Heart rate variability in conscious neonatal swine: spectral features and responses to short-term intermittent hypoxia
© Sica and Zhao; licensee BioMed Central Ltd. 2006
Received: 15 March 2006
Accepted: 16 June 2006
Published: 16 June 2006
Spectral analysis of the cardiac time series has been used as a tool for assessing levels of parasympathetic and sympathetic modulation of the sinoatrial node. In the present investigation we evaluated daily changes in heart rate variability spectra in conscious neonatal piglets that were either neurally intact (n = 5) or had undergone right stellate ganglionectomy (n = 5). The partial stellectomized animals and their intact litter mates were exposed to four days of intermittent hypoxia, each day comprising nine episodes of hypoxia alternating with nine episodes of normoxia. A time control group (n = 7) comprised animals from different litters that were not exposed to intermittent hypoxia. We hypothesized that exposure to intermittent hypoxia would increase sympathetic efferent neuronal modulation of heart rate variability spectra in neurally intact animals and in those with right stellate ganglionectomy, and that his effect would be observed in heart rate variability spectra computed from baseline recordings.
Overall, heart rate variability spectra during baseline conditions were dominated by high frequency activity, a reflection of parasympathetic efferent neuronal innervation and linkage to the ventilatory cycle manifested as respiratory sinus arrhythmia. Exposure to intermittent hypoxia did not alter daily baseline spectral features that would indicate an increase of sympathetic cardiac activity: low frequency (0.05 – 0.15 Hz) activity was unaffected and the ratio of low- to -high frequency activity remained less than unity indicating a predominance of high frequency activity. The resultant spectra were remarkably similar despite differences in cardiac sympathetic efferent neuronal innervation and experimental treatment. When spectra were computed from cardiac time series during representative hypoxic episodes, significant increases in activity across the low frequency region (0.05 – 0.15 Hz) of heart rate variability spectra were noted and were comparable in neurally intact animals and in those with right stellate ganglionectomy.
The findings of this investigation provided important information regarding sympathetic efferent neuronal innervation of the heart during the neonatal period. Both neurally intact animals and those with right stellate ganglionectomy had equivalent increases of activity in the low frequency region of heart rate variability spectra during hypoxic stimulation. Such a finding demonstrated the capability of residual cardiac sympathetic neuronal innervation to affect functionally appropriate changes in cardiac chronotropy.
Variability is an inherent feature of the cardiac interval time series reflecting joint modulation of sinoatrial pacemaker activity by sympathetic and parasympathetic systems. Autonomic influences on heart rate variability (HRV) are readily apparent in autopower spectra computed from short records (3 – 5 min) of electrocardiographic R wave to R wave (R-R) intervals. Such spectra typically exhibited peaks in two distinct regions, one a low frequency (LF) region, located between 0.05 and 0.15 Hz, the other a high frequency (HF) region located at the breathing rate and associated with changes in R-R interval durations during the ventilatory cycle, i.e., the respiratory sinus arrhythmia (RSA) [16, 29]. While LF activity is considered to represent sympathetic efferent cardiac innervation and HF activity due to parasympathetic efferent cardiac innervation, this functional separation is not totally supported by experimental evidence that suggested joint modulation of either region [1, 11, 16, 32]. Even though interactions between sympathetic and parasympathetic systems can occur, conditions of imposed stress may alter one or the other of the spectral regions, indicating selective activation of the sympathetic or parasympathetic system. For example, stimulation of peripheral chemoreceptors by hypoxia augmented activity in the LF region [20, 35, 37], whereas activation of central chemoreceptors by hypercapnia augmented HF activity [36, 37]. Hypoxia-induced elevation of sympathetic efferent neuronal activity is of interest because it may play an etiological role in the genesis of human cardiovascular disease [6, 26].
