Articles in PresS. Physiol Genomics (October 19, 2004). doi:10.1152/physiolgenomics.00197.2003
PHENOTYPIC VARIATION IN CARDIOVASCULAR RESPONSES TO ACUTE HYPOXIC AND HYPERCAPNIC EXPOSURE IN MICE Matthew J. Campen1 , Yugo Tagaito2 , Jianguo Li3 , Alexander Balbir3 , Clarke G. Tankersley4 , Phillip Smith3 , Alan Schwartz3 , and Christopher P. O’Donnell5 1
Toxicology Division, Lovelace Respiratory Research Institute, Albuquerque, NM; 2 Department of Anesthesiology, Chiba University School of Medicine, Japan; 3 Department of Medicine, Division of Pulmonary and Critical Care, Johns Hopkins University, Baltimore, Maryland, USA; 4 Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA; 5 Department of Medicine, Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh, Pennsylvania
Running Title: Cardiova scular responses during hypoxia and hypercapnia
Please Address Correspondence to: Christopher P. O’Donnell Division of Pulmonary, Allergy, and Critical Care Medicine Department of Medicine NW628 MUH 3459 Fifth Avenue Pittsburgh PA 15213 412 692 2880 412 692 2888 (fax) email:
[email protected] MANUSCRIPT # PG-00197-2003
Copyright © 2004 by the American Physiological Society.
ABSTRACT
The impact of genetic variation on cardiovascular responses to hypoxia and hypercapnia is not well understood. Therefore, we determined the acute changes in systemic arterial blood pressure (P SA) and heart rate (HR) in seven strains of commonly used inbred mice exposed to acute periods of hypoxia (10% O2 ), hypercapnia (5% CO2 ), and hypoxia/hypercapnia (10% O2 + 5% CO2 ) during wakefulness. Hypercapnia induced an essentially homogeneous response across strains, with P SA maintained at or slightly above baseline, and HR exhibiting a typical baroreceptor- mediated bradycardia. In contrast, exposure to hypoxia elicited a marked heterogeneity in cardiovascular responses between strains. The change in P SA during hypoxia ranged from maintenance of normotension in the FVB/J strain to profound hypotension of approximately 30 mmHg in the DBA/2J strain. HR responses were highly variable between strains during hypoxia, and with the exception of the DBA/2J strain that exhibited significant bradyarrhythmias and consequent hypotension, the HR responses were unrelated to changes in P SA. The P SA response to combined hypoxia/hypercapnia represented a balance of the hypertension of hypercapnia and the hypotension of hypoxia in six of the seven strains. In the FVB/J strain, combined hypoxia/hypercapnia produced a hypertensive response that was greater than that of hypercapnia alone. These results suggest that genetic background affects the cardiovascular response to hypoxia, but not hypercapnia.
INTRODUCTION
Hypoxia is a powerful stimulus to the physiological systems that regulate the cardiovascular system. During hypoxia, the body attempts to maintain an adequate blood flow and supply of oxygen to the heart and brain, while decreasing blood supply to other organs and mobilizing blood from the splanchnic circulation (3, 7). Consequently, mean arterial blood pressure (P SA) is normally maintained or slightly elevated during hypoxia, whereas heart rate (HR) tends to decrease (6, 8). Recent studies in rats support the concept that variation in genetic background can have an impact on the pattern of cardiovascular responses to hypoxia. For example, Wistar Kyoto and Sprague-Dawley rats exposed to hypoxia both exhibit bradycardia, but the accompanying hypertensive response is greater in the Wistar Kyoto than the Sprague-Dawley rats (1). In contrast, Wistar rats exposed to acute hypoxia exhibit tachycardia and hypotension (5). Thus, genetic factors may be an important determinant in the cardiovascular response to hypoxia, yet no studies to date have systematically tested whether genetic variation can cause heterogeneity in hemodynamic responses to hypoxia. The purpose of the current study was to utilize several inbred mouse strains to determine whether specific genetic background can affect the cardiovascular responses to hypoxia, or combined hypoxic and hypercapnic exposure. We performed experiments in chronically- instrumented, awake mice from seven different inbred strains and hypothesized that differences in genetic background could cause strain-specific responses in blood pressure and HR during acute exposure to hypoxia and/or hypercapnia.
