| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Division of Respiratory, Environmental, and Critical Care Medicine, Department of Medicine, Louisville Veterans Affairs Medical Center, and the University of Louisville School of Medicine, Louisville, Kentucky 40292
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
ACKNOWLEDGEMENTS
FOOTNOTES
REFERENCES
ABSTRACT 
Fletcher, Eugene C., and Gang Bao. Effect of episodic
eucapnic and hypocapnic hypoxia on systemic blood pressure in hypertension-prone rats. J. Appl. Physiol. 81(5):
2088-2094, 1996.
Repetitive episodic (18-24 s twice per
minute) hypocapnic hypoxia (HH) administered chronically (7 h/day, 35 days) to Sprague-Dawley or Wistar-Kyoto rats results in a sustained
increase in daytime blood pressure (BP). We examined acute and chronic
BP response to episodic HH and eucapnic hypoxia (EH) in borderline
hypertensive rats [first generation (F1) cross between spontaneously
hypertensive and Wistar-Kyoto rats]. We hypothesized that episodic HH
and EH would create a greater increase in acute and chronic BP in this
breed of rat than in previously studied strains. We also examined
neural mechanisms by which BP changes from hypoxia are induced. BP and
heart rate were examined acutely in nine F1 rats during baseline, HH,
EH, EH with prazosin, and EH with prazosin and atropine. Five groups of
male F1 rats were studied after 35-day exposure to the following: Unhandled (n = 8): no treatment; Sham (n = 10):
episodic compressed air; HH (n = 14): daily episodic hypoxia
(2.7%); EH1 (n = 12): hypoxia 2.9%, CO2 8.4%;
and EH2 (n = 11): hypoxia 2.8% and CO2 10.5%.
Under acute conditions, HH caused a 34.2-mmHg and EH a 77.9-mmHg
increase in mean BP. Prazosin partially blocked the increase in BP.
Under chronic conditions, HH caused a 10.3-mmHg increase in daytime
mean BP, whereas EH caused a fall in mean BP of 16.6 and 9.3 mmHg in
the two separately studied groups. In the F1 rat, acute EH causes an
elevation of BP but chronic EH causes a fall in BP. The acute response
to EH is not predictive of what occurs after chronic exposure in the
hypertension-prone F-1 rat.
sleep apnea syndromes; anoxia; hypoxemia; sympathetic nervous
system; eucarbia
INTRODUCTION WE HAVE REPORTED that exposure to recurrent short
episodes (18-24 s) of hypocapnic hypoxia (HH) during behavioral
sleep for 7 h/day for 35 days can induce diurnal (awake) blood pressure (BP) elevation in unrestrained Sprague-Dawley (SD) and Wistar-Kyoto (WKY) rats (11). Subsequent studies in WKY rats using episodic HH
demonstrated that these BP elevations were blocked by carotid body
denervation (9) and by ablation of the peripheral sympathetic nervous
system when using the neurotoxin 6-OH-dopamine (10). Attempting to
better simulate the blood gas changes of sleep apnea in humans, we
challenged SD and WKY rats with eucapnic hypoxia (EH) and HH but found
no additional increase in mean arterial pressure (MAP) in 35-day
exposed animals (7).
Hypothesizing that episodic HH and EH might be more effective in a
hypertension-prone or borderline hypertensive rat, we studied this
model using a first generation (F1) hybrid of male spontaneously hypertensive rats (SHR) and female WKY rats. Previous studies have
shown that these rats remain borderline hypertensive unless challenged
with certain stimuli that induce hypertension (2, 20, 21). In the
present study, we proposed that episodic hypoxia might serve as such a
stimulus. We also examined the acute MAP response in these same
animals, first investigating the role of sympathetic and cholinergic
receptors in the MAP change to acute exposure to EH and, second,
examining possible changes in BP responsiveness to acute challenge
after chronic exposure. In a previous publication (7), we demonstrated
by serial arterial blood gas sampling that the range of fractional
concentration of inspired CO2
(FICO2) values needed to produce
eucapnia was 7-11%. Because we could not tell what
the actual mean 35-day FICO2 was by
daily measurement until the end of the trial, we elected to run both
low- (7-9%) and high- (9-11%) eucapnia groups.
