Spoken words are processed during dexmedetomidine-induced unresponsiveness.

BACKGROUND: Studying the effects of anaesthetic drugs on the processing of semantic stimuli could yield insights into how brain functions change in the transition from wakefulness to unresponsiveness. Here, we explored the N400 event-related potential during dexmedetomidine- and propofol-induced unresponsiveness. METHODS: Forty-seven healthy subjects were randomised to receive either dexmedetomidine (n=23) or propofol (n=24) in this open-label parallel-group study. Loss of responsiveness was achieved by stepwise increments of pseudo-steady-state plasma concentrations, and presumed loss of consciousness was induced using 1.5 times the concentration required for loss of responsiveness. Pre-recorded spoken sentences ending either with an expected (congruous) or an unexpected (incongruous) word were presented during unresponsiveness. The resulting electroencephalogram data were analysed for the presence of the N400 component, and for the N400 effect defined as the difference between the N400 components elicited by congruous and incongruous stimuli, in the time window 300-600 ms post-stimulus. Recognition of the presented stimuli was tested after recovery of responsiveness. RESULTS: The N400 effect was not observed during dexmedetomidine- or propofol-induced unresponsiveness. The N400 component, however, persisted during dexmedetomidine administration. The N400 component elicited by congruous stimuli during unresponsiveness in the dexmedetomidine group resembled the large component evoked by incongruous stimuli at the awake baseline. After recovery, no recognition of the stimuli heard during unresponsiveness occurred. CONCLUSIONS: Dexmedetomidine and propofol disrupt the discrimination of congruous and incongruous spoken sentences, and recognition memory at loss of responsiveness. However, the processing of words is partially preserved during dexmedetomidine-induced unresponsiveness. CLINICAL TRIAL REGISTRATION: NCT01889004.

Human baroreflex rhythms persist during handgrip and muscle ischaemia.

AIM: To determine whether physiological, rhythmic fluctuations of vagal baroreflex gain persist during exercise, post-exercise ischaemia and recovery. METHODS: We studied responses of six supine healthy men and one woman to a stereotyped protocol comprising rest, handgrip exercise at 40% maximum capacity to exhaustion, post-exercise forearm ischaemia and recovery. We measured electrocardiographic R-R intervals, photoplethysmographic finger arterial pressures and peroneal nerve muscle sympathetic activity. We derived vagal baroreflex gains from a sliding (25-s window moved by 2-s steps) systolic pressure-R-R interval transfer function at 0.04-0.15 Hz. RESULTS: Vagal baroreflex gain oscillated at low, nearly constant frequencies throughout the protocol (at approx. 0.06 Hz - a period of about 18 s); however, during exercise, most oscillations were at low-gain levels, and during ischaemia and recovery, most oscillations were at high-gain levels. CONCLUSIONS: Vagal baroreflex rhythms are not abolished by exercise, and they are not overwhelmed after exercise during ischaemia and recovery.

The effects of surgical levels of sevoflurane and propofol anaesthesia on heart rate variability.

BACKGROUND AND OBJECTIVE: We compared heart rate dynamics during surgical levels of propofol and sevoflurane anaesthesia in a highly standardized setting. METHODS: We recorded electrocardiography from 24 anaesthetized healthy male subjects. In the first parallel part of the study, the subjects were anaesthetized either with sevoflurane (n = 8) or propofol (n = 8) targeted to match 1.0, 1.5 and 2.0 minimal alveolar concentration/effective concentration 50. In the second part, a separate group (n = 8) underwent four different anaesthetic regimens targeted to bispectral index 40: sevoflurane alone, sevoflurane + 70% nitrous oxide, propofol alone and propofol + 70% nitrous oxide. The electrocardiography data were analysed using conventional time and frequency domain methods, and the approximate entropy method, which estimates the complexity of the data. RESULTS: The induction of anaesthesia was followed by an overall reduction of heart rate variability, evident in all frequency bands in the spectral analysis, and also in the time domain measures. Approximate entropy decreased at 1 effective concentration 50 with propofol and at 2 minimal alveolar concentration with sevoflurane. In the second part of the study, the time domain variables and high-frequency spectral power were all similarly reduced by sevoflurane and propofol anaesthesia, with and without nitrous oxide. Approximate entropy tended to decrease during propofol anaesthesia. CONCLUSIONS: Hypnotic levels of sevoflurane and propofol anaesthesia suppressed the heart rate variability measured using conventional analysis methods. Deeper surgical levels of anaesthesia also reduce the complexity of heart rate variability.