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METHODS
Animals Adult, male mice (n = 6-12 per strain; 12-16 weeks of age) were purchased from The Jackson Laboratory, (Bar Harbor, ME) and housed in a microisolator facility (AAALAC-approved). The following strains were examined: A/J, BALB/cJ, C3H/HeJ, C57BL/6J, CBA/J, DBA/2J, and FVB/J. Temperature and humidity were continuously regulated at 20-22ºC and 40-60% RH, respectively. Food and water were available ad libitum throughout the study. Protocols were conducted on the seven strains concurrently to minimize bias. All studies were conducted with the approval of the Johns Hopkins Animal Care and Use Committee.
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Surgical Preparation All surgical procedures were performed under 1-2% isoflurane anesthesia using aseptic techniques. Electrodes for polysomnography were implanted as previously described (9). Briefly, three Teflon-coated wires were inserted into predrilled holes in the left frontal and left and right parietal regions. Two electromyographic (EMG) electrodes were stitched flat onto the surface of the muscle immediately posterior to the dorsal area of the mouse skull. The femoral artery was exposed by a 1.5 cm cutaneous incision and carefully separated from the femoral vein and nerve, as previously described (2) for determination of systemic arterial pressure (P SA). A 60-cm long renothane catheter (MRE025 Braintree Scientific, Inc., MA), heat-stretched and formed into a J-shape, was inserted with the aid of a 26- gauge needle and advanced approximately 0.5-1.0 cm towards the bifurcation of the aorta. The catheter was secured by suture and cyanoacrylate glue (Quicktite Superglue, Manco Inc., OH), then exteriorized at the base of the skull and secured to the EEG/EMG electrodes. The catheter was attached to a single channel fluid swivel (375/25 Instech Laboratories Inc., PA) and perfused slowly by an infusion pump (0.5 ml/day) with a sterile saline solution containing heparin (80 U/ml). P SA measurements were facilitated by a flow-through pressure transducer.
Monitoring and Data Analysis Both the PSG leads and the flow-through transducer were connected to a pen recorder during gas exposures (Grass Instruments; Quincy, MA). Data from the pen recorder were sampled at 300 Hz, converted to digital format (DI-200 data acquisition
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board; Dataq Instruments; Akron, OH), and saved on optical disks for storage with Windaq/200 acquisition software (Dataq Instrument s). P SA and HR were determined from signals averaged over 24 h. Gas Exposure Protocol: All exposures were conducted at approximately 30 M above sea level; thus, ambient pressure approximated 760 mmHg. Mice were placed in a cylindrical exposure chamber (0.7 L) with standard bedding. This chamber allowed free movement of the mouse, but was small enough to enable rapid exchange of gases. Room air (FiO 2 = 0.209) was forced through the chamber at 2 L/min. Mice were exposed to three different gases: (a) hypoxia (10% O2 + 90% N2 ), (b) hypercapnia (5% CO2 + 40% O2 + 55% N2 ), and (c) combined hypoxia/hypercapnia (10% O2 + 5% CO2 + 85% N2 ). Oxygen levels in the chamber were continuously recorded (OM-11, SensorMedics Oxygen Analyzer, Anaheim, CA). The exposures began after a 1-h period of acclimation to the exposure chamber. In all mice the polysomnogram was monitored during gas exposures to ascertain wakefulness. No exposures were conducted while mice were sleeping. Each exposure lasted 4 minutes, with 8 minutes of recovery time following different exposures (i.e., between hypercapnia and hypoxia), and 4 minutes of recovery between repetitions of the same exposures. Each mouse was exposed to a minimum of two repetitions of each gas challenge. We have previously published baseline P SA data for many of the strains across sleep/wake states (2). An arterial blood gas sample (80-100 µl) was obtained under room air conditions 30 min after completion of the final gas challenge and immediately analyzed on a blood gas analyzer (IL BG3; Instrumentation Laboratory, Lexington, MA). The blood loss was
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replaced with an infusion of approximately 100-200 µl of saline. On subsequent days, arterial blood samples were obtained after the 4- minute exposure to the hypoxic, hypercapnic, and combined hypoxic/hypercapnic exposures detailed above. The order of sampling was determined by block design and continued at 24-h intervals for as long as the catheter remained patent.
