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ABSTRACT |
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 TopAbstract IntroductionMethodsResultsDiscussionReferences |
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INTRODUCTION |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Although age affects the neural control of breathing, such as alterations in hypoxic or hypercapnic responses (Fukuda, 1991, 1992), little is known concerning the specific underlying neural mechanisms affected by age. In this study, we investigated the effects of age on a serotonin-dependent respiratory memory: long term facilitation (LTF) of respiratory motor output following episodic hypoxia.
Episodic hypoxia or electrical stimulation of carotid chemoafferent neurons elicits a long-lasting increase of respiratory motor output (i.e. LTF) in awake and anaesthetized mammals of several species (Millhorn et al. 1980a; Cao et al. 1992; Hayashi et al. 1993; Fregosi & Mitchell, 1994; Turner & Mitchell, 1997; Powell et al. 1998). In anaesthetized rats, LTF is commonly observed as an augmentation of integrated phrenic and hypoglossal (XII) nerve burst amplitude, with a smaller increase in burst frequency (Bach & Mitchell, 1996; Powell et al. 1998; Fuller et al. 2000). Serotonin receptor activation is necessary for LTF induced by episodic stimulation of the carotid sinus nerve (Millhorn et al. 1980b; Fregosi & Mitchell, 1994) or by episodic hypoxia (Bach & Mitchell, 1996; Kinkead & Mitchell, 1999). Furthermore, hypoxia-induced LTF requires 5-HT2 receptor activation during, but not following, episodic hypoxia in anaesthetized rats (D. Fuller, A. Zabka, T. Baker & G. Mitchell, unpublished observations). Thus, serotonin receptor activation is necessary to initiate, but not to maintain, LTF. Recent evidence suggests that the relevant serotonin receptors are within the respective motor nuclei since intraspinal administration of a serotonin receptor antagonist blocks phrenic, but not XII, LTF (T. Baker & G. Mitchell, unpublished observations).
The serotonergic system is influenced by age. For example, the number of serotonergic terminals, the concentrations of 5-HT and its metabolic products, 5-HT receptor density, and 5-HT reuptake protein are all affected by age, with considerable variation among different regions of the central nervous system (Van Luijtelaar et al. 1992; Ko et al. 1997). Age-related decreases in serotonergic innervation have been described in the XII nucleus of middle-aged male rats relative to young male rats (Behan & Brownfield, 1999). Although there is no specific information concerning age-associated changes in serotonergic innervation of the phrenic nucleus, 5-HT decreases with age in the dorsal and ventral horns of cervical spinal segments associated with the phrenic motor nucleus (Ko et al. 1997).
Since LTF is serotonin dependent, and serotonergic innervation decreases with age in XII and possibly in the phrenic motor nucleus, we tested the hypothesis that LTF in XII and phrenic nerve activity decreases with age in male rats. The results indicate that LTF is decreased in phrenic, and completely lost in XII, motor output in middle-aged male rats. Such an effect may be of significance to our understanding of age-associated changes in both respiratory and serotonergic function.
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METHODS |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Experimental groups
Experiments were conducted on male Sasco/Sprague-Dawley rats (Charles River Laboratories, Wilmington, MA, USA; rat colony K-62, Kingston, NY, USA). Two age groups were used for this study: young adults (n = 8, 3-4 months old, 374 ± 12 g; mean ± S.E.M.) and aged rats (n = 8, 13 months old, 601 ± 11 g). All experimental procedures were approved by the University of Wisconsin-Madison Animal Care and Use Committee.
Experimental preparation
Anaesthesia was initiated with isoflurane in an induction chamber and maintained (2.5-3.0 % isoflurane in 50 % O2, balance N2) first through a nose cone, and continued through a tracheal cannula placed to allow artificial ventilation (Small Animal Ventilator, Model 683, Harvard Apparatus Inc., Holliston, MA, USA). Rats were slowly converted to urethane (1.6 mg kg-1) through an intravenous catheter placed in a femoral vein. Supplemental urethane was administered as necessary to prevent blood pressure responses to toe pinch. Blood pressure was monitored through a femoral arterial catheter, and discrete blood samples (0.2 ml in a 0.5 ml heparinized glass syringe) were drawn to determine arterial blood gases (Pa,O2 and Pa,CO2), pH and base excess (ABL 500; Radiometer, Copenhagen, Denmark). Arterial blood values were corrected to the rectal temperature. Body temperature was maintained between 37 °C and 38 °C using a heated table.