Propranolol increases the complexity of heart rate fluctuations--a mode of antiarrhythmic action?

OBJECTIVE: To study the beta-blocking effect of propranolol on heart rate and arterial blood pressure fluctuations in healthy subjects using linear methods and a set of nonlinear models. METHODS: In a randomized, double-blind, placebo-controlled study, healthy young adults received a 40 mg oral dose of propranolol (n = 12) or placebo (n = 12). The effects of propranolol and placebo were assessed using time series of the RR interval (RRI) and systolic arterial blood pressure (SAP) obtained from continuous ECG and blood pressure signal recordings. Heart rate and systolic arterial blood pressure fluctuations were analyzed using nonlinear and linear methods of time series statistics. RESULTS: Propranolol significantly increased the complexity of heart rate fluctuations in terms of symbol dynamic (SymDyn) entropy and symbol dynamic percentage of forbidden words. Propranolol augmented cross entropy between RRI and SAP and increased fractal dimension of RRI. beta-blockade also affected linear measures of RRI fluctuations by increasing parasympathetic, respiration-related high-frequency (HF) variability and arterial baroreflex-related low-frequency (LF) variability. Propranolol administration, however, had no effect on the complexity of SAP fluctuations assessed using nonlinear time series statistics. CONCLUSIONS: beta-blockade by propranolol has a differential effect on RRI and SAP fluctuations in healthy subjects. Propranolol increases the complexity of RRI fluctuations. The effect is associated with the cardiac vagotonic drug action of propranolol. SAP fluctuations are almost unchanged. The increased complexity of RRI fluctuations may be a beneficial feature of beta-blockade, since many cardiovascular diseases decrease the complexity of RRI time series by dampening cardiovascular reflex actions.

Increased pulse pressure is associated with reduced baroreflex sensitivity.

Although pulse pressure (PP), heart rate variability (HRV) and baroreflex sensitivity (BRS) have been shown to predict cardiovascular events and mortality in various populations, their relationships have not been clarified. We examined these associations in two separate population-based samples of healthy middle-aged subjects. In population 1, data were obtained from 149 subjects (71 men and 78 women) aged 35-64 (mean 47.7) years, and in population 2, from 214 subjects (88 men and 126 women) aged 40-62 (mean 50.5) years. Increased 24-h ambulatory PP was related to decreased cross-spectral BRS independent of age and gender (beta=-0.28, P<0.001 for population 1; beta=-0.22, P=0.003 for population 2). This association remained significant when 24-h ambulatory diastolic blood pressure, body mass index, smoking and alcohol intake were added as covariates in the multivariate analysis. Increased ambulatory PP was also associated with increased beat-to-beat systolic arterial pressure variability. Associations between ambulatory PP and HRV were not significant after controlling for age and gender. Our results suggest that elevated PP does not affect overall HRV, but it interferes with baroreflex-mediated control of the heart rate. This association may be due to a common denominator, such as arterial stiffness, for PP and BRS.

Effect of cardiac vagal outflow on complexity and fractal correlation properties of heart rate dynamics.

