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Department of 1 Physiology, School of Medicine of Ribeirão Preto, University of São Paulo, 14049-900, Ribeirão Preto, SP, Brazil
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(Received 22 June 2006;
accepted after revision 30 August 2006; first published online 7 September 2006)
Corresponding author B. H. Machado: Department of Physiology, School of Medicine of Ribeirão Preto, University of São Paulo, 14049-900, Ribeirão Preto, SP, Brazil. Email: bhmachad{at}fmrp.usp.br
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Introduction |
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Although several studies involving CIH have been conducted in adult rats (Fletcher et al. 1992a, 1992b; Greenberg et al. 1999; Fletcher, 2001; Peng et al. 2003; Prabhakar et al. 2005), studies performed by McGuire & Ling, 2005) have demonstrated that the ventilatory long-term facilitation is greater in 1-month-old than in 2-month-old rats, indicating that, in the first weeks of life, rats are more susceptible to changes in the central nervous system in response to CIH. In addition, Bisgard et al. (2003) demonstrated that the initial 4 weeks of life are critical for the maturation of the carotid body and chemoreflex responses, since adults rats exhibited an attenuation of the ventilatory and phrenic responses to acute hypoxia when they had previously been exposed to hyperoxia throughout the period of 1–4 weeks of age. However, the possible changes experienced by juvenile rats just after exposure to chronic intermittent hypoxia, especially on the autonomic and respiratory responses to acute chemoreflex activation, are not yet established.
Taking into consideration that normoxia is required for normal maturation of chemoreflex responses during the first weeks of life (Bisgard et al. 2003), we hypothesized that juvenile rats (21 days old) exposed to chronic intermittent hypoxia could develop important changes in the cardiovascular and respiratory responsiveness to acute chemoreflex activation. In this way, we were able to test the hypothesis that chemoreflex responsiveness would be enhanced after juvenile rats were previously exposed to 10 days of CIH. To attain this goal, we performed experiments on the working heart–brainstem preparation (WHBP), which allows us to record heart rate (HR), phrenic nerve discharge (PND) and thoracic sympathetic nerve activity (tSNA), as well as to evaluate the changes in these parameters in response to acute peripheral chemoreflex activation with potassium cyanide (KCN). Another important advantage of using this experimental approach is the fact that the WHBP is an in situ unanaesthetized preparation.
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Methods |
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The Institutional Ethical Committee for Animal Experimentation of the School of Medicine of Ribeirão Preto, University of São Paulo, approved the procedures and experimental protocols used in this study.
Chronic intermittent hypoxia
Three-week-old rats were divided in two experimental groups: the CIH group (n = 12), in which rats were exposed to intermittent hypoxia, and the control group (n = 12), in which rats were maintained under normoxic conditions in similar chambers to those used for the CIH group. Rats were housed in collective cages (maximum of 6 animals per cage) and maintained inside Plexiglass chambers (volume, 210 l) equipped with gas injectors as well as sensors for O2, CO2, humidity and temperature. The CIH protocol consisted of 5 min of normoxia [inspired oxygen concentration (FIO2) of 20.8%] followed by 4 min of N2 (100%) injection into the chamber in order to reduce the FIO2 from 20.8 to 6% (which took about 200 s), remaining at this level for 40 s. After this period of hypoxia, O2 (100%) was injected to return the FIO2 back to 20.8%. This cycle of 9 min was repeated for 8 h day–1 (from 9.30 am to 5.30 pm) for 10 days. During the remaining 16 h, the animals were maintained at an FIO2 of 20.8%. The N2 and O2 injections were regulated by a solenoid valve system, the opening and closing of which was controlled by a computerized system (Oxycycler, Biospherix, Redfield, NY, USA). In other chambers, in the same room, the control group was exposed to an FIO2 of 20.8% for 24 h day–1 for 10 days. In both CIH and control chambers, the gas injections were performed at the upper level of the chamber in order to avoid direct jets of gas streaming into the cages at the level of the animals, thereby avoiding unnecessary stress.
Measurement of body weight
Rats were weighed every 2 days in order to determine the body weight gain over the 10 days of CIH.