Animal models of adult human disease in which hypoxia is thought to play a significant role, e.g., the obstructive sleep apnea syndrome, have relied upon long-term exposures to chronic-intermittent hypoxia in order to reproduce the hypertension associated with untreated obstructive sleep apnea [6, 26]. However, lengthy stimulus exposures are unsuitable for cardiovascular studies in large developing mammals because they would be separated from their mothers during the exposure periods, thereby disrupting established feeding and sleeping schedules. Further, prolonged periods of stimulation may not be required to produce changes in physiological function. For example, several recent studies in neonatal swine showed that exposure to a short protocol (48 min/d for 4 d) of intermittent hypercapnic hypoxia was sufficient to evoke cell death in brainstem regions involved in cardiorespiratory regulation [14, 15]. These findings raised the possibility that changes in neuronal circuits of neonatal piglets underlying cardiorespiratory control could occur following brief exposures to intermittent hypoxia (IH). Hence, one objective of the present study was to determine whether or not exposure to short-term IH would increase LF activity in HRV spectra, and consequently increase LF/HF ratios, the latter an index of the relative contributions of sympathetic and parasympathetic modulation to HRV . A second objective was evaluate the extent to which right stellate ganglionectomy would alter LF activity and LF/HF values in HRV spectra. The latter objective will be pursued because anatomical studies in swine showed that sympathetic efferent innervation of the sinoatrial node originated from peripheral ganglionic sites, i.e., middle cervical and stellate ganglia bilaterally . We hypothesized that baseline HRV spectra would exhibit increased activity in LF region and increased values of LF/HF ratios, reflecting exposure to IH on the previous day or days, and that such an effect would occur in both intact and right stellate ganglionectomized animals. A change in HRV spectra of such ganglionectomized animals, indistinguishable from sham operated litter mate controls, would demonstrate hypoxia-induced, functionally equivalent activity in anatomically distinct sympathetic efferent cardiac nerves.
Experiments were carried out using awake pigs since this species has been shown by us and others to be suitable for long-term monitoring of cardiovascular activity [11, 12, 17, 33, 38]. Further, the use of an awake animal model avoided anesthetic related effects on HRV; for example, anesthetized rats exhibited an inverse RSA wherein R-R intervals during inspiration had longer durations than those of expiration [4, 19, 34]. Piglets exposed to IH were either those with right stellate ganglionectomy (RSGX), or sham (SHAM) operated litter mate controls. RSGX was selected because animals with this type of denervation are distinguished from control animals by their characteristic change in cardiac chronotropy, Q-wave to T-wave (Q-T) interval prolongation [33, 38]. A third group comprised animals from different litters who did not receive IH stimulation. This control (CON) group was used to evaluate changes in HRV spectra due to passage of time. R-R interval time series of CON animals were also used to determine the relationships between interval durations and the ventilatory cycle because CON animals were likely to exhibit a more stable cardiac time series than those exposed to hypoxic stimulation.
Group median durations (seconds) of Q-T, R-R, and corrected Q-T (Q-Tc) intervals measured in animals with right stellate ganglionectomy (RSGX), sham (SHAM) operated control animals, and time control (CON) animals.
Statistical evaluation of HRV spectral features, areas of LF or HF regions, and LF/HF ratios, showed no effect of daily exposures to IH in either RSGX or SHAM treatment groups, neither was there any effect of passage of time on HRV spectra of CON animals. Hence, all statistical comparisons described below were made using data accumulated over the four baseline days
Baseline HRV spectra
Locations of low and high frequency peaks (LF, HF; respectively) in baseline records of heart rate variability spectra in animals with right stellate ganglionectomy (RSGX), sham (SHAM) operated control animals, and time control (CON) animals. Data are given as the group medians, 25th and 75th percentiles.
LF PEAK (Hz)
HF PEAK (Hz)
Median; 25%, 75%
Median; 25%, 75%
0.08; 0.06, 0.09
0.66; 0.5, 0.96
0.08; 0.06, 0.10
0.52; 0.48, 0.67
0.09; 0.07, 0.11
0.59; 0.56, 0.68
Ventilation-related changes in R-R interval durations
Changes in cardiac intervals and HRV spectra during IH
Spectral area encompassed by low frequency activity (0.05 – 0.15 Hz) for right stellectomized (RSGX) and sham operated controls (SHAM) during baseline and hypoxia, 8th or 9th episode of intermittent hypoxia. Data are given as the group medians, 25th and 75th percentiles.