1. Cardiac vagal outflow is the major factor determining the magnitude of heart rate (HR) variability analysed by traditional time and frequency domain methods. New analysis techniques, such as fractal and complexity methods, have been developed to probe non-linear features in HR behaviour that may not be detectable by traditional methods. 2. We investigated the effects of vagal blockade (glycopyrrolate i.v. 5 microg kg-1 h-1 for 2 h, n = 8 vs. unmedicated control group, n = 8) and various breathing patterns (n = 12) on two non-linear measures of HR variability--detrended fluctuation analysis (DFA) and approximate entropy (ApEn)--in healthy male volunteers. 3. Glycopyrrolate decreased the mean (+/-SD) ApEn from 1.46 +/- 0.18 to 0.85 +/- 0.24 (P = 0.001 in comparison with the control group), and increased the short-term (alpha 1) and intermediate-term (alpha 2) fractal scaling exponents of DFA, alpha 1 from 0.96 +/- 0.19 to 1.43 +/- 0.29 (P = 0.003) and alpha 2 from 1.13 +/- 0.10 to 1.34 +/- 0.14 (P < 0.001). 4. Decrease in fixed respiration rate from 15 to 6 breaths min-1 increased alpha 1 from 0.83 +/- 0.25 to 1.18 +/- 0.27 (P < 0.001), but decreased alpha 2 from 0.88 +/- 0.09 to 0.45 +/- 0.17 (P < 0.001) and ApEn from 1.26 +/- 0.12 to 1.10 +/- 0.14 (P = 0.028). Rapid breathing (24 min-1) had no influence on these non-linear measures of HR variability. Hyperventilation (15 min-1, tidal volume increased voluntarily by 0.5 l) decreased alpha 1 from 0.83 +/- 0.25 to 0.66 +/- 0.28 (P = 0.002) but did not affect alpha 2 or ApEn. 5. To conclude, vagal blockade alters the fractal scaling properties of R-R intervals (alpha 1, alpha 2) and reduces the complexity (ApEn) of HR behaviour. Both the fractal and complexity measures of HR variability can also be influenced by changes in the breathing pattern.

Reduced heart rate variability in hypertension: associations with lifestyle factors and plasma renin activity.

Limited information exists on the relations between heart rate variability, hypertension, lifestyle factors and renin-angiotensin-aldosterone system. A total of 191 newly diagnosed yet untreated hypertensive men and women, 35-54 years of age, were compared with an age- and gender-stratified random population sample of 105 normotensive men and women to find out independent determinants of heart rate variability. Heart rate variability was computed from 5-min ECG time series using the standard deviation of normal-to-normal RR intervals (SDNN), the square root of the mean of squared differences between adjacent normal RR intervals (RMSSD) and the fast Fourier transform spectral analysis. All absolute measures of heart rate variability were reduced in hypertension (P<0.001 for each, ANOVA). In multivariate regression analyses, reduced heart rate variability was independently associated with higher heart rate (P<0.001 for all absolute measures of heart rate variability), higher age (P=0.001 for SDNN, total and LF powers; P<0.001 for RMSSD and HF power) and higher mean arterial pressure (P<0.05 for total power, P<0.01 for the other absolute measures) but not with sodium and alcohol intakes, body mass index and smoking. Increased plasma renin activity (PRA) was an independent attributor of reduced HF power (P<0.05) and reduced RMSSD (P<0.01). Increased blood pressure and heart rate are associated with decreased heart rate variability without any direct effects on heart rate variability of lifestyle factors. High PRA is an independent determinant of diminished modulation of vagal activity.

Cardiovascular effects of ophthalmic 0.5% timolol aqueous solution and 0.1% timolol hydrogel.

The objective of this randomized, double-masked, cross-over study was to compare the cardiovascular effects of two glaucoma formulations, ophthalmic 0.5% timolol aqueous solution and 0.1% timolol hydrogel. Twenty-four young healthy subjects received for 2 weeks either twice daily 0.5% timolol solution or once daily 0.1% timolol hydrogel. Heart rate (HR), blood pressure, atrio-ventricular conduction (PR interval), corrected QT time (QTc) and heart rate variability (HRV) were measured in supine position and during head-up tilted position. The mean peak concentrations of timolol in plasma were significantly higher after administration of 0.5% aqueous solution than after 0.1% hydrogel. A 0.5% timolol aqueous solution decreased HR on average by 3 bpm in supine position and by 7 bpm in head-up tilted position while no significant effects were observed with 0.1% timolol hydrogel. During tilt test HR was significantly lower after administration of timolol aqueous solution than after timolol hydrogel (mean +/- SD, 77 +/- 11 bpm versus 86 +/- 13 bpm, P < 0.05). Timolol aqueous solution slightly decreased QTc during tilt (5.9 +/- 5.6 ms, P < 0.01). During tilt tests, timolol aqueous solution slightly increased atrio-ventricular conduction (7.2 ms, P = 0.02). No significant differences were found in HRV. These results indicate that in healthy volunteers, ophthalmic 0.5% timolol aqueous solution produces more pronounced cardiac beta-blocking effects than 0.1% timolol hydrogel.