Statistics Measurements of P SA and HR were averaged ove r 1-minute periods throughout the 4-minute exposure period and compared to a control period consisting of the 2- minute interval immediately preceding the start of the gas exposure. Mean + s.e. values for PSA and HR were determined for each strain during the control period and at 1- minute intervals during the gas exposure period. Statistical differences in cardiovascular parameters during exposure to hypoxia and hypercapnia within each strain were assessed by within subject, one-way ANOVA, and if the ANOVA was significant, a Dunnett’s post hoc test was used to determine whether there was a change in P SA or HR at any time point during gas exposure relative to the control period. Statistical differences in the change in P SA between strains were determined by between subject, one-way, ANOVA, and if the ANOVA was significant, the Scheffé’s Method post hoc test was used to identify which strains were significantly different.
RESULTS
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Hypoxia Exposure to 10% O2 induced varying levels of hypotension in most strains, with DBA/2J mice displaying the most extreme decrease in P SA (~30 mmHg). Figure 1 demonstrates a typical tracing from a DBA/2J mouse; note severe periods of arrhythmiainduced pulse deficit (downward deflections) in the DBA/2J mouse consequent with hypotension. Other strains (A/J, C3H/HeJ, C57BL/6J, and CBA/J) exhibited a moderate hypotension (8-16 mmHg below control), while BALB/cJ and FVB/J strains showed no significant change from baseline (data summarized in Figure 2 and 3). The HR changes appeared unrelated to alterations in P SA, with HR increasing in BALB/cJ and C3H/HeJ mice, decreasing in DBA/2J and FVB/J mice, and not significantly changing in A/J, C57BL/6J, and CBA/J mice (Figure 4). DBA/2J mice were particularly sensitive to hypoxia, demonstrating the most severe hypotension and bradycardia to the point of complete AV-node conduction block. Arrhythmias were frequently observed in these mice, with the most severe occurring in the final 2 minutes of the hypoxic exposure (Figure 5). Arrhythmias (defined as a > 50% difference in pulse interval from the preceding interval) were characterized electrocardiographically in a separate group of DBA/2J mice (n = 4) and consisted primarily of bradycardic slowing and Type-II AV- node blockade, indicated by the presence of P-waves without ventricular deflections.
Hypercapnia During exposure to 5% CO2 , all strains demonstrated slight increases in P SA (Figures 2 and 3). The only significant difference between strains occurred between the
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A/J and DBA/2J strain (Figure 3). HR values decreased concomitantly in all strains, presumably due to baroreflex modulation (Figure 4). No hypercapnia-related increase in arrhythmogenesis was observed in any strain (Figure 5).
Combined Hypoxia and Hypercapnia When administered concomitantly, the individual effects of hypoxia and hypercapnia appeared to negate each other, resulting in little or no net P SA change from baseline in most strains (Figure 2 and 3). The FVB/J mouse demonstrated the most pronounced increase in P SA, and was the only strain in which the hypertensive effect of combined hypoxia and hypercapnia was greater than that of hypercapnia alone (P = 0.02 by paired t-test). HR responses were variable, although bradycardia was the predominant response in most strains (Figure 4). No significant incidence of arrhythmia was associated with combined hypoxia and hypercapnia in any strain (Figure 5).
Blood Gases Although each strain was exposed to identical inspired levels of hypoxia and hypercapnia, it is possible that differences in blood levels of PaO 2 and PaCO2 were in part responsible for the cardiovascular differences we observed between strains. Our intention was to measure blood gas levels during room air breathing and during hypoxia, hypercapnia, and combined hypoxia and hypercapnia exposure in each animal. However, due to the variable period of time that catheters remained patent and the requirement of a minimum period of 24 h between repeat samples to minimize blood loss, it was not possible to obtain comprehensive measurements in all strains, and subsequently the data
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have been pooled across strains in Table 1. There was, however, no indication from the data we did collect of any major differences between strains with respect to blood gases during hypoxic and hypercapnic exposure.