Median; 25%, 75%
Median; 25%, 75%
0.5; 0.21, 0.94
1.3; 0.74, 2.24
1.8; 1.01, 2.25*
2.8; 1.78, 3.74*
% INCREASE: BASELINE → HYPOXIA
285.0; 62.88, 617.19
76.5; -0.42, 338.7
We hypothesized that IH would evoke changes in cardiac beat-to-beat dynamics of neonatal swine such that indices of sympathetic activation, increased LF areas and LF/HF ratios greater than unity, would emerge over the course of the IH protocol. Intermittent hypoxia did not alter any index of HRV spectral activity whether piglets were intact, i.e., SHAM group, or had undergone RSGX. In fact our finding that LF areas of SHAM animals were significantly larger than those of RSGX animals was found to be a result of increased LF activity on a single day; despite such an occurrence LF areas of SHAM animals were not different from those of CON animals who breathed room air. Such similarity in regulation of cardiac chronotropy was also apparent during hypoxic episodes. During IH, RSGX and SHAM animals had similar increases in LF activity of HRV spectra and similar durations of Q-Tc intervals. These findings supported the hypothesis that a stressor recruited sympathetic efferent neuronal activity from contralateral intrathoracic neurons to affect the sinoatrial node . Additionally, this residual sympathetic innervation could have altered activity of postganglionic parasympathetic neurons that innervated the sinoatrial node as demonstrated in in vitro studies of right atrial ganglionic neurons in neonatal swine .
The observation that conscious neonatal piglets exhibited changes in R-R interval durations during baseline conditions, indicative of RSA, is novel, but not unexpected as RSA is a prominent feature of R-R interval time series in a number of different mammalian species including human infants and adults (citations in references [4, 18]). Such a pervasive feature suggests a common neuroanatomical organization . In fact, we and others have shown that the organization of the brainstem vagal motor complex in piglets was similar to that of other species, with cardioinhibitory neurons located in the nucleus ambiguus [10, 21]. Electrophysiological studies in felines showed that cardioinhibitory neurons in the nucleus ambiguus exhibited inhibitory postsynaptic potentials during inspiration followed by depolarization and action potentials during early and late expiration . Likewise, whole cell recordings of nucleus ambiguus neurons in an en bloc neonatal rat brainstem preparation revealed an inspiration-related inhibition that was associated with marked increases of gabaergic and glycinergic inhibitory postsynaptic currents . The aforementioned studies provided strong support for a neural origin for RSA that involved phasic interactions between brainstem neurons involved in shaping central respiratory activity and those providing parasympathetic efferent preganglionic outflows to postganglionic neurons innervating sinoatrial tissue. Hence, the progressive increase in R-R interval durations of piglets during the time course of expiration (depicted in Figs. 4C and 4D) may be viewed as representative of the expiration-related depolarization exhibited by feline nucleus ambiguus neurons . Our finding that R-R intervals with the longest durations occurred at the expiratory to inspiratory transition and those with the shortest durations at the inspiratory to expiratory transition may simply represent species and/or maturational differences in durations and intensities of inhibitory and depolarizing currents. It is also likely that age-related differences in organization of the respiratory phases may have influenced the durations of R-R intervals. For example, we did not observe phrenic activity in earlier studies of neonatal cats or piglets [24, 25] that corresponded to post-inspiration phrenic discharge (i.e. Stage 1 expiration) during which cardioinhibitory neurons in mature cats fired action potentials  An absence of post-inspiratory activity could mean that the temporal course of inspiration-related inhibition in the neonatal piglet is different, and this difference could explain the temporal dispersion of R-R intervals across the respiratory cycle. The absence of post-inspiratory activity suggested that inspiration-related inhibition included the transition zone between inspiratory and expiratory phases. In fact, our finding that R-R interval durations were shortest during this transition supported that idea. A change in the timing of phasic inhibition would be accompanied by changes in the temporal features of expiration-related depolarization such that it might include the beginning of the inspiratory phase, thereby, accounting for the occurrences of R-R intervals with the longest durations at the expiratory to inspiratory phase transitions. Further such an overlap of expiration-related depolarization with the onset of inspiration would delay the appearance of phasic inhibition of cardioinhibitory neurons as indicated by the observation that significant shortening in durations of R-R intervals occurred first during mid-inspiration (see Fig. 4D). The foregoing neural schema, while speculative, provides a reasonable explanation for the respiratory-related differences in R-R interval durations noted in this study.
A shortcoming of our investigation was that we did not fully evaluate the sources of RSA by application of ganglionic blockade. Nevertheless, substantial evidence for a neural origin for RSA was provided by animal and human studies that showed marked reduction of HF activity after parasympathetic blockade [1, 11, 17, 39]. However, the possibility that mechanical effects of respiration, i.e., changes in intrathoracic pressure and/or cardiac filling, contributed to RSA cannot be discounted since RSA has been demonstrated in studies of transplanted human hearts, albeit at a much reduced level compared to normal control subjects [3, 27, 30].