To prevent spontaneous breathing efforts and interference with the ventilator, all animals were bilaterally vagotomized and paralysed (pancuronium promide, 2.5 mg kg-1 I.V.). End-tidal CO2 was measured with a flow-through capnograph (Capnogard, Novametrix; Wallingford, CT, USA), with sufficient response time to measure end-expiratory gases in rats.
The left phrenic and XII nerves were isolated via a dorsal approach, cut distally, desheathed, submerged in mineral oil and placed on bipolar silver wire electrodes. Nerve activities were amplified (X 10 000), band-pass filtered (100 Hz to 10 kHz) (Model 1700, A-M Systems, Inc., Carlsborg, WA, USA) and integrated (time constant = 50 ms, Model MA-821RSP, CWE Inc., Ardmore, PA, USA). Integrated nerve signals were digitized and processed with computer software (WINDAQ software, DATAQ Instruments, Akron, OH, USA). To terminate an experiment, rats were killed by an overdose of urethane (I.V.).
Experimental protocol
Nerve signals were allowed to stabilize for approximately 60 min following surgery under hyperoxic (Pa,O2 > 150 mmHg) and normocapnic conditions. The CO2 apnoeic threshold was then determined by increasing the ventilation rate to lower Pa,CO2 until phrenic nerve activity ceased, and then by decreasing ventilation until rhythmic phrenic nerve activity resumed. The latter value was assigned to be the apnoeic threshold. Baseline nerve activities were established by increasing Pa,CO2 2-3 mmHg above this CO2 apnoeic threshold. Baseline blood gas values were assessed before starting the protocol. All subsequent blood samples were compared to this initial baseline value. Strict isocapnic conditions (± 1 mmHg from baseline Pa,CO2) were maintained throughout an experiment by monitoring end-tidal CO2 and making adjustments in ventilation rate and/or inspired CO2 as necessary. To prevent alveolar atelectasis, lungs were hyperinflated approximately every 60 min.
A typical experimental protocol is illustrated in Fig. 1. The protocol started with three episodes of hypoxia of 5 min duration (FI,O2 = 0.12-0.13, target Pa,O2 35-45 mmHg), separated by 5 min intervals, and followed by 60 min of isocapnic hyperoxic baseline conditions. A protocol ended with 5 min of hypercapnia (PET,CO2 = 80-90 mmHg) to assess maximal nerve activity. Arterial blood samples were drawn at 15, 30 and 60 min after the final hypoxic episode to confirm isocapnic conditions. Rats were excluded from analysis if Pa,CO2 deviated by more than 1 mmHg from baseline. Therefore, changes in Pa,CO2 had minimal impact on the results of this study. Experiments were also excluded if arterial blood pressure dropped by more than 20 mmHg from baseline at the end of a protocol.
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MAP, mean arterial blood pressure (mmHg); the bracket indicates 0-150 mmHg. Marks indicate time points at which blood samples were taken and data were analysed: baseline (BL), last minute of first hypoxic episode (H1), 15, 30 and 60 min post-episodic hypoxia, and hypercapnic challenge (HC). The second and third hypoxic episodes are designated by H2 and H3. A, one example from a young male rat exhibiting an LTF of approximately 70 % in both nerves at 60 min post-episodic hypoxia. B, from an aged male rat, showing no LTF in either neurogram.
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Data analysis
Phrenic and XII nerve activities were recorded throughout the protocol. Peak integrated amplitude (
Phr and XII), burst frequency (bursts min-1), and mean arterial blood pressure (MAP) were measured at the following time points (Fig. 1): baseline, last minute of first hypoxic episode (short term hypoxic response), 15, 30, and 60 min after the final hypoxic episode, and the last minute of the hypercapnic response (max. CO2 response). Nerve activity was averaged over approximately 60 s in each condition. Changes in amplitude from baseline were normalized as a percentage of baseline nerve activity (% baseline) and as a percentage of the hypercapnic response (% maximum). All conclusions were the same, regardless of the normalization used with the one exeption that LTF in the XII neurogram was no longer significantly different at 30 min post-episodic hypoxia between young and aged rats when data were normalized as the percentage CO2 maximum. Thus, only percentage baseline data are presented in this paper. Changes in burst frequency were expressed as a difference from baseline in bursts per minute.
A two-way ANOVA with a repeated measure design (SigmaStat v. 2.0, Jandal Corporation, San Rafael, CA, USA) was performed, followed by a post hoc least significant difference test for individual comparisons. Differences were considered significant if P < 0.05. All data reported are means ± S.E.M.