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DISCUSSION
In the current study we utilized a variety of mouse strains with chronically implanted arterial catheters to determine whether genetic background influences the cardiovascular responses to acute periods of hypoxia and hypercapnia. We observed remarkable homogeneity in the PSA and HR responses to hypercapnia across all seven strains, suggesting that cardiovascular responses to hypercapnia, which are predominantly mediated by central chemoreceptor activation of peripheral sympathetic nerve activity (6), are relatively resistant to genetic influences. In contrast, there was marked variation between strains in the cardio vascular response to hypoxia, and to combined hypoxia/hypercapnia. In the discourse that follows, we examine possible reasons for the heterogeneity of cardiovascular responses to hypoxia and discuss the unique responses in the FVB/J strain and the DBA/2J strain.
Heterogeneity of Responses to Hypoxia and Combined Hypoxia/Hypercapnia The cardiovascular responses to hypoxia and combined hypoxia and hypercapnia varied considerably in terms of both the magnitude and direction of response. A number of genetic factors ranging from ventilatory response, which determines the level of PaO 2 and PaCO2 in the arterial blood, through autonomic output to the heart and peripheral blood vessels could contribute to this observed variability in cardiovascular responses to hypoxia and hypercapnia. Exposure to hypoxia or combined hypoxia/hypercapnia caused an opposite pattern of cardiovascular responses between some strains. For example, during combined
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hypoxia/hypercapnia, HR increased in the C3H/HeJ strain, but decreased in the CBA/J strain. Despite this opposite response in HR, pHa, PaCO2 , and PaO 2 levels during exposure to 10% O2 and 5% CO2 were similar between C3H/HeJ (7.34 ± 0.03 units, 40.5 ± 1.8 mmHg, 50.0 ± 3.3 mmHg; n = 4) and CBA (7.36 ± 0.02 units, 39.8 ± 1.1 mmHg, 53.0 ± 2.7 mmHg; n = 4) animals. Thus, it is unlikely that the differences in cardiovascular responses to either hypoxia or combined hypoxia/hypercapnia are solely dependent on blood gas variability between strains. Assuming that arterial blood gas levels and arterial oxygen disassociation curves were comparable during the various gas challenges, genetic variation between strains may therefore be dependent on the chemoreceptor-autonomic reflex arc. The uniformity of cardiovascular responses to hypercapnia, however, suggests that neural pathways from the central chemoreceptors, through central integration to peripheral autonomic output are resistant to genetic variation. The same may not be true for hypoxic chemoreceptors and their subsequent activation of neural reflexes controlling sympathetic output to the heart and peripheral vessels. Indeed, we have shown that structure and function of the carotid body, the dominant hypoxic chemoreceptor, can be markedly different between strains (12). Thus, variation in the carotid body or the down-stream components of the neural reflex arc controlling HR and vascular tone may significantly contribute to the genetic differences in cardiovascular responses between strains exposed to hypoxia or hypoxia/hypercapnia. Another possible mechanism contributing to cardiovascular differences between strains is the ability of vascular resistance vessels to vasodilate in response to hypoxia. The ability of hypoxia to locally decrease vascular resistance through adensosine,
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prostaglandin, or nitric oxide pathways is considerable in systemic vessels (7). For example, in a canine model of obstructive sleep apnea, the acute hypertensive response that occurs during a period of experimentally- induced airway obstruction is reversed to a pronounced hypotensive response after chemical blockade of the autonomic nervous system (8). Furthermore, the fall in blood pressure after autonomic blockade is eliminated when airway obstruction is induced in the presence of hyperoxia. Thus, it is possible that the variation between strains in the P SA responses to hypoxia and combined hypoxia/hypercapnia in the present study is in part dependent on genetic differences in local hypoxic vasodilation. Finally, there was no evidence that differences in baseline P SA contributed to the variability of responses to hypoxia. In a previous study, we observed significant straindependent differences in baseline 24-h P SA, as well as differences in P SA modulation during REM and non-REM sleep stage s (2). It is possible that differences in baseline P SA between strains can affect the magnitude and direction of the cardiovascular responses during acute exposure to hypoxia and hypercapnia. Correlational analysis revealed that baseline P SA from the awake mice in the current study had no relationship with either the direction or magnitude of P SA responses to any gas challenge. Furthermore, values determined from 24-h baseline P SA in the previous study (2), which were lower but similar in pattern to those obtained during wakefulness in the present study, also bore no correlation to the cardiovascular responses to gas challenge. Therefore, the variability in cardiovascular responses to hypoxia and combined hypoxia/hypercapnia is more likely dependent on factors such as genetic differences in acute vasodilatory responses to hypoxia than to chronic regulatory control of baseline PSA.