Our study provided important information regarding autonomic modulation of HRV during the first month of life for the piglet, a time frame generally accepted as equivalent to periods of vulnerability during the first six months of human life [5, 13, 23]. First, the equivalence of LF activity in SHAM and RSGX animals on baseline days and during episodes of intermittent hypoxia demonstrated that functionally appropriate regulation of cardiac chronotropy could be attained by recruitment of residual intrathoracic sympathetic ganglionic neurons. Second, the presence of RSA in the cardiac time series of developing mammals has important functional consequences. RSA has been hypothesized as a mechanism whereby changes in R-R interval durations occur at appropriate times in the ventilatory cycle so that ventilation to perfusion ratios are optimized, making for efficient exchange of pulmonary gases as demonstrated in adult humans and dogs [7, 9, 22]
This research was approved by our Institutional Animal Care and Use Committee. The experimental procedures complied with the "Guiding Principles in the Use and Care of Animals" approved by the Council of American Physiological Society and also with Federal and State regulations. Near-term pregnant sows (Sus scrofa) were acquired from Parson's Farm in Massachusetts and delivered to our Division of Laboratory Animal Resources. Sows gave birth with no complications, and piglets were housed with their respective sows for the duration of each study, sows were then returned to Parson's farm.
Piglets ranging in age from 7 – 16 d, and from 2.2 – 5.0 kg in weight underwent the various surgical procedures described below. Briefly, two to five days after birth, animals were anesthetized with Saffan (2 ml/kg, i.m.), a catheter was placed in a lateral ear vein for continuous infusion of 5% Dextrose – lactated Ringer's solution (6–11 ml/kg/h), and for periodic administration of Saffan (68 mg/kg/30 min). All piglets were intubated and ventilated mechanically with 100% O2 at tidal volumes of 10.0 – 15.0 ml/kg and at frequencies ranging from 24 – 40 strokes/min. The electrocardiogram (ECG) was monitored throughout each procedure. Core body temperature was measured and kept within normal limits (38-39°C) using a servo-regulated heating system. The details of our sterile surgical protocols are described in more detail in our previously published studies [33, 38].
RSGX and SHAM operated groups (n = 5 animals per group). For animals undergoing RSGX, the thoracic wall was opened along the mid-sternal line and the entire sternum was divided. Following exposure of the right stellate ganglion, all nerves entering and exiting the ganglia were isolated, ligated, and cut. The ganglion was then removed and stored in 10% formalin for later histologic study. Animals serving as SHAM operated controls were litter mates of RSGX animals, and underwent similar surgical procedures, i.e., dissection to the level of the right stellate ganglion, but no manipulation of the ganglion or its innervation. The sternum, subcutaneous muscles, and skin were then sutured by layers.
Following thoracic surgery, telemetry transmitters (PhysioTel ® Multiplus™, type TL11M3-D70-PCPT, Data Sciences International, St. Paul, MN) were placed into a subcutaneous pouch made on the lower part of the right lateral abdomen. Transmitter sensors for ECG recording were tunneled subcutaneously from the site of the pouch and placed in a Lead II configuration. Next, a pressure sensitive catheter was inserted through the right femoral artery and advanced into the abdominal aorta for recording aortic blood pressure (AoP). A second pressure sensitive catheter was then inserted subcutaneously through a small opening made on the right lateral thoracic wall to record changes in intrathoracic pressure, a measure of ventilation (VENT). The tips of each sensor were securely sutured to adjoining tissues, and all wounds closed with non-absorbable sutures.
CON group (n = 7 animals). This group comprised animals chosen from litters other than those used for selection of RSGX and SHAM animals. These animals did not undergo thoracic surgery, but did undergo surgery for implantation of telemetry transmitters.
Following the completion of surgical procedures, anesthesia was discontinued, piglets were extubated and carefully monitored until they were ambulatory. Antibiotics (Bicillin C-R, 0.2 ml/day; Amiglyde-V, 5 mg/kg/day) and an analgesic (Buprenex, 0.005 ml/kg/day) were administered immediately after completion of surgery and over the next three days. All medications were provided by our Division of Animal Laboratory Resources.