The impetus for this research is the clinical association between
chronic obstructive sleep apnea with episodic hypoxia and systemic
hypertension in humans (6, 8). It is theorized that chronic recurrent
stimuli such as episodic hypoxia, recurrent arousal, effort of thoracic
muscles against obstruction, or a combination thereof provide stress
sufficient to cause chronic hypertension in genetically susceptible
individuals (6).
METHODS
1-adrenoceptor antagonist
prazosin (1 mg/kg; Sigma Chemical, St. Louis, MO), and the same
measurements were repeated. Next, the rats were injected with atropine
(0.24 mg/kg; Eli Lilly, Indianapolis, IN), and measurements were
repeated. Five F1 rats (instrumented as above) from the EH-2 group (see
below) along with five sham controls were tested acutely with HH and EH
(see Hypoxic chambers) at baseline and within 48 h after 35 days of exposure to EH (or compressed air for the sham animals). HR and
BP were recorded and compared at both baseline and follow-up.
Chronic studies.
Fifty five male 12- to 14-wk-old F1 rats were used to study the effects
of chronically (7 h/day, 35 days) administered episodic HH and EH on
systemic BP. Abdominal aorta catheters were introduced and exteriorized
by the same techniques and maintained chronically by flushing with a
heparin solution (18). MAP was measured as above over 2-3 h,
several days before placement of rats in the chambers, and within 48 h
of cessation of the daily episodic gas exposure. The lowest stable MAP
recorded continuously for 10 min or more was taken as the value for the
recording session. The tracings were read unblinded but independently
by two investigators. Disagreements were usually not more than 2 mmHg
apart and were averaged.
The chronic-exposure rats were divided into the following groups:
Unhandled rats (n = 8), which received no treatment; Sham rats (n = 10), placed daily in hypoxia chambers but subjected only to episodic compressed air; HH rats (n = 14), exposed to daily episodic nitrogen (nadir
FIO2 = 2-4%) for 35 days;
and two groups of EH rats subjected to the same level of hypoxia but
with 7-9% CO2 (EH-1; n = 12) and
9-11% CO2 (EH-2; n = 11), introduced along
with the nitrogen. The FICO2 values
required to establish EH were determined in a previous study (7) by
drawing 50 arterial blood samples on separate occasions from 33 pilot
rats exposed to repetitive episodic HH and EH, varying
FICO2 values from 6 to 13%. By
these gases, a FICO2 of 7-9%
produced an arterial PCO2 of 36 Torr, and
FICO2 of 9-11% produced an
arterial PCO2 of 40 Torr.
Terminal blood and morphometric studies.
Since we flushed the catheters with a mixture of normal saline and
heparin about every 3 days, many catheters were patent after 35 days.
In about one-half of the animals, however, the catheters had closed,
and the same technique of arterial catheter placement was repeated. The
final BP measurement (always within 48 h of the last day of episodic
hypoxia) was made in conscious unrestrained animals. Total body weight
(TBW) was recorded at baseline and after the 35-day study period. At
termination, anesthesized rats were rapidly exsanguinated, the heart
was removed, atria and great vessels were dissected away, the right and
left ventricle (LV) were separated, and the two muscles were weighed.
All aspects of the protocol were approved by the Animal Studies
Subcommittee, University of Louisville. Animals were housed in
designated animal facilities and provided rat chow and water ad
libitum.
Statistical methods.
Morphometric and BP measurements made at baseline and change from
baseline to final were compared across all groups by one-way analysis
of variance for repeated measures with post hoc Bonferroni and
Student's t-test when applicable. The null hypothesis was rejected at P < 0.05. Deviation from the mean is
reported as ± 1 SE.
RESULTS
|
|||||||||||||||||||||||||||||||||||||||||
156 ± 14 beats/min; and 79.1 ± 0.8 mmHg and 155 ± 18 beats/min after 35 days
of exposure (Table 2). The results for five animals exposed to sham
(compressed air) for 35 days are also shown in Table 2. Under the same
acute conditions (HH or EH), values at baseline and during the
follow-up were not significantly different for sham or chronic EH
exposure.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||
16.6 ± 2.2 and 9.3 ± 2.7 mmHg fall in MAP, respectively, at the end of 35-day exposure. Both
of these changes were significantly different from groups 1, 2, and 5 but not from each other. The HH group showed a +10.3 ± 1.7 mmHg increase in MAP after 35 days (Table 3). The mean 35-day
FIO2/FICO2
values determined from daily measurement of each cage are shown
in Table 3. Baseline MAP was statistically lower in group 5 vs.
