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Department of Environmental Health, Life Science and Human Technology, Nara Women's University, Kita-Uoya Nishimachi, Nara, 630-8506, Japan
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(Received 15 March 2004;
accepted after revision 4 June 2004;
first published online 11 June 2004)
Corresponding author K. Miki: Department of Environmental Health, Life Science and Human Technology, Nara Women's University, Kita-Uoya Nishimachi, Nara, 630-8506, Japan. Email: k.miki{at}cc.nara-wu.ac.jp
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Introduction |
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The aim of the present study was to generate the entire baroreflex stimulus–response curve for sympathetic nerve activity during the natural sleep–wake cycle in rats. To achieve this aim, rats were chronically instrumented for determination of vigilance state, cardiovascular function and renal sympathetic nerve activity (RSNA). Artificial changes in Pa were made by intravenous administration of vasoactive drugs during NREM, REM sleep and grooming state. The entire baroreflex curve for RSNA and HR was quantified by fitting the data to a logistic model. In this way, we studied the hypothesis of whether baroreflex control of RSNA could be altered in a state-dependent manner.
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Methods |
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Experiments were performed on 12 adult female Wistar rats weighing 267.9 ± 2.8 g (mean ±S.E.M.). Animals were housed individually and kept in a temperature (24°C)- and humidity (60%)-controlled chamber with a 12 h: 12 h light–dark cycle (light on at 07.00 h) (Espec, Osaka, Japan). Food and water were available ad libitum. All procedures were in accordance with the Guiding Principles in the Care and Use of Animals in the Fields of Physiological Sciences published by the Physiological Society of Japan (Physiological Society of Japan, 2002) with the prior approval of the Animal Care Committee of Nara Women's University.
Instrumentation of animals
The animals were operated on in two stages. All procedures were performed aseptically in an operating theatre. The rats were anaesthetized with pentobarbital sodium (45 mg kg–1 I.P.). During the first surgical procedure, the electroencephalogram (EEG), electrocardiogram (ECG), and electromyogram (EMG) electrodes were implanted. EEG electrodes were implanted over the frontal cortex (anteroposterior +2 mm, mediolateral –2 mm from bregma), the parietal cortex (anteroposterior –3 mm, mediolateral –2 mm from bregma) and over the cerebellum (1.5 mm posterior to lambda). Three stainless steel miniature screws (1.0 mm diameter), which served as electrodes, were screwed into the skull and secured with dental cement. The bipolar EMG electrodes were implanted bilaterally in both trapezius muscles. The bipolar ECG electrode was implanted under the skin at the manubrium of the sternum and xiphoid process. The electrodes were exteriorized between the ears and passed through the centre of a circled-cut Ducron sheet, fixed into place and sutured to the skin.
At least 5 days after the first surgery, the catheters and electrodes were implanted as described in our previous reports (Miki et al. 2002, 2003b). Briefly, the arterial catheter was placed into the abdominal aorta via the tail artery. Two small venous catheters were placed into the superior vena cava via the common jugular vein. A pair of 60 cm polyethylene tubes (PE 10, Intramedic, Sparks, MD, USA) were tied and advanced into the superior vena cava so that the tips lay just above the right atrium. One of the venous catheters was used for the infusion of phenylephrine hydrochloride and the other for sodium nitroprusside infusion. RSNA was recorded from an implanted bipolar electrode. The left kidney was exposed retroperitoneally through a left flank incision, a branch of the renal nerve running on or beside the renal artery was carefully isolated, bipolar stainless steel wire electrodes were hooked onto the nerve and both were embedded in a two-component silicone rubber (see Miki et al. 2002 for full details). The electrodes and catheters were also exteriorized between the ears and protected by a plastic tube.
On completion of surgery, antibiotics were given intraperitoneally (Fradiomycin, Mochida-Seiyaku, Tokyo, Japan). A blanket and jelly were provided after the surgery. Animals were examined at least twice a day. The examination score included posture, activity, breathing, coat and eyes, body weight, food intake, urine volume, faecal volume. For the control of postoperative pain, a non-steroidal anti-inflammatory drug (diclofenac sodium, Voltaren; 0.5–3 mg kg–1, Novartis Japan, Tokyo, Japan) mixed with jelly was given orally when necessary. Arterial and venous catheters were filled with heparin sodium solution (1000 i.u. ml–1) and were flushed every day. The animals were housed individually in transparent plastic cages and allowed standard laboratory rat chow and water ad libitum thereafter. We terminated experiments if the body weight of the animal decreased by more than 20% of the pre-surgical body weight. In the present study, no such situation arose. At the end of the study protocol, rats were humanely killed using an intravenous overdose of pentobarbital sodium (> 200 mg kg–1).