Four to seven days postoperatively, a RSGX animal and a SHAM operated control animal were brought to our laboratory for exposure to IH. Animals were placed in adjoining Lucite chambers (12.5" w, 12" h, 19" l) fitted with diffusers to distribute gas, and with small vents to allow egress of gas to prevent build-up of pressure within boxes. Hypoxic exposures were made over four successive days, after a morning feeding, and carried out at room temperature. For technical reasons (see next section), simultaneous recordings of signals from animals in nearby chambers were impossible. Hence, one animal of each pair was randomly selected to receive hypoxia first. Prior to hypoxic exposures animals were allowed to adapt to the novel environmental conditions. Once the animals were well-adapted to the chamber, i.e., lying prone with eyes open, a 5 min baseline recording was made. Chamber oxygen and carbon dioxide content were monitored continuously by an oxygen sensor (KE-25, Kent Scientific Inc.), and a carbon dioxide monitor (Ohmeda 5200). The IH protocol comprised 9 episodes of hypoxia alternating with 9 episodes of normoxia, each episode lasted 4 min. This pattern of alternating gas exposures was controlled by hardware and software developed in our laboratory. During hypoxia, chamber oxygen concentration was lowered rapidly from 20 – 21% O2 to 6 – 7% O2, and then held at that level for three minutes, after which chamber oxygen concentration was rapidly increased to 20 – 21% O2, and maintained at that level for three minutes. Transitions from room air to hypoxia and from hypoxia to room air required one minute. All signals were monitored continuously throughout each recording session and for at least 30 min after terminating the final hypoxic episode of each day.
Animals in the CON group were placed in exposure chambers on four successive days. Following adaptation and baseline recording, the temporal sequence of events was identical to those experienced by RSGX and SHAM animals, with the exception that transitions were from room air to room air. Hence, these animals experienced the same environmental stimuli as IH exposed animals, but no exposure to hypoxia.
Piglets were separated from their sows for approximately 2 h on days one through three of the four day protocol. On day four, approximately two hours after the termination of the experimental protocol, animals were anesthetized with Nembutal (70 mg/kg, i.p.) and heart, lungs, and kidneys were harvested for detection and amplification of neuronal nitric oxide synthase using a semi-quantitative PCR technique. These data will be reported in another manuscript.
Signals were transmitted over a non-commercial portion of the amplitude modulated radio band. As each transmitter uses the same broadcast frequency, monitoring animals in close proximity to one another would induce cross-talk between signals broadcast from individual transmitters. Hence, it was necessary to carry out the experimental protocol one animal at a time. Telemetry receivers (RMC-1, Data Sciences International, Inc.) were placed beneath each exposure chamber and were connected to a data exchange matrix (Data Sciences International, Inc.) that transmitted signals to the acquisition system via a local area network type cable. A continuous measure of laboratory barometric pressure was provided by an Ambient Pressure Reference monitor (APR-1, Data Sciences International, Inc.) and corrected pressures recorded by AoP and VENT pressure catheters. Telemetry signals were acquired at a rate of 1 kHz using commercially available hardware and software (Dataquest™ A.R.T., Data Sciences International, Inc.). Baseline recordings were reviewed for the presence of arrhythmia and/or excessive movement artifacts. Records containing such events were not analyzed further.
All graphical and spectral analyses were carried out using DADiSP/2002™ (DSP Development Corp.) The effect of RSGX on cardiac chronotropy was demonstrated by computing the durations of Q-T and R-R intervals in five non-successive cardiac cycles on each baseline day. Non-contiguous intervals were used to any local trends in the data. Likewise, measurements of O-T intervals were made during the final episode of hypoxia on each exposure day. Q-T interval durations were measured graphically by displaying the digitized ECG file, and by manually placing software marks at the beginning of the Q-R-S complex and the end of the T wave. The duration of the uncorrected Q-T interval was computed as the time difference between the two software marks. Likewise, marks were place at the peaks of the appropriate R waves, and the temporal differences between adjacent R waves gave the R-R interval durations. These measurements were then used to obtain heart rate corrected Q-T interval durations using Bazett's  formula: Q-Tc = Q-T/(R-R)½.
To determine whether ECG R-R interval durations demonstrated respiratory modulation, the ventilatory cycle was partitioned into four segments: inspiration, transition from inspiration to expiration, expiration, transition from expiration to inspiration. This was accomplished by first using a level-crossing algorithm to position software generated pulses at the temporal locations of peaks in R waves in approximately 200 cardiac cycles. Next, R-wave derived pulses were plotted along with corresponding respiratory cycles, and R-R interval durations computed for each ventilatory segment.
Spectral analysis was carried on all signals by computing power spectral density histograms, bin widths were 0.005 Hz in all cases. Each recording was truncated to a record of continuous data, 150 s in duration, and free of arrhythmias and/or movement artifacts. Best power of two power spectral density histograms were then computed, and smoothed using a five point moving average. Last, each spectrum was normalized by dividing each bin by the total spectral area computed using Simpson's rule. In this manner, area under the curve was derived for the LF region, 0.05 – 0.15 Hz (28 bins), and for the HF region, 28 bins encompassing the ventilatory related peak. As well, LF/HF ratios were computed to evaluate the relative sympathetic – parasympathetic contribution to HRV.