General experimental procedures
The experiments were performed in an in situ unanaesthetized decerebrated working heart–brainstem preparation (WHBP), as previously described by Paton (1996). Rats were anaesthetized deeply with halothane (AstraZeneca do Brazil Ltda., Cotia, SP, Brazil) in a small chamber, and the level of anaesthesia was assessed by absence of response to a noxious pinch of either the paw or the tail. Following subdiaphragmatic transection (performed under the effect of anaesthesia), the rostral half of the animal was submerged in cooled (3–5°C) carbogen gassed (95% O2 and 5% CO2) artificial cerebrospinal fluid (ACSF), decerebrated at the precollicular level and skinned. The descending aorta was isolated, and the heart exposed by removal of the left ribs and the lungs. The dorsal surface of the brainstem was exposed by removal of the occipital bone and cerebellum. Then, the WHBP was moved to a recording chamber, and the descending aorta was cannulated and perfused retrogradely with ACSF (mM): NaCl, 125; NaHCO3, 24; KCl, 5; CaCl2, 2.5; MgSO4, 1.25; KH2PO4, 1.25; dextrose, 10; and oncotic agent (Ficoll® 70, 1.25%; Sigma, St Louis, MO, USA) using a roller pump (Watson-Marlow 502s, Falmouth, UK) via double-lumen cannula. A neuromuscular blocker (vecuronium bromide, 0.04 mg ml–1, Norcuron Organon Teknika, Sao Paulo, Brazil) was used to prevent chest wall respiratory movements. Perfusion pressure was maintained within a narrow range (50–70 mmHg) by adjusting the flow rate of the perfusion pump. The perfusate was gassed with carbogen continuously, warmed to 32°C and filtered using a nylon mesh (pore size, 25 µm; Millipore, Bellerica, MA, USA). Due to perfusion, via aorta, all the tissues including those on external surface were properly irrigated and consequently kept moist.
Recordings of electrocardiogram and nerve activities
Left phrenic nerve activity was recorded from its central end using a glass suction electrode held in a micromanipulator (Narishige, Tokyo, Japan). Rhythmic ramping phrenic nerve discharge (PND) gave a continuous physiological index of the viability of the preparation. The electrocardiogram (ECG) was visible on the phrenic nerve recording, which allowed us to evaluate the heart rate (HR) by using a low-pass filter. Sympathetic nerve activity (tSNA) was recorded from the thoracic sympathetic chain at the level of T5–T10 using a second glass suction bipolar electrode. Signals were AC amplified, bandpass filtered (8 Hz to 3 kHz) and displayed on a computer using the software Spike 2 (Cambridge Electronic Design, Cambridge, UK).
Acute activation of peripheral chemoreceptors
Potassium cyanide solution (0.05 ml of 0.05% solution) was injected into the descending aorta of the WHBP via the perfusion cannula to excite peripheral chemoreceptors, as previously described (Paton et al. 1999, 2002; Antunes et al. 2005; Braga & Machado, 2006).
Data analysis
All data were analysed off-line using Spike 2 software with custom-written programs. Baseline and peak HR reflex responses were measured. The frequency of bursts of the PND was measured in a time-dependent way (counted each 10 s, starting 40 s before the microinjection and ending 50 s after microinjection of KCN). The rectified and integrated signals of the tSNA (100 ms time constant) were measured for a period covering 10 s before and 10 s after chemoreflex activation. Data of tSNA were normalized as a percentage of control values, and changes in the tSNA during chemoreflex stimulation were calculated as the difference between the peak of the response and the baseline measured before each stimulus, as previously described (Braga & Machado, 2006; Braga et al. 2006). The statistical significance of the changes was assessed by one-way ANOVA followed by Tukey's post hoc test (P < 0.05 accepted as significant) to evaluate the changes in the tSNA and HR after chemoreflex activation. To evaluate the time course responses in the frequency of PND, the significance of effects was assessed by two-way ANOVA followed by Tukey's post hoc test (P < 0.05 accepted as significant). All values are expressed as the means ±S.E.M., and n is the number of preparations.
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Figure 1A shows representative traces from one WHBP that illustrate the changes in the frequency of the PND (raw and integrated), HR and tSNA (integrated and raw) in response to chemoreflex activation after rats were exposed to 10 days of CIH. Figure 1B shows equivalent representative traces from a control rat. Note that after peripheral chemoreflex activation there is an intense bradycardia, an increase in the frequency of the phrenic nerve discharge and a significant increase in the thoracic sympathetic nerve activity, which are the responses typical of peripheral chemoreflex activation.
Effect of CIH on the sympathoexcitation elicited by chemoreflex activation
The chemical stimulation of the peripheral chemoreceptors using potassium cyanide in control rats produced an increase in the tSNA of 48 ± 2% (n = 12). The same dose of potassium cyanide elicited a greater increase in the tSNA in the CIH than in the control group (79 ± 4%, n = 12). The significant difference between groups (P < 0.001) presented in Fig. 2 indicates that the responsiveness of the tSNA to activation of the peripheral chemoreceptors in CIH rats is enhanced. The injection of saline (vehicle control, 0.05 ml) into the descending aorta of the WHBP produced negligible effect on the parameters recorded (data not shown).