group 3, but no other differences in baseline data were
significant. There was a significant difference in body weight change
among groups over the 35-day period with all of the hypoxia-exposed
rats (groups 3-5) gaining less weight than Unhandled and
Sham control groups (Table 4). There was a
slightly greater LV/TBW ratio in both of the EH groups when compared
with the other three groups at the time of study termination.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
, Change in MAP; 
, change in HR. n =
No. of rats; see text for further explanation of groups. * Significant change from baseline.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
DISCUSSION
We have previously demonstrated that 35 days of episodic hypoxia in
sleeping rats, mimicking the episodic hypoxia of sleep apnea in humans,
can cause a (awake) diurnal increase in MAP of 13.7 mmHg (11). Intact
carotid chemoreceptors and sympathetic nerves are necessary to cause
prolonged diurnal elevation of BP in this model (9, 10). Asphyxia vs.
HH has not been found to accentuate the MAP changes (7). Taken in
context of work done in humans with apnea, it appears that hypoxia
activates the chemoreceptors, which, in turn, activate the sympathetic
nervous system, acutely elevating BP. The new and significant findings of this study are that 1) chronic exposure of borderline
hypertensive (F1) rats to EH causes a lowering of BP rather than
elevation seen with HH, or EH in other strains; 2) acute
exposure to both HH and EH produce the same increase in MAP seen in
other rat strains thus far tested (SD, WKY, Hilltop, Zucker); 3)
despite a lowering of diurnal MAP in response to chronic EH, the
MAP and HR response to acute HH and EH remain the same; 4) most
of the acute MAP response to EH is 1-adrenoceptor
mediated; and 5) the bradycardia from EH appears to be
cholinergically mediated.
The main thrust of research in humans and some animal models of sleep apnea has been to examine the acute BP response to apnea, since long-term models are difficult to develop and expose (17, 25). The rat is a good model to examine both short- and long-term effects of blood gas changes simulating those resulting from apnea in humans, since long-term BP changes can occur in a reasonable time span of exposure. The animals can be studied in the conscious, unrestained, and unanesthetized state. Also, the rat is the best studied of all animal models with regard to chronic BP elevation. Many strains display different BP responses to environmental manipulations addressing basic mechanisms of hypertension.
The addition of CO2 to the hypoxic gas mixture creating EH
acutely increased the MAP response more than twofold (Table 1). This
was not an unexpected finding. Somers et al. (31) previously demonstrated an increase in MAP by using EH in humans, whereas HH
produced no change in MAP. EH is a greater stimulus to peripheral chemoreceptors than HH and, therefore, might be expected to produce a
greater pressor response through the sympathetic nervous system (27).
The fact that the sympathetic 1-blocker prazosin reduced the pressor response by 50% is further evidence that the chemoreceptor response to EH is in part 1-adrenergically mediated. The
fact that prazosin did not eliminate the MAP response to EH indicates that other nonadrenergic mechanisms such as local vascular factors may
also contribute to this BP response. Atropine eliminated bradycardia without affecting the MAP response, indicating that phasic vagal activity is responsible for the accompanying bradycardia.
The data regarding myocardial weights show that EH-exposed rats had increased LV/TBW ratios. The increase LV weight is a consistent finding in previous studies (7, 9-11) and appears more related to hypoxia exposure than to elevation of diurnal BP. For example, in sympathetic denervated rats exposed to episodic hypoxia, there was an increase in LV/TBW without elevation in systemic BP (10). The same occurred in carotid body-denervated rats that were exposed to episodic hypoxia but did not develop elevated BP (9). Other authors have observed this without explanation. We cannot explain why the HH group did not show an increase in LV/TBW.
The SHR was described as a model of chronic hypertension expressed in response to genetic predisposition (26). It was developed from inbreeding of WKY animals with elevated BP. The F1 rat is the first generation cross of an SHR male and WKY female. This rat has been shown to develop hypertension in response to psychological stress (shock-shock conflict paradigm) and high-sodium diet (9-11). Mechanisms of acute BP elevation in this model are increased total peripheral resistance, cardiac index, and HR (15), which are probably sympathetic nervous system activated, as evidenced by elevated norepinephrine levels (28). The chronic BP elevation in response to stress is associated with normal or low renin activity (19). A recent study has shown, after 16 wk of stress, increased norepinephrine neurotransmitter levels in the ventromedial and paraventricular nuclei (centers thought to be important in sympathetic outflow), possibly reflecting decreased neurotransmitter release, an adaptive response to the chronically elevated pressures (24).