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Hypoxic Responses in FVB/J and DBA/2J Mice The two extremes of cardiovascular responsiveness to hypoxic exposure occurred in FVB/J and DBA/2J mice. Of all the strains examined, the FVB/J strain demonstrated the least change in peripheral vascular resistance during hypoxia, as suggested by the maintenance of P SA without increases in HR. Furthermore, the FVB/J strain showed the largest hypertensive response to combined hypoxia and hypercapnia. The pattern of cardiovascular responses to hypoxia seen in the FVB/J strain most closely resemble that reported in humans (3), and may provide an important model for future research. The absence of a significant vasodilatory response in the FVB/J mice may be related to a reduced sensitivity in adensosine, prostaglandin, or nitric oxide pathways that mediate local hypoxic vasodilation (7). Thus, the FVB/J is an interesting and clinically relevant strain to further dissect the contributions of reflex- mediated sympathetic nerve activity and local hypoxic vasodilation in the blood pressure response to hypoxia. An unusual response observed in the current study was the marked bradycardia during hypoxia exhibited in DBA/2J mice. One possible explanation is that the arrhythmias resulted from transient heart block due to stimulation of chemoreceptors or extracardiac bronchopulmonary reflexes (4). The previous demonstration that the DBA/2J strain has a large and sensitive carotid body (12), and the largest ventilatory response to hypoxia of several inbred strains (11), provides support for pulmonary afferents as a mediator of the profound bradycardia. However, there was no significant presence of arrhythmias in DBA/2J mice during combined hypoxic and hypercapnic exposure, when ventilation and activation of bronchopulmonary reflexes will be
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considerably higher than during hypoxia alone (10). While it may be that hypercapnic activation of sympathetic pathways antagonizes the vagally- mediated bradycardia, it is unclear from the present study whether the marked arrhythmia in DBA/2J mice during hypoxia is due to reflex modulation of cardiac vagal activity, or perhaps represents a direct effect of hypoxia on the rhythmicity of the heart. Either way, the cardiovascular response to hypoxia in the DBA/2J strain provides an intriguing model for further study.
Summary The cardiovascular response to hypercapnia was remarkably homogeneous between inbred strains. In contrast, hypoxia caused a heterogeneous response between inbred strains in which blood pressure was maintained or fell precipitously and HR increased, decreased, or remained unchanged. Although we did not investigate the relative contribution of arterial blood gas levels, sensory reflex arcs, or effector output mechanisms as mediators of the heterogeneous cardiovascular responses to hypoxia, our study provid es relevant data for any future study assessing cardiorespiratory responses using inbred mouse strains. Moreover, we have also identified that the FVB/J strain closely models human cardiovascular responses to acute hypoxia and hypercapnia, and that the DBA/2J strain demonstrates a unique cardiac susceptibility to acute hypoxic exposure.
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ACKNOWLEDGEMENTS
This research was funded by NIH grants HL51292 and NRSA F32HL68417.
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REFERENCES
Reference List
1. Bao G, Randhawa PM and Fletcher EC. Acute blood pressure elevation during repetitive hypocapnic and eucapnic hypoxia in rats. J Appl Physiol 82: 10711078, 1997.