Spontaneous baroreflex sensitivity as a dynamic measure of cardiac anticholinergic drug effect.

1. In this study, the analysis of spontaneous baroreflex sensitivity (BRS) was applied to the dynamic assessment of cardiac anticholinergic drug effect in healthy male volunteers. 2. The anticholinergic effects of single intravenous (i.v.) injections of atropine (10 microg kg(-1)), glycopyrrolate (5 microg kg(-1)) and scopolamine (5 microg kg(-1)), as well as a 2-h infusion of glycopyrrolate (5 microg kg(-1) h(-1)) were investigated. Baroreflex sensitivity, a validated measure of cardiac parasympathetic reflex regulation, was repeatedly measured from 5-min recordings of electrocardiogram (ECG) and continuous blood pressure by using the sequence technique, a method based on detection of spontaneous fluctuations in blood pressure and heart rate. 3. Single injections of atropine, glycopyrrolate and scopolamine decreased the mean BRS by 71 +/- 32, 68 +/- 23 and 27 +/- 45%, respectively, whereas the slow glycopyrrolate infusion gradually decreased BRS (up to 83 +/- 11% reduction) and increased both systolic (SAP) and diastolic arterial pressures (DAP) (on an average, by 9 mmHg). 4. During the withdrawal of the parasympathetic blockade (indicated by increasing BRS), the proportion of baroreflex sequences in the recordings increased transiently from 10 up to 20-25%, probably reflecting the restoration of the baroreflex integrity and the baroreflex-induced attempt to counteract the blood pressure increase. 5. The sequence method to study BRS seems to be feasible in the assessment of cardiac anticholinergic drug effects, and it also provides good time resolution for the dynamic measurements.

Time domain, geometrical and frequency domain analysis of cardiac vagal outflow: effects of various respiratory patterns.

The purpose of this study was to compare the applicability of four different measures of heart rate variability (HRV) in the assessment of cardiac vagal outflow, with special reference to the effect of breathing pattern. The anticholinergic effects of an intravenous glycopyrrolate infusion (5 microg x kg(-1) x h(-1) for 2 h) during spontaneous and controlled (15 min(-1)) breathing rate were investigated in eight volunteers, and the effects of different fixed breathing rates (6-15-24 min(-1)) and hyperventilation in 12 subjects. Cardiac vagal activity was assessed by ECG recordings in which the following measures of HRV were computed: the high-frequency (HF) spectral component, the instantaneous RR interval (RRI) variability (SD1) analysed from the Poincaré plots, the percentage of differences between successive RRIs greater than 50 ms (pNN50), and the square root of the mean squared differences of successive RRIs (RMSSD). On average, glycopyrrolate reduced the HF spectral component by 99.8%, SD1 by 91.3%, pNN50 by 100% and RMSSD by 97.0%. The change of breathing pattern from controlled to spontaneous decreased significantly the HF component and pNN50, but did not affect SD1 or RMSSD. Rapid breathing rate (24 min(-1)) decreased the HF component, but had no effects on the other measures. A controlled breathing rate is needed for a reliable assessment of cardiac vagal outflow by the spectral analysis technique. The quantitative geometrical analysis of short-term RRI variability from the Poincaré plots and the time domain measure RMSSD were not significantly affected by changes in the breathing rate, suggesting that these indices are more suitable for the measurement of cardiac vagal outflow during the 'free-running' ambulatory conditions.

The effects of amitriptyline, citalopram and reboxetine on autonomic nervous system. A randomised placebo-controlled study on healthy volunteers.