The present study with F1 rats was undertaken to examine the hypothesis that a genetically hypertension-prone rat might respond to the stress of chronic episodic hypoxia with a large elevation in BP. The F1 rats showed the same baseline and 35-day postexposure acute response to EH as SD and WKY rats (20) but lowered their diurnal MAP in response to long-term exposure, opposite to these other strains (7, 9-11). This is an important finding for several reasons. First, had the acute response to EH decreased after 35 days of EH, it might have been postulated that a blunted chemoreceptor-sympathetic response to recurrent EH accounted for the lack of diurnal increase in MAP. Second, it indicates that in genetically different strains the acute BP response to episodic hypoxia may bear no relationship to the long-term response. Third, genetics must certainly play a major role in determination of the chronic BP response to environmental stress. The main thrust of research in this area in the human apnea hypertension relationship assumes that acute elevations in BP during apnea equate to or are sustained after long-term exposure. In light of the current findings, it must now be asked whether acute BP changes mechanistically relate to chronic BP changes (at least in the model of chronic episodic hypoxia), an important area of interest affecting morbidity in sleep apnea.
Why would the F1 rat elevate MAP in response to acute EH yet lower MAP with 35-day episodic EH exposure? This experiment and other studies (1, 13, 14, 30) have shown that acute elevation of MAP in response to hypoxia (hypocapnic, eucapnic, and asphyxia) are sympathetically mediated, as demonstrated either by increased sympathetic nerve output during the challenge or by inhibiting the response with sympathetic blockers (1). The natural assumption is that chronic BP elevation is an extension of overactive sympathetic activity, either nerve or mediator induced. Although the chronic HH results support this, the EH results in this model (F-1) do not. Increased sympathetic activity chronically might be expected to cause increased MAP unless compensatory mechanisms (e.g., baroreceptor resetting) acted to reduce the MAP to normal levels. Under these circumstances, it does not seem likely that MAP would be decreased to a lower than baseline level. To reconcile these results, one would have to postulate that the addition of eucapnia to the episodic hypoxia somehow 1) averted chronic increased sympathetic activity; 2) was in itself "anti-hypertensive"; or 3) that chronically increased sympathetic activity may not be the cause of diurnal BP increase in this setting.
There is some evidence that whereas EH causes a more marked acute BP response than HH, the former produces a smaller rise in sympathetic activity than the latter (31). Using intraneural recordings of sympathetic nerve activity in humans, Somers et al. (30, 31) showed that HH produced no MAP rise but a marked increase in sympathetic activity compared with EH. EH only caused increased sympathetic activity if accompanied by apnea. These authors attribute the lower level of sympathetic activity during EH to modulating effects of pulmonary afferents and respiratory alkalosis on sympathetic outflow as well as baroreceptor reflex inhibition of sympathetic nerve activity in the face of an acute rise in BP. A lower sympathetic nerve activity from EH vs. HH might explain a lesser diurnal increase in chronic BP in response to chronic episodic EH but it does not explain an actual fall in diurnal BP from chronic exposure.
Although it is widely assumed that chronic sympathetic activation plays a role in elevation of diurnal BP in response to recurrent arousal, hypoxia, or intrathoracic pressure changes of apnea, there is no direct evidence to support this. Elevated sympathetic activity in response to acute apnea is well demonstrated by sympathetic nerve recordings during apnea (13) and even sustained for up to 20 min or more after termination of apnea (24a). However, studies showing elevated catecholamines in urine (12) or plasma (23), with reversion to baseline after correction of the apnea, do not prove that sympathetic activity is chronically elevated, since these levels were elevated during repetitive acute apneas. It is likely that increased sympathetic activity in diurnal hypertension will not be manifested by the usual humeral signs of increased sympathetic activity but by changes in central nervous system nuclei known to be active in sympathetic output (16).