Measurements
EEG, ECG, EMG and RSNA signals were amplified by a differential amplifier (MK-2, Biotech, Kyoto, gain: x 10 000 and bandwidth: 0.16–50 Hz for EEG; gain: x 1000 and bandwidth: 0.16–150 Hz for ECG; gain: x 100 and bandwidth: 100–2000 Hz for EMG; gain: x 10 000 and bandwidth: 150–2000 Hz for RSNA). Pa was measured by connecting the arterial catheters to pressure transducers (DX-100, Nihon Kohden, Tokyo). Heart rate (HR) was determined with a cardiotachometer (AT-601G, Nihon Kohden, Tokyo) triggered by the ECG. The amplified RSNA was integrated using a voltage integrator with a time constant of 100 ms (AD-600G, Nihon Kohden, Tokyo, Japan). The signals for ECG, EEG, EMG, Pa, HR, RSNA, and integrated RSNA were displayed continuously on an oscilloscope and recorded simultaneously on a thermal head paper recorder (ORP1200, Yokogawa, Tokyo, Japan) and a magnetic tape recorder (RX-8016, TEAC, Tokyo, Japan). The EEG, EMG, Pa, HR and integrated RSNA signals were sampled for analog-to-digital conversion at 1 ms intervals. The digitized EEG signal was Fourier analysed in 1 s epochs using a computerized data acquisition program (Visual Designer 4.0, Intelligent Instrumentation, Tucson, AZ, USA). The power spectrum was averaged simultaneously in two frequency bands: delta (0.5–4 Hz) and theta (6–9 Hz). The digitized EMG signal was simultaneously converted to the mean square root value. With the aid of the data acquisition program (Visual Designer 4.0), data for the power spectrums of EEG, Pa, the root mean square value of EMG, HR and integrated RSNA were averaged simultaneously and continuously every 1 s, displayed on the computer monitor, and stored on a hard disk.
Experimental protocols
After surgery, rats were allowed a minimum of 3 days to recover. Experiments were performed with the animals in their home cage, and they were given free access to food and water. Each experiment was performed over 2 or 3 h following an hour's rest after all electrodes, probes and catheters had been connected to a measuring instrument. The behaviour of the animal was monitored by the investigator through a small acrylic window of the chamber.
Behavioural patterns were classified as REM sleep, NREM sleep, and grooming by the investigators based on the EEG, EMG data displayed on the computer monitor and visual observation throughout the experimental period. During REM sleep, the EEG was characterized by the predominant theta activity and there was a dramatic suppression of the EMG. During NREM sleep, the EEG amplitude was larger and dominated by both delta and theta-frequency components and the EMG was low. Grooming behaviour was identified by visual observation.
To quantify baroreflex control of HR and RSNA, artificial perturbations to Pa were made by intravenous bolus infusions of phenylephrine hydrochloride (10 µg in 200 µl saline solution over 40 s) to increase Pa up to 
170 mmHg, and sodium nitroprusside (10 µg in 200 µl saline solution over 40 s) to decrease Pa to 60 mmHg, during each state. Figure 1 depicts typical recordings of ECG, EEG, EMG, Pa, HR, RSNA and integrated RSNA obtained during REM sleep with pharmacological manipulations of Pa. Since the REM sleep periods lasted 30–90 s in most instances, the pharmacological manipulations were undertaken in separate REM episodes. The data for the RSNA and HR responses to the infusions of phenylephrine and nitroprusside were pooled for each experiment and then fitted to the sigmoidal logistic equation.
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A logistic sigmoid function described by Kent et al. (1972) was used to analyse baroreflex curves:
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The maximum response is the upper plateau of the curve. Pa,thr and Pa,sat are the Pa at which HR or RSNA was within 5% of its maximum or minimum response, respectively. The operating range implies the range of Pa over which HR and RSNA responded.