RATIONALE: In therapeutic use, amitriptyline, reboxetine and citalopram have all been associated with apparent anticholinergic-like side effects (dry mouth, constipation, etc.), despite the very low antimuscarinic activity of reboxetine and citalopram in vitro. OBJECTIVES: We hypothesised that the spectral analysis of heart rate variability (HRV) might detect differences between amitriptyline, citalopram and reboxetine in their anticholinergic activities following a single peroral administration. METHODS: In this double-blind, cross-over study, amitriptyline (75 mg), citalopram (20 mg), reboxetine (4 mg) and placebo were randomly given at 1-week intervals to eight healthy male volunteers. Drug and catecholamine concentrations in plasma were determined repeatedly. The drug effect was assessed with periodic recordings of electrocardiogram (ECG) and blood pressure, and with measurements of salivary secretion. The ECG recordings were subjected to spectral analysis of HRV, in which the high frequency (HF) power of R-R interval (RRI) variability was supposed to reflect cardiac parasympathetic tone. RESULTS: Reboxetine increased heart rate and blood pressure and reduced the HF power of RRI and 3,4-dihydroxyphenylglycol (DHPG) plasma concentrations. Amitriptyline diminished salivary secretion and had a prominent sedative action. Measurements after citalopram did not differ significantly from placebo. CONCLUSIONS: Reboxetine, despite its low antimuscarinic activity in vitro, had distinct effects on the HF power of RRI, consistent with anticholinergic activity in vivo. Amitriptyline had a measurable anticholinergic effect in the salivary glands, but, surprisingly, not in the heart. We suggest that the sedative effect of amitriptyline could alter cardiac sympathovagal balance and, therefore, counteract the anticholinergic drug effect.

Perfusion heterogeneity in human skeletal muscle: fractal analysis of PET data.

Muscle blood flow has been shown to be heterogeneous at the voxel by voxel level in positron emission tomography (PET) studies using oxygen-15 labelled water. However, the limited spatial resolution of the imaging device does not allow direct measurement of true vascular flow heterogeneity. Fractal dimension (D) obtained by fractal analysis describes the relationship between the relative dispersion and the size of the region studied, and has been used for the assessment of perfusion heterogeneity in microvascular units. This study was undertaken to evaluate fractal characteristics of PET perfusion data and to estimate perfusion heterogeneity in microvascular units. Skeletal muscle blood flow was measured in healthy subjects using [15O]water PET and the fractal characteristics of blood flow in resting and exercising skeletal muscle were analysed. The perfusion heterogeneity in microvascular units was estimated using the measured heterogeneity (relative dispersion, RD = SD/mean) and D values. Heterogeneity due to methodological factors was estimated with phantoms and subtracted from the flow data. The number of aggregated voxels was inversely correlated with RD both in phantoms (Pearson r = -0.96-0.97) and in muscle (Pearson r = -0.94) when both parameters were expressed using a logarithmic scale. Fractal dimension was similar between exercising (1.13) and resting (1.14) muscles and significantly lower than the values in the phantoms with different activity levels (1.27-1.29). Measured flow heterogeneity values were 20% +/- 6% (exercise) and 27% +/- 5% (rest, P < 0.001), whereas estimated flow heterogeneity values in microvascular units (1 mm3) were 35% +/- 14% (exercise) and 49% +/- 14% (rest, P < 0.01). In conclusion, these results show that it is feasible to apply fractal analysis to PET perfusion data. When microvascular flow heterogeneity is estimated using fractals, perfusion appears to be more heterogeneous in microvascular units than when obtained by routine spatial analysis of PET data. Analysis of flow heterogeneity using PET and fractals could provide new insight into physiological conditions and diseases associated with changes in peripheral vascular function.

Comparison of vagal baroreflex function in nonpregnant women and in women with normal pregnancy, preeclampsia, or gestational hypertension.

OBJECTIVE: Our aim was to compare baroreflex function among nonpregnant women and among women with normal pregnancy, preeclampsia, or gestational hypertension. STUDY DESIGN: Baroreflex function was tested in 20 women with preeclampsia, in 20 age- and gestational age-matched normotensive gravid women, in 20 age-matched nonpregnant women, and in 20 nonmatched women with gestational hypertension. The baroreflex was measured by several modalities. RESULTS: Vagal baroreflex gain measured by cross-spectral analysis of parallel spontaneous heart rate and blood pressure changes is significantly decreased in normal pregnancy (15.8 +/- 7.2 vs 10.8 +/- 4.1 ms/mm Hg; P = 0.001), in comparison with vagal baroreflex gain in nonpregnant women. Baroreflex gain is further reduced in preeclamptic pregnancy (10.8 +/- 4.1 vs 7.2 +/- 2.6 ms/mm Hg; P = 0.003) and in gestational hypertension (10.8 +/- 4.1 vs 6.5 +/- 2.7 ms/mm Hg; P = 0.001), compared with that in normal pregnancy. Similar differences were seen with other baroreflex testing modalities. CONCLUSIONS: The normal reduction of baroreflex gain in pregnancy is further depressed in subjects with hypertensive disorders of pregnancy.