Could episodic eucapnia itself be vasodilatory, thereby counteracting the effects of episodic hypoxia/sympathetic activation? CO2 has both systemic (peripheral and central nervous system chemoreceptor activation) and direct local vascular effects (vasodilatation). There is no evidence that direct effects of eucarbia or hypercarbia could have a chronic BP-lowering effect. Deviations from normal BP have not been reported in patients with chronic CO2 retention. Indeed, as demonstrated by the present data, acute EH is a greater stimulus to acute elevation of systemic BP, whereas in previous studies this is accompanied by heightened sympathetic activity (1).
Another possibility is that chronic sympathetic activity has little to do with diurnal BP elevation in the setting of recurrent episodic hypoxia, arousal, or apnea. Recurrent episodic hypoxia could lead to upregulation of endogenous organ vasoactive amines, such as vessel wall angiotensin, leading to vasoconstriction, perhaps smooth muscle hypertrophy, and increase in vascular resistance (4). Another possibility is that endothelium-derived contracting factors such as thromboxane A2, prostaglandin H2, endothelin, oxygen free radicals, etc., are upregulated by recurrent vasoconstriction in response to hypoxia (22). Finally, endothelium-derived relaxing factors such as nitric oxide, prostacyclines, and prostaglandin E2 might be downregulated by the recurrent hypoxia.
Yet unanswered is why the borderline-hypertensive rat lowers its diurnal BP in response to episodic EH yet elevates it in response to HH. Because none of the other strains of rats tested in our laboratory, including SD, WKY (7, 9- 11), Hilltop, and Zucker rats (unpublished observation) lower their acute or chronic BP in response to EH, we must conclude that the F1 rat has a peculiar genome differing from these other strains, which results in lowering of BP in this experimental model. A recent publication implicates five to six genomic regions explaining ~43% of variation of salt-loaded systolic BP in a cross between Brown-Norway and SHR rats (29). Thus polygenic traits such as BP may be quite complicated. There may be genomic regions were CO2 or chemoresponsiveness contribute to BP control. In this highly inbred selected animal, it is possible that an otherwise unexpressed genome is phenotypically expressed as lowering of BP in response to EH, whereas in other strains it is not. This study indicates that it is important to examine and develop practical models of systemic hypertension to examine the mechanism and role of genetics in chronic hypertension related to hypoxic sleep disorders.
ACKNOWLEDGEMENTS
This study was supported by the General Research Service of the Veterans Administration.
FOOTNOTES
Received 7 November 1995; accepted in final form 17 July 1996.
REFERENCES
| 1. | Bao, G., P. M. Randhawa, and E. C. Fletcher. Mechanism of acute blood pressure elevation during repetitive hypocapnic and eucapnic hypoxia in rats (Abstract). Am. J. Respir. Crit. Care Med. 149: A562, 1994. |
| 2. | Cox, R. H., J. W. Hubbard, J. E. Lawler, B. J. Sanders, and V. P. Mitchell. Cardiovascular and sympathoadrenal responses to stress in swim-trained rats. J. Appl. Physiol. 58: 1207-1214, 1985. |
| 4. | Dzau, V. J., G. H. Gibbons, and R. E. Pratt. Molecular mechanisms of vascular renin-angiotensin system in myointimal hyperplasia. Hypertension Dallas 18, Suppl. II: II-100-II-105, 1991. |
| 5. | Fink, G. D., W. J. Bryan, M. Mann, J. Osborn, and A. Werber. Continuous blood pressure measurement in rats with aortic baroreceptor deafferentation. Am. J. Physiol. 241 (Heart Circ. Physiol. 10): H268-H272, 1981. |
| 6. | Fletcher, E. C. Primary hypertension and obstructive sleep apnea: What is the connection? Am. J. Med. 98: 118-128, 1995. |