To avoid the effects of uneven density of Y (HR or RSNA) axis data along the X (Pa) axis, all data were averaged over each 5.0 mmHg bin of Pa. Mean values of RSNA, HR and Pa within every 5.0 mmHg bin of Pa were used for curve fitting. Baroreflex response curves were constructed, and their parameters were calculated for each trial of the pharmacological manipulation of arterial pressure in each animal and then averaged across the animals. The averaged A1, A2, A3 and A4 were then used to generate average baroreflex curves (Figs 3 and 4) and first derivatives of the curves (Fig. 5).
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Statistical analysis was performed using analysis of variance (ANOVA) for repeated measures. When the F values were significant (P < 0.05), individual comparisons were made using the Fisher's least significant difference test (Sachs, 1982). Values are reported as means ±S.E.M.P < 0.05 was taken to indicate a significant difference.
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Results |
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The shift in the baroreflex curve for RSNA (Fig. 3, Tables 1 and 2) observed during grooming was greater than that during REM sleep, causing significant increases in the minimum response (by 24.7%, P < 0.05), the response range (by 92.5%, P < 0.05), the maximum response (by 117.1%, P < 0.05), Pa,thr (by 12.7 mmHg, P < 0.05), the centring point (A3, by 9.9 mmHg, P < 0.05) and the maximal gain (by 5.43 mmHg–1, i.e. 59.5%, P < 0.05; Fig. 5A).
Grooming shifted the baroreflex curve for HR upward relative to NREM sleep (Fig. 4, Tables 1 and 2); the parameters relating to the shift in the Y-axis, the maximum and minimum responses, increased by 38.0 beats min–1 (P < 0.05) and by 61.2 beats min–1 (P < 0.05), respectively, while the response range decreased by 23.2 beats min–1 (P < 0.05); as to the parameters relating to the shift in the X-axis, Pa,thr increased by 10.5 mmHg (P < 0.05) while Pa,sat did not change, resulting in a reduction of the operating range by 9.7 mmHg (P < 0.05); the gain coefficient and the maximal gain, which depend on the response range and operating range, increased significantly, by 0.051 mmHg–1 (i.e. 41.1%, P < 0.05) and 1.49 beats min–1 mmHg–1 (i.e. 31.6%, P < 0.05, Fig. 5B), respectively.
When the baroreflex curve for HR obtained during grooming was compared with the curves obtained during REM sleep (Fig. 4, Tables 1 and 2) and NREM sleep, the magnitude of the shift was similar. Thus there were significant increases in the minimum response (A4, by 66.8 beats min–1, P < 0.05) and the maximum response (by 49.9 beats min–1, P < 0.05), with no changes in the response range; Pa,thr increased by 9.5 mmHg (P < 0.05) but there were no changes in Pa,sat, resulting in the operating range being decreased by 9.0 mmHg (P < 0.05), which in turn caused an increase in the maximal gain by 1.58 beats min–1 mmHg–1 (i.e. 41.9%, P < 0.05, Fig. 5B).
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Discussion |
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Shift in baroreflex curve for RSNA
REM sleep results in a profound state-dependent modulation of Pa and HR, suggesting that sympathetic nerve activity plays a crucial role in modulating Pa and HR during this state (Baust et al. 1968; Futuro-Neto & Coote, 1982; Parmegianni & Morrison, 1990). Indeed, in the present study, the average level of RSNA decreased significantly by 42.0% during REM sleep relative to NREM sleep, which is consistent with previous report in cats (Baust et al. 1968; Futuro-Neto & Coote, 1982) and rats (Miki et al. 2003a). There is a lack of data on the full range of baroreflex curve parameters for RSNA during REM sleep. We demonstrated in the present study that REM sleep shifted the Pa–RSNA baroreflex curve downward, which could explain the decrease in the average level of RSNA during REM sleep. Because the entire baroreflex curve for Pa–RSNA during REM sleep was simply shifted downward without altering the minimum response or any parameters related to a horizontal shift (Figs 3 and 5A), the outcome was that RSNA during REM sleep was lower relative to NREM sleep when the systemic arterial pressure was below 110 mmHg.