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RESULTS |
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The CO2 apnoeic threshold was 4 mmHg lower in young than in aged rats. Through individual determinations of the CO2 apnoeic threshold, and establishing baseline conditions 2-3 mmHg above this level, we attempted to standardize our (relative) baseline conditions. Isocapnic conditions were successfully maintained at this baseline value throughout the protocols, thus preventing changes in Pa,CO2 from influencing phrenic or XII nerve activity (Table 1). The ratio of baseline/maximal CO2 response was not different between young and aged rats for phrenic nerve activity (YM = 0.5; AM = 0.5) and, thus, this factor should not have influenced our results. However, there was a difference in this same ratio for XII activity (YM = 0.3; AM = 0.5; P < 0.001) suggesting that the dynamic range was smaller in aged rats. During hypoxic episodes, Pa,O2 did not differ between young and aged rats (Pa,O2 = 37 ± 2 and 36 ± 1 mmHg, respectively). Phrenic and XII nerve activity responses to acute hypoxia were not different between the two groups (
Phr: YM = 87 ± 17 versus AM = 89 ± 15 % baseline; XII: YM = 160 ± 38 versus AM = 113 ± 21 % baseline; both P > 0.05).
Typical protocols in one young and one aged male rat, with tracings of phrenic and XII motor output and mean arterial blood pressure, are shown in Fig. 1. Mean data for post-hypoxia Phr, XII and burst frequency responses are shown in Fig. 2. In young rats, Phr increased progressively following episodic hypoxia, indicating the development of phrenic LTF (Fig. 2A). In aged male rats, phrenic LTF was significantly attenuated compared to young rats (P = 0.01). For example, 60 min post-hypoxia, the change in phrenic LTF in aged rats (Phr = 25 ± 8 %) was significantly less than in young rats (Phr = 56 ± 14 %; P < 0.05).
XII also increased progressively following episodic hypoxia in young male rats, indicating the presence of XII LTF (P < 0.05); however, LTF was not observed in aged male rats (P > 0.05; Fig. 2B). At 60 min post-hypoxia, XII LTF was significantly greater in young than in aged rats (XII = 73 ± 16 and 4 ± 7 %, respectively; P < 0.05). LTF in the XII nerve of aged rats was completely abolished; there was no statistically significant change from baseline nerve activity at any time post-episodic hypoxia. Following hypoxic episodes, there were no significant changes in burst frequency relative to baseline in either age group (both P > 0.05; Fig. 2C).
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 , YM) and 13 month (aged) male rats ( , AM)
LTF was measured as the increase from baseline in the peak amplitude of integrated phrenic (A) and XII (B) nerve activity (
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Aged rats were moderately hypertensive as compared to young rats (Fig. 3). MAP was significantly elevated in aged versus young rats before episodic hypoxia (116 ± 8 versus 90 ± 7 mmHg, P < 0.05), and 30 and 60 min following hypoxia (125 ± 8 and 108 ± 7 versus 96 ± 5 and 96 ± 5 mmHg, respectively; P < 0.05). During hypoxic episodes, MAP decreased in both groups, as is typical in hypoxic anaesthetized rats, but the decrease was not different between age groups.
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,YM) and 13 month (aged) male rats (, AM)
MAP was measured under baseline conditions (BL), during hypoxic episodes (H1, H2, H3), and 15, 30 and 60 min after the final hypoxic episode and was higher in aged rats at all time points. † Significant differences between groups (P < 0.05). Values are means ± S.E.M.
MAP was measured under baseline conditions (BL), during hypoxic episodes (H1, H2, H3), and 15, 30 and 60 min after the final hypoxic episode and was higher in aged rats at all time points. † Significant differences between groups (P < 0.05). Values are means ± S.E.M.
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DISCUSSION |
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Consistent with previous reports, episodic hypoxia elicits long term facilitation of phrenic and XII motor output in young male Sprague-Dawley rats from Sasco/Charles River (Bach & Mitchell, 1996; Fuller et al. 2000, 2001). LTF decreases dramatically with age in male rats. The decrease is more pronounced in XII versus phrenic nerve activity, leading to a complete abolition of XII LTF in aged male rats. These findings suggest an age-related deterioration of serotonergic modulation of respiratory motor output. This age-related effect seems particularly prevalent in upper airway function as exemplified by XII activity.