| 7. | Fletcher, E. C., G. Bao, and C. C. Miller III. Effect of recurrent episodic hypocapnic, eucapnic, and hypercapic hypoxia on systemic blood pressure. J. Appl. Physiol. 78: 1516-1521, 1995. |
| 8. | Fletcher, E. C., R. D. DeBehnke, W. G. Malitz, and M. S. Lovoi. Undiagnosed sleep apnea syndrome among patients with essential hypertension. Ann. Int. Med. 103: 190-195, 1985. |
| 9. | Fletcher, E. C., J. Lesske, R. Behm, C. C. Miller, and T. Unger. Carotid chemoreceptors, systemic blood pressure, and chronic episodic hypoxia mimicking sleep apnea. J. Appl. Physiol. 72: 1978-1984, 1992. |
| 10. | Fletcher, E. C., J. Lesske, J. Culman, C. C. Miller III, and T. Unger. Sympathetic denervation blocks blood pressure elevation episodic hypoxia. Hypertension Dallas 20: 612-619, 1992. |
| 11. | Fletcher, E. C., J. Lesske, W. Qian, C. C. Miller, and T. Unger. Repetitive, episodic hypoxia causes diurnal elevation of systemic blood pressure in rats. Hypertension Dallas 19: 555-561, 1992. |
| 12. | Fletcher, E. C., J. Miller, J. W. Schaaf, and J. G. Fletcher. Urinary catecholamines before and after tracheostomy in patients with obstructive sleep apnea and hypertension. Sleep 10: 35-44, 1987. |
| 13. | Fukuda, Y., A. Sato, A. Suzuki, and A. Trzebski. Autonomic and cardiovascular responses to changing blood oxygen and CO2 levels in the rat. J. Auton. Nerv. Sys. 28: 61-74, 1989. |
| 14. | Hedner, J., H. Ejnell, J. Sellgren, T. Hedner, and G. Wallin. High muscle nerve sympathetic activity in the sleep apnea syndrome. J. Hypertens. 6: S529-S531, 1988. |
| 15. | Hubbard, J. W., R. H. Cox, B. J. Sanders, and J. E. Lawler. Changes in cardiac output and vascular resistance during behavioral stress in the rat. Am. J. Physiol. 251 (Regulatory Integrative Comp. Physiol. 20): R82-R90, 1986. |
| 16. | Judy, W. V., A. Watanabe, D. P. Henry, H. R. Besch, W. R. Murphy, and G. M. Hockel. Sympathetic nerve activity: role in regulation of blood pressure in SHR. Circ. Res. 38, Suppl. II: II-21-29, 1976. |
| 17. | Kimoff, R. J., H. Makino, R. L. Horner, L. F. Kozar, F. Lue, A. S. Slutsky, and E. A. Phillipson. Canine model of obstructive sleep apnea: model description and preliminary application. J. Appl. Physiol. 76: 1810-1817, 1994. |
| 18. | Kurowski, S. Z., K. J. Slavik, and J. E. Szilagyi. A method for maintaining and protecting chronic arterial and venous catheters in conscious rats. J. Pharmacol. Methods 26: 249-256, 1991. |
| 19. | Lawler, J. E., G. F. Barker, J. W. Hubbard, R. H. Cox, and G. W. Randall. Blood pressure and plasma renin activity responses to chronic stress in the borderline hypertensive rat. Physiol. Behav. 32: 101-105, 1984. |
| 20. | Lawler, J. E., G. F. Barker, J. W. Hubbard, and R. G. Schaub. Effects of stress on blood pressure and cardiac pathology in rats with borderline hypertension. Hypertension Dallas 3: 496-505, 1981. |
| 21. | Lawler, J. E., B. J. Sanders, Y. F. Chen, S. Nagahama, and S. Oparil. Hypertension produced by a high sodium diet in the borderline hypertensive rat (BHR). Clin. Exp. Hypertens. Part A Theory Pract. 9: 1713-1731, 1987. |
| 22. | Lusher, T. F., C. M. Boulanger, Y. Dohi, and Z. Yang. Endothelium-derived contracting factors. Hypertension Dallas 19: 117-130, 1992. |
| 23. | Marrone, O., L. Riccobono, A. Salvaggio, A. Mirabella, A. Bonanno, and M. R. Bonsignore. Catecholamines and blood pressure in obstructive sleep apnea syndrome. Chest 103: 722-27, 1993. |
| 24. | Mitchell, V. P., and J. E. Lawler. Norepinephrine content of descrete brain nuclei in acutely and chronically stressed borderline hypertensive rats. Brain Res. Bull. 22: 545-547, 1989. |
| 24a. | Morgan, B. J., D. C. Crabtree, M. Palta, and J. Skatrud. Combined hypoxia and hypercapnia evokes long-lasting sympathetic activation in humans. J. Appl. Physiol. 79: 205-213, 1995. |