2. Campen MJ, Tagaito Y, Jenkins TP, Smith PL, Schwartz AR and O'Donnell CP. Phenotypic differences in the hemodynamic response during REM sleep in six strains of inbred mice. Physiol Genomics 11: 227-234, 2002.
3. Hedner JA, Wilcox I, Laks L, Grunstein RR and Sullivan CE. A specific and potent pressor effect of hypoxia in patients with sleep apnea. Am Rev Respir Dis 146: 1240-1245, 1992.
4. James TN, Urthaler F and Hageman GR. Reflex heart block. Baroreflex, chemoreflex and bronchopulmonary reflex causes. Am J Cardiol 45: 1182-1188, 1980.
5. Murasato Y, Hirakawa H, Harada Y, Nakamura T and Hayashida Y. Effects of systemic hypoxia on R-R interval and blood pressure variabilities in conscious rats. Am J Physiol 275: H797-H804, 1998.
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6. O'Donnell CP, Schwartz AR, Smith PL, Robotham JL, Fitzgerald RS and Shirahata M. Reflex stimulation of renal sympathetic nerve activity and blood pressure in response to apnea. Am J Respir Crit Care Med 154: 1763-1770, 1996.
7. Ray CJ, Abbas MR, Coney AM and Marshall JM. Interactions of adenosine, prostaglandins and nitric oxide in hypoxia- induced vasodilatation: in vivo and in vitro studies. J Physiol 544: 195-209, 2002.
8. Schneider H, Schaub CD, Chen CA, Andreoni KA, Schwartz AR, Smith PL, Robotham JL and O'Donnell CP. Neural and local effects of hypoxia on cardiovascular responses to obstructive apnea. J Appl Physiol 88: 1093-1102, 2000.
9. 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.
10. Tankersley C, Kleeberger S, Russ B, Schwartz A and Smith P. Modified control of breathing in genetically obese (ob/ob) mice. J Appl Physiol 81: 716723, 1996.
11. Tankersley CG, Fitzgerald RS and Kleeberger SR. Differential control of ventilation among inbred strains of mice. Am J Physiol 267: R1371-R1377, 1994.
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12. Yamaguchi S, Balbir A, Schonfield B, Coram J, Tankersley C, Fitzgerald RS, O'Donnell CP and Shirahata M. Structural and functional differences of the carotid body between DBA/2J and A/J strains of mice. J Appl Physiol 94: 15361542, 2003.
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FIGURE LEGENDS
Figure 1: Representative P SA tracing from DBA/2J mice during repeated 4- minute exposures to hypoxia (10% O2 ). PSA values were determined by femoral artery catheterization. X-axis grid marks are at 40-sec intervals.
Figure 2: Systemic arterial pressure responses to hypoxia (10% O2 ), hypercapnia (5% CO2 ), and combined hypoxia and hypercapnia (10% O2 and 5% CO2 ) in seven strains of mice. Data shown are averages (± s.e.) for each strain for a 1- minute control (c) period and each minute throughout the 4-minute exposure (1, 2, 3, and 4). Statistical differences in PSA during gas exposure were assessed by within subject, one-way ANOVA, and if the ANOVA was significant a Dunnett’s post hoc test was used to determine whether there was a change in P SA at any time point during gas exposure relative to the control period (* indicates P < 0.001).
Figure 3: Individual responses for change in mean systemic arterial pressure (P SA) during exposure to hypoxia (10% O2 ; top panel), hypercapnia (5% CO2 ; middle panel), and combined hypoxia and hypercapnia (10% O2 and 5% CO2 ; lower panel) in seven inbred strains. Values represent differences between control and the 4th minute of challenge. Statistical differences from DBA/2J strain are designated by • ;
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statistical differences from C57BL/6J strain are designated by #; statistical differences from FVB/2J strain are designated by †.
Figure 4: Heart rate responses to hypoxia (10% O2 ), hypercapnia (5% CO2 ), and combined hypoxia and hypercapnia (10% O2 and 5% CO2 ) in seven strains of mice. Data shown are averages (± s.e.) for each strain for a 1-minute control (c) period and each minute throughout the 4-minute exposure (1, 2, 3, and 4). Statistical differences in heart rate during gas exposure were assessed by within subject, one-way ANOVA, and if the ANOVA was significant, a Dunnett’s post hoc test was used to determine whether there was a change in heart rate at any time point during gas exposure relative to the control period (* indicates P < 0.001).
