation (25). In this report, measurements were made after administration of the vehicle used for L-NAME and again confirm BN response. There was, however, no statistical increase in posthypoxic f from baseline f in the SD, perhaps indicating that the intraperitoneal vehicle injection had an effect. For this reason, a time control study of two consecutive vehicle injections was performed in SD; in this sub-study, the second injection had no effect. Therefore, we conclude that L-NAME was the active intervention in uncovering posthypoxic f decline in the SD.
The absence of a significant fall inE in response
to hyperoxia is generally attributed to resting carotid body activity (7), but more recently Coles and Dick (5)
have assigned the frequency component of the response to specific
pontine region. Our pharmacological study would not distinguish
mechanisms but suggests that the phenomenon may be related to the
degree of tonic NOS suppression at baseline. For instance, NOS activity
at the carotid body level in the SD would prevent any further
depression of ventilation in the posthyperoxic period, whereas blockade
of NOS activity not only increases baseline ventilatory values but also
uncovers a depression in E in the response to reoxygenation.
Another process to consider is PHFD, an event in large part
controlled by pontine cell groups in the A5 region. (5). A role of NOS in modulating these neurons has not been identified. Given
other evidence showing a role for central NOS activity in metabolic and
temperature responses to hypoxia (8, 22), the working
hypothesis is that nNOS may be involved in shaping this response at the
level of the ventrolateral pons. Strain differences in rats may reflect
differences in the distribution and/or activity of nNOS-containing
neurons at this location.
In addition to the pontine A5 region, NO acts as a neurotransmitter in
other regions of the brain, such as the cortex and medulla, either
directly or indirectly through cardiovascular effects. The metabolic
effect of L-NAME would be something to consider if only one
strain had been examined; however, the observations between SD and BN
suggest that the posthypoxic frequency decline occurs independently of
body temperature.
NO also acts at the level of the carotid body. A role of the peripheral
chemoreceptor in the Dejours phenomenon, and the posthypoxic decline in
ventilation in particular, is supported by studies in both
animals (13, 14).
Effects on steady-state chemosensitivity.
With acute hypoxia NOS activity in the carotid body is probably
inhibited, decreasing NO concentrations and increasing afferent peripheral chemoreceptor activity (4, 18). Responsiveness, measured as the difference between resting ventilation and minute 5 of a chemochallenge, was similarly affected in all components of
ventilation in SD and BN (Fig. 3). The reciprocal effects on f and
VT was such that E was unaffected.
Limitations. We only administered a single dose of L-NAME. The weight of the animals in each strain was significantly different; however, the dose by weight that produced a significant change in the Dejours phenomenon would be significantly lower than that used for BN, in which the phenomenon was still present and unchanged. It is also possible that different doses may alter ventilatory responses and do so differently among these and other strains.
Only L-NAME, a general NOS blocker, was utilized, and we could did not determine the mechanisms, isoforms, or location of the effects of NO suppression. L-NAME has known effects on heart rate and blood pressure, which also might contribute directly or indirectly to strain differences. The effects of NOS blockade in the Wistar rat are to reduce the fall in body temperature (average of
0.73°C) with hypercapnic challenge without affecting HCVRs. We
could not detect significant differences among strains in regard to
oxygen consumption or temperature at rest. There was a fall in carbon
dioxide production (less in SD) so that it is possible that other
systemic differences could account for the differences in the strains
in regard to the Dejours effect.
Animals were without food and water for the duration of ~80 min while
the testing protocol was being followed. This might result in changes
in metabolism, as the order was always a study after vehicle followed
by one after L-NAME. However, in control experiments using
vehicle followed by vehicle in place of L-NAME and
following an identical protocol, metabolism increased by a small albeit
insignificant degree. Therefore, we do not believe the effect is the
result of the order of testing or of brief periods of fasting. The
advantages of this study design were an avoidance of day-to-day effects
and the fact that each animal acted as its own control.
Although we restricted the time of testing to the midday hours and
after a time of acclimatization to the laboratory setting, there was no
attempt to objectively record state. Observational determinations of
the body position and relative quiescence of the animal suggest that
during and after challenges there occurred increased movements and
alertness, and during resting breathing measures were made during
observed quiet wakefulness. However, the time of testing was during the
inactive period of the day for these animals, and changes in vigilance
might have affected results.