Spectral analysis of the systolic portion of the AoP signal was performed by first positioning software generated pulses at the peaks of systole using the peak finding function in DADiSP, thereby creating a file of voltage values of peaks and the times of their occurrences. Similarly, pulses were positioned at the peaks of R waves, thereby creating a file of voltage values and times of occurrences. These data were demeaned, convolved with a Hanning window to reduce sidelobe leakage, and autopower spectra computed to give systolic AoP variability and HRV. Heart rate (HR) was given by the location of the primary peak in the systolic AoP autopower spectra. For the VENT signal, data were demeaned, convolved with a Hanning window, and then used to compute autopower spectra histograms. The locations of primary peaks in VENT spectra gave ventilatory frequencies.
Statistical comparisons were made using nonparametric tests since most data were neither normally distributed nor were variances equivalent. Hence, data in tables are given as group median values along with 25th and 75th percentiles. Friedman's repeated ANOVA on ranks was used to evaluate changes in spectral features, e.g., area under the curve for LF and HF regions, and also LF/HF ratios that occurred over the four successive baseline days. Two group comparisons were made using the Mann-Whitney Rank Sum test and the Kruskal-Wallis ANOVA on ranks with post hoc Dunn's tests was used for three group comparisons. The Wilcoxon Signed Rank test for pairwise comparisons. Statistical tests were performed using SigmaStat v.3.1(Systat Software, Inc.) with level for statistical significance established at p < 0.05.
– abdominal aortic blood pressure
– group of animals serving as time controls
– high frequency region of spectrum
– heart rate variability
– intermittent hypoxia
– low frequency region of spectrum
– ratio of low to high frequency area
– duration of interval from beginning of Q-wave to end of T-wave
– corrected Q-T interval duration
– duration of interval between adjacent R-waves
– respiratory sinus arrhythmia
– group of animals with right stellate ganglionectomy
– control group comprising litter mates of RSGX animals
This research was supported by NIH grants HL-20864 and HD-28931. We would also like to thank Mrs. Susan Ingenito for her excellent technical assistance.
- Akselrod S, Gordon D, Ubel FA, Shannon DC, Barger AC, Cohen RJ: Power spectrum analysis of heart rate fluctuation: a quantitative probe of beat-to-beat cardiovascular control. Science. 1981, 213: 220-222.View ArticlePubMedGoogle Scholar
- Bazett HC: An analysis of time relations in electrocardiograms. Heart. 1920, 7: 353-370.Google Scholar
- Bernardi L, Keller F, Sanders M, Reddy PS, Griffith B, Meno F, Pinsky MR: Respiratory sinus arrhythmia in the denervated human heart. J Appl Physiol. 1989, 67: 1447-1455.PubMedGoogle Scholar
- Bouairi E, Neff R, Evans C, Gold A, Andresen MC, Mendelowitz D: Respiratory sinus arrhythmia in freely moving and anesthetized rats. J Appl Physiol. 2004, 97: 1431-1436. 10.1152/japplphysiol.00277.2004.View ArticlePubMedGoogle Scholar
- Cote A, Porras H, Meehan B: Age-dependent vulnerability to carotid chemodenervation in piglets. J Appl Physiol. 1996, 80: 323-331.PubMedGoogle Scholar
- Fletcher EC: Physiological consequences of intermittent hypoxia. J Appl Physiol. 2001, 90: 1600-1605. 10.1063/1.1368868.View ArticlePubMedGoogle Scholar
- Giardino ND, Glenny RW, Borson S, Chan L: Respiratory sinus arrhythmia is associated with efficiency of pulmonary gas exchange in healthy humans. Am J Physiol Heart Circ Physiol. 2002, 284: H1585-H1591.View ArticleGoogle Scholar