Effects of CIH on the basal heart rate and on the bradycardic response to chemoreflex activation
Rats exposed to 10 days of CIH exhibited an increase in the basal HR when compared with the control group (414 ± 25 versus 306 ± 24 beats min–1, P < 0.0023; Fig. 3A). In addition, the bradycardic response elicited by the chemical stimulation of the peripheral chemoreceptors using potassium cyanide was greater in the CIH than in the control rats (–218 ± 20 versus –163 ± 16 beats min–1, P < 0.0443; Fig. 3B).
Effect of CIH on the basal frequency of PND and on PND in response to chemoreflex activation
Figure 4 summarizes the changes in the frequency of PND on time domain in response to chemoreflex activation after rats were exposed to 10 days of CIH or in control conditions. Note that there is no difference in the baseline of the frequency of PND between CIH and control groups (n.s.). At 10 s after the chemoreflex activation, the magnitude of the ventilatory response was similar in both CIH and control groups (0.62 ± 0.03 versus 0.55 ± 0.03 Hz, n.s.). However, at 20 and 30 s after the stimulus, the frequency of the PND of CIH rats remained significantly elevated when compared with the control group (0.52 ± 0.03 versus 0.35 ± 0.03 Hz and 0.40 ± 0.02 versus 0.31 ± 0.03 Hz, respectively, both P < 0.001), characterizing the presence of an increase in the PND responsiveness to chemical stimulation of the peripheral chemoreceptors.
Effect of 10 days of CIH on body weight
In order to avoid major differences in the final body weight gain, at the beginning of their respective protocols (CIH or control), rats had a very close body weight (49 ± 2 g). Juvenile rats submitted to 10 days of CIH presented lower body weight gain when compared with the control group (50 ± 2 versus 65 ± 3 g, P < 0.05), suggesting that the growth rate was compromised by the chronic hypoxic stimulus.
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Discussion |
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The most important finding of the present study is the significant increase in the sympathetic responsiveness to acute chemoreflex activation in juvenile rats previously submitted to 10 days of CIH. Several studies in the literature support the concept that in the first weeks of life, CIH is more effective in producing changes in the central nervous system. For instance, McGuire & Ling (2005) demonstrated that the long-term facilitation of ventilatory responses is greater in 1-month-old rats than in 2-month-old rats. In addition, Bisgard et al. (2003) demonstrated that the initial 4 weeks of life are critical for the maturation of the carotid body and chemoreflex responses, since adult rats exhibited an attenuation of the ventilatory and phrenic responses to acute hypoxia when they had previously been exposed to hyperoxia throughout the period of 1–4 weeks of age. Moreover, studies performed in rats exposed to CIH during the first 30 days of life showed a reduction in the number of neurones receiving vagal and glossopharyngeal projections in the nucleus tractus solitarii (NTS) and nucleus ambiguus, as well as an increase in the number of neurones receiving projections in the rostral ventrolateral medulla (RVLM; Reeves et al. 2006). These are important anatomical lines of evidence that alterations within selected brainstem nuclei may develop after CIH. Thus, early postnatal environmental exposures, including CIH, may lead to long-term alterations in cardiorespiratory control.
Although the mechanisms underlying CIH-induced changes in the central nervous system in mediating the increase in the sympathoexcitatory response to chemoreflex activation are unclear, we have some evidence to believe that changes might occur at different levels in the central nervous system as well as in the peripheral sensory system. Studies performed in adult rats have suggested that the carotid body cells show an increase in their sensitivity after CIH, and reactive oxygen species seem to be involved in this process (Peng et al. 2003; Prabhakar et al. 2005). Moreover, another possible site where the modulation of the sympathetic activity might occur is the RVLM. Neurones located in the RVLM project to the intermediolateral cell column in the spinal cord and are excited when peripheral chemoreceptors are stimulated. These RVLM neurones are critical for the maintenance of resting arterial pressure and important to the sympathoexcitatory response of the chemoreflex (Reis et al. 1994). In addition to RVLM, evidence for plasticity in brainstem neurones comes from studies demonstrating that mRNA levels of tyrosine hydroxylase are increased in neurones of the caudal NTS after hypoxia (Dumas et al. 1996). Although the carotid body cells, spinal cord, NTS and RVLM neurones seem to be involved in the facilitation of the sympathoexcitatory response to chemoreflex activation, at this point we cannot determine the sites in the central nervous system that contribute to this facilitation.