By contrast, grooming shifted the Pa–RSNA baroreflex curve to the right and upward compared to the curve obtained during NREM sleep (Fig. 3), which is essentially consistent with previous reports during moderate exercise in humans (Fadel et al. 2001; Kamiya et al. 2001) and during treadmill exercise in the rat (Miki et al. 2003b). It is well established that sympathetic nerve activity increases during exercise in the rat (Miki et al. 2002, 2003b), rabbit (O'Hagan et al. 1993), cat (Matsukawa et al. 1991) and man (Fadel et al. 2001; Kamiya et al. 2001). In agreement with previous studies, we observed an increase in RSNA by 49.9% during grooming, which could be well explained by the right and upward shift of the Pa–RSNA baroreflex curve induced by grooming (Fig. 3). This shift in the Pa–RSNA baroreflex curve during grooming would cause the RSNA to increase at all levels of Pa compared with that during NREM sleep. Although, the increase in Pa occurring during grooming would act to suppress RSNA via the baroreflex, it was not sufficient to overcome the rise in RSNA caused by the acute shift of the Pa–RSNA baroreflex curve. This could explain the simultaneous increases in Pa and RSNA during grooming. Together, the above results demonstrated that baroreflex control of RSNA is most likely altered acutely in a state-dependent manner (Figs 3 and 5A), influencing the average level of RSNA during REM sleep, NREM sleep and grooming.
Shift of baroreflex curve for HR
The sensitivity of the baroreflex control of HR during REM sleep has been estimated by a linear regression analysis between Pa and HR, obtained during either spontaneous Pa and HR fluctuations or infusion of vasoactive drugs in rats (Zoccoli et al. 2001), cats (Knuepfer et al. 1986), and men (Nakazato et al. 1998; Legramante et al. 2003). The sensitivity of the baroreflex control of HR during REM sleep has been reported not to change (Nakazato et al. 1998; Zoccoli et al. 2001) or to decrease (Knuepfer et al. 1986). The present study successfully described the full range of the baroreflex curve for HR and demonstrated that the Pa–HR baroreflex curve generated in REM sleep was almost identical to that measured during NREM sleep (Figs 4 and 5B). These data indicate that the sensitivity of the baroreflex control of HR remains unchanged during REM sleep, and are consistent with previous reports in the rat (Zoccoli et al. 2001), where baroreflex-mediated fluctuations in HR (BRSP) did not change during REM sleep, and in the human (Nakazato et al. 1998), where the relationship between heart beat interval and systolic blood pressure remained unchanged during REM sleep. It is of interest that the operating pressure (112.6 mmHg) during REM sleep observed in the present study, which denotes an average level before pharmacological manipulation of Pa, was depressed to a point below the centring pressure (124.3 mmHg), where the gain is maximal (Fig. 5B). This may be one of the reasons why the slope of the regression line between Pa and HR obtained during a dynamic increase in Pa was different from that obtained during the descending phase of Pa, when Pa and HR fluctuate spontaneously (Legramante et al. 2003). If the baroreflex sensitivity for HR is estimated using a linear regression method, when Pa changes within only a part of the operating range, the estimated slope (baroreflex sensitivity) would be different, even though the full range of the Pa–HR baroreflex curve remains unchanged. This may explain, in part, the inconsistent reports on the sensitivity of baroreflex control for HR during REM sleep in previous reports (Knuepfer et al. 1986; Nakazato et al. 1998; Zoccoli et al. 2001; Legramante et al. 2003).
State-dependent modulation of baroreflex control of RSNA and cardiovascular function
It was surprising that Pa increased significantly despite the reductions of RSNA and HR and the vertical suppression in the Pa–RSNA baroreflex curve which occurred simultaneously during REM sleep relative to NREM sleep. The mechanisms underlying the increase in Pa during REM sleep are not evident from the present study. However, one possible explanation could involve regional differences in sympathetic nerve activities that may occur during REM sleep. Indeed, this was first described by Futuro-Neto & Coote (1982), and was supported by our recent publication (Miki et al. 2003a). By contrast, the cause-and-effect relationship between RSNA, HR and the Pa–RSNA baroreflex curve during grooming seems to be relatively simple compared with that during REM sleep. It is likely that the central neural processing leading to grooming behaviour and/or afferent input originating from muscle mechano- and chemoreceptors could exert excitatory influences on the baroreflex control of RSNA, resulting in the right–upward shift of the Pa–RSNA baroreflex curve. This in turn would increase RSNA, possibly including cardiac and visceral sympathetic nerve activities and then cause an increase in cardiac performance and vasoconstriction of visceral and non-contracting muscle, leading finally to a rise in Pa. Although we have not measured baroreflex control of RSNA during other behavioural states, for example drinking, eating and sexual behaviour, it might be safe to extend the present results and conclude that the baroreflex control of RSNA is likely to be altered in state-dependent manner (Figs 3 and 5A).
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