- Gilbey MP, Jordan D, Richter DW, Spyer KM: Synaptic mechanisms involved in the inspiratory modulation of vagal cardio-inhibitory neurones in the cat. J Physiol. 1984, 356: 65-78.PubMed CentralView ArticlePubMedGoogle Scholar
- Hayano J, Yasuma F, Okada A, Mukai S, Fujinami T: Respiratory sinus arrhythmia. A phenomenon improving pulmonary gas exchange and circulatory efficiency. Circulation. 1996, 94: 842-847.View ArticlePubMedGoogle Scholar
- Hopkins DA, Gootman PM, Gootman N, Armour JA: Anatomy of medullary and peripheral autonomic neurons innervating the neonatal porcine heart. J Auton Nerv Syst. 1997, 64: 74-84. 10.1016/S0165-1838(97)00017-9.View ArticlePubMedGoogle Scholar
- Kuwahara M, Suzuki A, Tsutsumi H, Tanigawa M, Tsubone H, Sugano S: Power spectral analysis of heart rate variability for assessment of diurnal variation of autonomic nervous activity in miniature swine. Lab An Sci. 1999, 49: 202-208.Google Scholar
- Kuwahara M, Tsujino Y, Tsubone H, Kumagai E, Tsutsumi H, Tanigawa M: Effects of pair housing on diurnal rhythms of heart rate and heart rate variability in miniature swine. Exp Anim. 2004, 53: 303-309. 10.1538/expanim.53.303.View ArticlePubMedGoogle Scholar
- Lowry TE, Forster HV, Pan LG, Serra A, Wenninger J, Nash R, Sheridan D, Franciosi RA: Effects on breathing of carotid body denervation in neonatal piglets. J Appl Physiol. 1999, 87: 2128-2135.PubMedGoogle Scholar
- Machaalani R, Waters KA: Correlations between brainstem NMDA receptor changes and active neuronal cell death after intermittent hypercapnic hypoxia in the developing piglet. Brain Res. 2003, 975: 141-148. 10.1016/S0006-8993(03)02603-9.View ArticlePubMedGoogle Scholar
- Machaalani R, Waters KA: Increased neuronal cell death after intermittent hypercapnic hypoxia in the developing piglet brainstem. Brain Res. 2003, 985: 127-134. 10.1016/S0006-8993(03)03003-8.View ArticlePubMedGoogle Scholar
- Malliani A, Pagani M, Lombardi F: Methods for assessment of sympatho-vagal balance: power spectral analysis. Vagal Control of the Heart: Experimental Basis and Clinical Implications. Edited by: Levy MN, Schwartz PJ. 1994, New York: Futura, 7: 433-454. [The Bakken Research Center Series]Google Scholar
- Mesangeau D, Laude D, Elghozi J-L: Early detection of cardiovascular autonomic neuropathy in diabetic pigs using blood pressure and heart rate variability. Cardiovasc Res. 2000, 45: 889-899. 10.1016/S0008-6363(99)00406-X.View ArticlePubMedGoogle Scholar
- Neff RA, Wang J, Baxi S, Evans C, Mendelowitz D: Respiratory sinus arrhythmia. Endogenous activation of nicotinic receptors mediates respiratory modulation of brainstem cardioinhibitory parasympathetic neurons. Circ Res. 2003, 93: 565-572. 10.1161/01.RES.0000090361.45027.5B.View ArticlePubMedGoogle Scholar
- Rentero N, Cividjian A, Trevaks D, Pequignot JM, Quintin L, McAllen RM: Activity patterns of cardiac vagal motoneurons in rat nucleus ambiguus. Am J Physiol Regul Integr Comp Physiol. 2002, 283: R1327-R1334.View ArticlePubMedGoogle Scholar
- Rey S, Del Rio R, Alcayaga J, Iturriaga R: Chronic intermittent hypoxia enhances cat chemosensory and ventilatory responses to hypoxia. J Physiol. 2004, 560: 577-586. 10.1113/jphysiol.2004.072033.PubMed CentralView ArticlePubMedGoogle Scholar
- Ruggiero DA, Zhao N, Anwar M, Sica AL: Organization of the newborn piglets vagal motor complex: insights into integrated autonomic control mechanisms. Auton Neurosci. 2004, 115: 41-53. 10.1016/j.autneu.2004.08.003.View ArticlePubMedGoogle Scholar
- Sasano N, Vesely AE, Hayano J, Sasano H, Somogyi R, Preiss D, Miyasaka K, Katsuya H, Iscoe S, Fisher JA: Direct effect of PaCO2 on respiratory sinus arrhythmia in conscious humans. Am J Physiol Heart Circ Physiol. 2001, 282: H973-H976.View ArticleGoogle Scholar