LTF, a form of respiratory motor plasticity, is in itself plastic. LTF is subject to considerable variation due to individual experiences or preconditioning treatments such as cervical dorsal rhizotomy (Kinkead et al. 1998; Bach et al. 2000) and chronic intermittent hypoxia (Ling et al. 1998). Genetic factors such as rat strain also influence the magnitude of LTF (Fuller et al. 2001). However, there is no existing information concerning variations of LTF with age and/or sex. To our knowledge, this is the first report concerning age-associated differences in any form of plasticity in respiratory motor control in adult mammals.
5-HT plays a pivotal role in the control of breathing (Bianchi et al. 1995; Bonham et al. 1995) and in the development of LTF (McCrimmon et al. 1995; Fuller et al. 2000). Thus, we suggest that decreasing LTF with age results from decreased capacity for serotonergic modulation within respiratory motor nuclei. Although Van Luijtelaar et al. (1992) demonstrated that the number of serotonergic neurons in the raphe nuclei was maintained in aged male rats, 5-HT immunoreactivity decreased with age in the XII motor nucleus (Behan & Brownfield, 1999), and 5-HT concentrations decrease in the cervical spinal segments associated with the phrenic nucleus (Ko et al. 1997). Based on these observations, we suspect that decreased serotonergic innervation in these respective areas reflects decreased capacity for serotonergic modulation. However, in addition to decreased serotonin terminal density, changes in the synthesis, release, reuptake and/or degradation of 5-HT, or reduced receptor density could also contribute to decreased serotonergic modulation within respiratory motor nuclei in aged male rats.
Under control (i.e. baseline) conditions, and at any time after episodic hypoxia, mean arterial blood pressure was elevated in aged as compared to young male rats. It is tempting to speculate that there is a link between hypertension in aged male rats and reduced serotonergic function. 5-HT has an inhibitory effect on sympathetic preganglionic neurons of the intermediolateral column of the spinal cord (Minson et al. 1990). Thus, if serotonergic innervation of the sympathetic preganglionic neurons were reduced, the inhibitory effect could be diminished, leading to increased sympathetic outflow, vasoconstriction and increase of blood pressure. However, the possible link between hypertension of aged male rats and reduced serotonergic modulation remains to be investigated.
In the XII motor output, there was a difference in the baseline/CO2 maximal response ratio suggesting that the potential XII response was smaller in aged rats. However, XII motor output in aged rats never exceeded baseline levels after episodic hypoxia, suggesting that a greater response range would not have changed the outcome. Regardless of the normalization method (percentage of baseline or CO2 maximal response), young rats had significantly greater phrenic and XII LTF 60 min post-episodic hypoxia when compared to aged rats.
The lack of hypoxia-induced LTF in aged male rats reflects an inability to respond normally to repetitive hypoxic challenges. Further, it reflects an age-related deterioration in the capacity for modulation of respiratory motor output. Although the physiological role of LTF or the consequences of its loss remain unclear, we speculate that age-related loss of serotonin-dependent LTF may contribute to age-related breathing disorders such as sleep disordered breathing. Sleep-related breathing disorders, particularly obstructive sleep apnoea, occur mainly in the male population and their incidence increases with age (Hla et al. 1994; Ware et al. 1999). If the normal role of LTF in upper airway muscles is to increase upper airway tone, it might offset the tendency for airway collapse in individuals predisposed to obstructive apnoea because of congenitally narrowed airways (Sforza et al. 2000). Further, chronic repetitive apnoeas may exaggerate LTF in young adults (Ling et al. 1998), thereby increasing compensation for an already compromised airway. However, this compensatory strategy may be lost with age, predisposing subjects to further apnoeas (Babcock & Badr, 1998). These ideas remain speculative and must be tested directly. However, they do imply that age-dependent effects on LTF may be quite different in females, since obstructive sleep apnoea has minimal prevalence in women until the onset of menopause (Bixler et al. 2000).
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Acknowledgements
This study was supported by NIH grants NHLBI 53319, 36780 and 65383.
Corresponding author
G. S. Mitchell: Department of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin, 2015 Linden Drive West, Madison, WI 53706, USA.
Email: mitchell{at}svm.vetmed.wisc.edu
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G. S. Mitchell, T. L. Baker, S. A. Nanda, D. D. Fuller, A. G. Zabka, B. A. Hodgeman, R. W. Bavis, K. J. Mack, and E. B. Olson Jr. Physiological and Genomic Consequences of Intermittent Hypoxia: Invited Review: Intermittent hypoxia and respiratory plasticity J Appl Physiol, June 1, 2001; 90(6): 2466 - 2475. [Abstract] [Full Text] [PDF]
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