Figure 5: Arrhythmogenesis during exposure to hypoxia (10% O2 ), hypercapnia (5% CO2 ), and combined hypoxia and hypercapnia (10% O2 and 5% CO2 ) in seven strains of mice. Data shown are averages (± s.e.) for each strain for a 1- minute control (c) period and each minute throughout the 4-minute exposure (1, 2, 3, and 4). Statistical differences in arrhythmogenesis during gas exposure were assessed by within subject, one-way ANOVA, and if the ANOVA was significant, a Dunnett’s post hoc test was used to determine whether there was a change in arrhythmogenesis at any time point during gas exposure relative to the control period (* indicates P < 0.001).
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Table 1: Blood gas values for all strains (pooled average ± s.e.) following the hypoxic, hypercapnic, and combined challenges.
Control
10% O2
5% CO2 + 40% CO2
10% O2 +5% CO2
pH
7.42 ± 0.03
7.52 ± 0.04*
7.33 ± 0.02*
7.36 ± 0.04*†
pCO2
32.1 ± 4.1
22.2 ± 4.2*
44.3 ± 2.0*
40.3 ± 2.9*†
pO2
85.9 ± 8.9
39.7 ± 4.9*
131.7 ± 12.3*
51.9 ± 5.2*†
* Denotes significant difference from control; † denotes significant difference from hypoxia (10% O2 ) alone, P < 0.05.
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Figure 1.
DBA/2J 130
SYSTEMIC ARTERIAL PRESSURE (mmHg) 30 21
INSPIRED OXYGEN (%) 5
4 minutes
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Figure 2.
Systemic Arterial Pressure (mmHg)
140 130
* *
120
* *
110
* *
*
*
100
* *
*
90
*
*
*
80
*
70 Hypoxia
60
C 1 2 3 4
A/J
C 1 2 3 4
Balb/cJ
Hypercapnia
Hypoxia and Hypercapnia
C 1 2 3 4
C 1 2 3 4
C3H/HeJ
C57BL/6J
C 1 2 3 4
CBA/J
C 1 2 3 4
DBA/2J
C 1 2 3 4 Minutes
FVB/J
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Figure 3.
Change in P SA (mmHg)
20
0
-20 Hypoxia Hypoxia
-40
• P=0.001
• P=0.002
# P=0.051 # P=0.019
# P=0.003
• P=0.029
Change in P SA (mmHg)
-60 20
0
-20 Hypercapnia Hypercapnia
-40 • P=0.029
Change in P SA (mmHg)
-60 20
0
-20 Combined Combined
-40 † P=0.029
-60
A/J
† P=0.015 † P=0.002 † P=0.002
Balb/cJ C3H/HeJ C57BL/6J
CBA/J
DBA/2J
FVB/J
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Figure 4.
800
Heart Rate (bpm)
700
* 600
*
* * *
† *
†
* † *
* † *
500
* 400
* Hypoxia
300
C 1 2 3 4
A/J
C 1 2 3 4
Balb/cJ
Hypercapnia
C 1 2 3 4
C 1 2 3 4
C3H/HeJ
C57BL/6J
Hypoxia and Hypercapnia
C 1 2 3 4
CBA/J
C 1 2 3 4
C 1 2 3 4 Minutes
DBA/2J
FVB/J
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Figure 5.
30 Hypoxia
Hypercapnia
Hypoxia and Hypercapnia
Arrhythmia Frequency (#/min)
25
*
20
15
10
5
0
C 1 2 3 4
A/J
C 1 2 3 4
Balb/cJ
C 1 2 3 4
C 1 2 3 4
C3H/HeJ
C57BL/6J
C 1 2 3 4
CBA/J
C 1 2 3 4
DBA/2J
C 1 2 3 4 Minutes
FVB/J
25