- Serra A, Brozoski D, Hodges M, Roethle S, Franciosi R, Forster HV: Effects of carotid and aortic chemoreceptor denervation in newborn piglets. J Appl Physiol. 2001, 92: 893-900.View ArticleGoogle Scholar
- Sica AL, Gandhi MR: Efferent phrenic nerve and respiratory neuron activities in the developing kitten: spontaneous discharges and hypoxic responses. Brain Res. 1990, 524: 254-262. 10.1016/0006-8993(90)90699-C.View ArticlePubMedGoogle Scholar
- Sica AL, Gandhi MR, Steele AM: Central patterning of inspiratory activity in the neonatal period. Dev Brain Res. 1991, 64: 77-86. 10.1016/0165-3806(91)90211-Z.View ArticleGoogle Scholar
- Sica AL, Greenberg HE, Ruggiero DA, Scharf SM: Chronic-intermittent hypoxia: a model of sympathetic activation in the rat. Respir Physiol. 2000, 121: 173-184. 10.1016/S0034-5687(00)00126-2.View ArticlePubMedGoogle Scholar
- Slovut DP, Wenstrom JC, Moeckel RB, Wilson RF, Osborn JW, Abrahms JH: Respiratory sinus dysrhythmia persists in transplanted human hearts following autonomic blockade. Clin Exp Pharmacol Physiol. 1998, 25: 322-330.View ArticlePubMedGoogle Scholar
- Smith FM: Extrinsic inputs to intrinsic neurons in the porcine heart in vitro. Am J Physiol Regul Integr Comp Physiol. 1999, 276: R455-R467.Google Scholar
- Stauss HM: Heart rate variability. Am J Physiol Regul Integr Comp Physiol. 2003, 285: R927-R931.View ArticlePubMedGoogle Scholar
- Taha BH, Simon PM, Dempsey JA, Skatrud JB, Iber C: Respiratory sinus arrhythmia in humans: an obligatory role for vagal feedback from the lungs. J Appl Physiol. 1995, 78: 638-645.PubMedGoogle Scholar
- Taylor EW, Jordan D, Coote JW: Central control of the cardiovascular and respiratory systems and their interactions in vertebrates. Physiol Rev. 1999, 79: 855-916.PubMedGoogle Scholar
- Taylor JA, Myers CW, Halliwill JR, Seidel H, Eckberg DL: Sympathetic restraint of respiratory sinus arrhythmia: implications for vagal-cardiac tone assessment in humans. Am J Physiol Heart Circ Physiol. 2001, 280: H2804-H2814.PubMedGoogle Scholar
- Tong S, Ingenito S, Anderson JE, Gootman N, Sica AL, Gootman PM: Development of a swine animal model for the study of sudden infant death syndrome (SIDS). Lab Anim Sci. 1995, 45: 398-403.PubMedGoogle Scholar
- Tzeng Y-C, Galletly DC, Larsen PD: Paradoxical respiratory sinus arrhythmia in the anesthetized rat. Auton Neurosci. 2005, 118: 25-31. 10.1016/j.autneu.2004.12.003.View ArticlePubMedGoogle Scholar
- Yasuma F, Makoto H, Hayano J-I: Impact of acute hypoxia on heart rate and blood pressure variability in conscious dogs. Am J Physiol Heart Circ Physiol. 2000, 279: H2344-H2349.PubMedGoogle Scholar
- Yasuma F, Makoto H, Hayano J-I: Augmentation of respiratory sinus arrhythmia in response to progressive hypercapnia in conscious dogs. Am J Physiol Heart Circ Physiol. 2001, 280: H2336-H2341.PubMedGoogle Scholar
- Yasuma F, Makoto H, Hayano J-I: Differential effects of hypoxia and hypercapnia on respiratory sinus arrhythmia in conscious dogs. Jpn Circ J. 2001, 65: 738-742. 10.1253/jcj.65.738.View ArticlePubMedGoogle Scholar
- Zhao N, Khan M, Ingenito S, Sica AL, Gootman N, Gootman PM: Electrocardiographic changes during postnatal development in conscious swine with cardiac autonomic imbalance. Auton Neurosci. 2001, 88: 167-174. 10.1016/S1566-0702(01)00236-3.View ArticlePubMedGoogle Scholar
- Zhang R, Iwasaki K, Zuckerman JH, Behbehani K, Crandall CG, Levine BD: Mechanism of blood pressure and R-R variability: insights from ganglion blockade in humans. J Physiol. 2002, 543: 337-348. 10.1113/jphysiol.2001.013398.PubMed CentralView ArticlePubMedGoogle Scholar
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.