There are limitations to the barometric measurement of ventilation,
despite its attractiveness in regard to making measurements in
unrestrained animals. VT estimation is critically dependent on chamber integrity, choice of bias flow, chamber size, and the temperature of both the chamber and the animal. Absolute accuracy of
VT is always a problem, even with the use of calibration
volumes, as there exist differences in the pressure wave that is
detected as VT created by spontaneous breathing or by a
given calibrating syringe at a given calibrating frequency. In the
best-case scenario, differences of up to 10% may occur between
VT measured by plethysmograph and directly from an
anesthetized animal; correlation coefficients remain high enough
(>0.75) to show correlation even under the more extreme conditions. In
the present study, unanesthetized animals were tested under
environmentally similar circumstances (chamber size, material,
temperature, humidity, etc. being equal). The fact that the temperature
of the animal was similar after vehicle indicates that the relative
VT differences reflect biological changes induced by
L-NAME. The quantitative error introduced by a falling body
temperature and by the substantial temperature difference (1°C) after
L-NAME means that the estimates of relative VT
are altered. We chose not to computationally adjust for these temperature changes. Such an approach would have to consider a correction for humidity and, therefore, introduces other uncertainties. The interpretation of the data can be made by using frequency alone,
which is an excellent signal and is not altered as a signal by
temperature or humidity.
In conclusion, there occur strain differences between SD and BN both in
metabolism and ventilation at rest both after vehicle and after
L-NAME. Administration of a broad NOS inhibitor increases resting ventilation in SD to a far greater extent than in BN. The
Dejours phenomenon, observed consistently in BN, is also seen in SD
after L-NAME administration. Both HVR and HCVR are
similarly affected in both strains. These findings suggest that SD has
a higher level of NO function at baseline compared with BN. NOS polymorphisms, or other variations in the genetic mechanisms
influencing the NO systems, may play a significant role in metabolic
behavior, baseline ventilation, and ventilatory responses to reoxygenation.
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ACKNOWLEDGEMENTS |
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We thank Dr. Evelyn Schlenker and Dr. David Kline for comments and review. Edwin Price provided editorial comment and assistance.
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FOOTNOTES |
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This work is supported by a Veterans Affairs Merit Award, a Sleep Academic Award, and National Heart, Lung, and Blood Institute Grants HL-58844, HL-03650, HL-07953, and HL-25830.
Address for reprint requests and other correspondence: K. P. Strohl, VAMC 111j(w), 10701 East Blvd., Cleveland, OH 44106 (E-mail: KPSTROHL{at}aol.com).
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.
10.1152/japplphysiol.00677.2001
Received 29 June 2001; accepted in final form 8 May 2002.
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TOP
ABSTRACT
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METHODS
RESULTS
DISCUSSION
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F. J. Golder, A. G. Zabka, R. W. Bavis, T. Baker-Herman, D. D. Fuller, and G. S. Mitchell Differences in time-dependent hypoxic phrenic responses among inbred rat strains J Appl Physiol, March 1, 2005; 98(3): 838 - 844. [Abstract] [Full Text] [PDF]
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S. K. Iyengar, C. M. Stein, K. Russo, B. O. Erokwu, and K. P. Strohl The fa leptin receptor mutation and the heritability of respiratory frequency in a Brown Norway and Zucker intercross J Appl Physiol, September 1, 2004; 97(3): 811 - 820. [Abstract] [Full Text] [PDF]
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E. H. Schlenker, C. K. Kost Jr., and M. M. Likness Effects of long-term captopril and L-arginine treatment on ventilation and blood pressure in obese male SHHF rats J Appl Physiol, September 1, 2004; 97(3): 1032 - 1039. [Abstract] [Full Text] [PDF]
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E. R. Price, F. Han, T. E. Dick, and K. P. Strohl 7-Nitroindazole and posthypoxic ventilatory behavior in the A/J and C57BL/6J mouse strains J Appl Physiol, September 1, 2003; 95(3): 1097 - 1104. [Abstract] [Full Text] [PDF]
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