| 25. | O'Donnell, C. P., E. D. King, A. R. Schwartz, P. L. Smith, and J. L. Robotham. Blood pressure and hormonal responses to airway obstruction in the sleeping dog (Abstract). Am. J. Respir. Crit. Care Med. A560, 1994. |
| 26. | Okamoto, K., and K. Aoki. Development of a strain of spontaneously hypertensive rats. Jpn. Circ. J. 27: 282-293, 1967. |
| 27. | Pelletier, C. L. Circulatory responses to graded stimulation of the carotid chemoreceptors in the dog. Circ. Res. 31: 431-443, 1972. |
| 28. | Sanders, B. J., R. H. Cox, and J. E. Lawler. Cardiovascular and renal responses to stress in borderline hypertensive rat. Am. J. Physiol. 255 (Regulatory Integrative Comp. Physiol. 24): R431-R438, 1988. |
| 29. | Schork, N. J., J. D. Krieger, M. R. Trolliet, K. G. Franchini, G. Koike, E. M. Krieger, E. S. Lander, V. J. Dzau, and H. J. Jacob. A biometrical genome search in rats reveals the multigenic basis of blood pressure variation. Gen. Res. 5: 164-172, 1995. |
| 30. | Somers, V. K., A. L. Mark, and F. M. Abboud. Interaction of baroreceptor and chemoreceptor reflex control of sympathetic nerve activity in normal humans. J. Clin. Invest. 87: 1953-1957, 1991. |
| 31. | Somers, V. K., A. L. Mark, D. C. Zavala, and F. M. Abboud. Influence of ventilation and hypocapnia on sympathetic nerve responses to hypoxia in normal humans. J. Appl. Physiol. 67: 2095-2100, 1989. |
This article has been cited by other articles:
|
|
 |
|
  J. B. Snow, V. Kitzis, C. E. Norton, S. N. Torres, K. D. Johnson, N. L. Kanagy, B. R. Walker, and T. C. Resta Differential effects of chronic hypoxia and intermittent hypocapnic and eucapnic hypoxia on pulmonary vasoreactivity J Appl Physiol, January 1, 2008; 104(1): 110 - 118. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. J. Campen, L. A. Shimoda, and C. P. O'Donnell Acute and chronic cardiovascular effects of intermittent hypoxia in C57BL/6J mice J Appl Physiol, November 1, 2005; 99(5): 2028 - 2035. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Bradford Festschrift for R. G. O'Regan - Sensing and adaptation to alterations in respiratory gases: oxygen and carbon dioxide: Effects of chronic intermittent asphyxia on haematocrit, pulmonary arterial pressure and skeletal muscle structure in rats Exp Physiol, January 1, 2004; 89(1): 44 - 52. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. S. T. LEUNG and T. DOUGLAS BRADLEY Sleep Apnea and Cardiovascular Disease Am. J. Respir. Crit. Care Med., December 15, 2001; 164(12): 2147 - 2165. [Full Text] [PDF]
|
|
|
|
 |
|
 L. F. Hayward Evidence for alpha -2 adrenoreceptor modulation of arterial chemoreflexes in the caudal solitary nucleus of the rat Am J Physiol Regulatory Integrative Comp Physiol, November 1, 2001; 281(5): R1464 - R1473. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. McGuire and A. Bradford Chronic intermittent hypercapnic hypoxia increases pulmonary arterial pressure and haematocrit in rats Eur. Respir. J., August 1, 2001; 18(2): 279 - 285. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. A. Fagan Physiological and Genomic Consequences of Intermittent Hypoxia: Selected Contribution: Pulmonary hypertension in mice following intermittent hypoxia J Appl Physiol, June 1, 2001; 90(6): 2502 - 2507. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Kraiczi, J. Magga, X. Y. Sun, H. Ruskoaho, X. Zhao, and J. Hedner Hypoxic pressor response, cardiac size, and natriuretic peptides are modified by long-term intermittent hypoxia J Appl Physiol, December 1, 1999; 87(6): 2025 - 2031. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. Borovsky, M. Herman, G. Dunphy, A. Caplea, and D. Ely CO2 asphyxia increases plasma norepinephrine in rats via sympathetic nerves Am J Physiol Regulatory Integrative Comp Physiol, January 1, 1998; 274(1): R19 - R22. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Visit Other APS Journals Online |