Studies by Greenberg et al. (1999) documented that chronic intermittent hypoxia increases sympathetic responsiveness to hypoxia and hypercapnia. However, some considerations need to be addressed at this point. First, their hypoxic protocol was different from that used in the present study. They exposed adult rats for 30 days to hypoxia in a protocol in which the animals were exposed to 10% O2 only for 5–7 s every minute, while in the present study, we employed a protocol in which juvenile rats were submitted to 6% O2 for 40 s every 9 min for 8 h day–1 over 10 days. An indicative aspect of the efficacy of our protocol is the fact that our rats submitted to 10 days of CIH presented a lower body weight gain in relation to control animals. Second, Greenberg et al. (1999) did not find any difference in the baseline of the heart rate or in the bradycardia elicited by chemoreflex activation. One possible explanation for these differences is that Greenberg et al. (1999) used adult rats (2-month-old rats), compared with the 3-week-old rats used in the present study. There is evidence in the literature that the responsiveness to CIH is more intense in 1-month-old rats than in 2-month-old rats (McGuire & Ling, 2005). Therefore, the observations of the present study extend the findings of previous studies that not only the sympathetic but also the bradycardic response and the duration of the augmentation in the frequency of the phrenic nerve discharge to chemoreflex activation were significantly increased in CIH rats submitted to a new and acute chemical stimulation of the peripheral chemoreceptors.
Although the dose of KCN used to activate chemoreceptors in both CIH and control groups was the same, the greater increase in the sympathetic response to chemoreflex activation cannot be attributed to the significant difference in body weight between groups (CIH, 99 ± 5 g versus control, 114 ± 5 g, P < 0.05). Recently, we demonstrated that chemoreflex activation in rats weighing 70–90 g resulted in an increase in the tSNA of about 50% (Braga & Machado, 2006), which is similar to that observed in the control group in the present study. Thus, the greater increase in the sympathoexcitatory response to chemoreflex activation in juvenile rats submitted to CIH results from an increased responsiveness to chemoreflex activation.
In addition to the increase in the sympathetic responsiveness to chemoreflex activation in CIH rats, we demonstrated that the bradycardic response to acute hypoxia was also greater in CIH rats when compared with control animals. One possible explanation for this is the fact that the basal heart rate is increased after 10 days of CIH, suggesting that the parasympathetic outflow is somehow compromised in the resting condition. We might, at this point, dissociate these two different aspects of parasympathetic function (resting and during hypoxia). In the resting condition, the baroreflex control (beat to beat) is affected by CIH, which is characterized by a reduction in the number of axonal varicosity terminals around cardiac ganglionic neurones involved in the baroreflex control, suggesting that vagal activity is reduced (Soukhova-O'Hare et al. 2006). During chemoreflex activation, however, another pool of vagal fibres would be recruited to increase the parasympathetic outflow to the heart, facilitating the bradycardia elicited by this challenge. Whether the parasympathetic outflow is overactive in CIH rats only during chemoreflex activation, leading to a greater bradycardia when compared with the control group, remains a matter for further investigation.
In relation to the changes in the frequency of phrenic nerve discharge in response to chemoreflex activation, our findings show that CIH produces a significant long-lasting increase in the frequency of PND, which is in accordance with previous studies (Ling et al. 2001; McGuire et al. 2003; Prabhakar & Peng, 2003). The facilitatory effect of CIH on the hypoxic sensory response has been attributed to a potentiation of carotid body chemosensory responses to hypoxia (Prabhkar & Peng, 2003). Recent studies by Jacono et al. (2005) have demonstrated that the prolongation of the hypoxic sensory response involves 5-HT2 receptors, since ketaserin, a 5-HT2 antagonist, completely prevented the 5-HT-induced prolongation of the hypoxic sensory response in preparations of ex vivo carotid bodies harvested from anaesthetized adult rats. In addition to the possible increase in the O2 sensitivity of the arterial chemoreceptors determining the increase in the hypoxic sensory response and the role of 5-HT2 receptors in the prolongation of this response, we cannot exclude the possibility that areas of the central nervous system related to the processing of afferent information from arterial chemoreceptors, such as the NTS, are also involved in this response. Further studies are required, however, to determine the effective sites and neurotransmitters involved in the increase of the hypoxic sensory response observed in our study.
In conclusion, we demonstrated that juvenile rats previously exposed to 10 days of chronic intermittent hypoxia and then subjected to acute chemoreflex activation exhibit a significant increase in sympathetic responsiveness, as well as in bradycardia, and a long-lasting increase in the frequency of phrenic nerve discharge compared with control animals. In rats, this intermittent hypoxic stimulus seems to produce, in addition to well-documented changes in the glomus cells of the carotid body, important changes in the neuronal pathways involved in autonomic and respiratory control, which allow greater responses when they are submitted to chemical stimulation of the peripheral chemoreceptors. The neurochemical mechanisms in the brainstem underlying these important autonomic and respiratory changes are presently under investigation in our laboratory.
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References |
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