Respiratory modulation of human autonomic rhythms.

We studied the influence of three types of breathing [spontaneous, frequency controlled (0.25 Hz), and hyperventilation with 100% oxygen] and apnea on R-R interval, photoplethysmographic arterial pressure, and muscle sympathetic rhythms in nine healthy young adults. We integrated fast Fourier transform power spectra over low (0.05-0.15 Hz) and respiratory (0.15-0.3 Hz) frequencies; estimated vagal baroreceptor-cardiac reflex gain at low frequencies with cross-spectral techniques; and used partial coherence analysis to remove the influence of breathing from the R-R interval, systolic pressure, and muscle sympathetic nerve spectra. Coherence among signals varied as functions of both frequency and time. Partialization abolished the coherence among these signals at respiratory but not at low frequencies. The mode of breathing did not influence low-frequency oscillations, and they persisted during apnea. Our study documents the independence of low-frequency rhythms from respiratory activity and suggests that the close correlations that may exist among arterial pressures, R-R intervals, and muscle sympathetic nerve activity at respiratory frequencies result from the influence of respiration on these measures rather than from arterial baroreflex physiology. Most importantly, our results indicate that correlations among autonomic and hemodynamic rhythms vary over time and frequency, and, thus, are facultative rather than fixed.

Effects of noradrenaline on human vagal baroreflexes.

BACKGROUND: Baroreflex sensitivity (BRS) is depressed in conditions associated with high sympathetic nerve activity in proportion to circulating noradrenaline (NA) levels. Despite the prognostic importance of measurements of BRS in patients, there is little information on how high NA levels affect arterial baroreflex function. AIM: To understand better the role of NA in cardiovascular homeostasis. METHODS: We gave incremental intravenous NA infusions (at 50 and 100 ng/kg/min) to 12 healthy young men. We measured RR intervals and photoplethysmographic arterial pressures and estimated BRS with cross-spectral and sequence methods during metronome-guided respiration at 0.25 Hz. RESULTS: The high NA infusion rate significantly increased respiratory-frequency (0.15-0.40 Hz) RR interval spectral power and decreased low-frequency (0.04-0.15 Hz) systolic pressure spectral power compared with baseline levels (P < 0.05 for both). Cross-spectral BRS increased from an average (+/- SD) baseline level of 17.3+/-6.6 to 34.1+/-20.8 ms/mmHg at the high NA infusion rate (P < 0.05). Sequence BRS values did not increase significantly during NA infusions. The percentage of sequences with parallel changes in systolic pressures and RR intervals decreased progressively from a baseline level of 16.0+/-12.9 to 10.1+/-7.4 during the low NA infusion rate and to 6.2+/-6.2% during the high rate (P < 0.05 and 0.01, respectively). CONCLUSIONS: Increases in circulating NA to high physiological levels do not depress BRS but interfere with the close baroreflex-mediated coupling that is usually present between arterial pressure and heart rate.

The effect of estrogen replacement therapy on cardiac autonomic regulation.

OBJECTIVE: To study the effects of estrogen replacement therapy (ERT) and sleep stage on autonomic cardiac regulation. SRUDY DESIGN: Seventy-one healthy postmenopausal women received transdermal ERT and placebo separated by a washout in a randomized, placebo-controlled, double-blind, cross-over trial. Polysomnography was conducted at the end of each treatment. Heart rate variability (HRV) was assessed in epochs of the awake state, stage 2, slow wave and REM sleep. The effects of estradiol and sleep stages on HRV were analyzed. RESULTS: ERT decreased heart rate in the awake state and quiet sleep, but not in REM sleep. ERT did not change the heart rate variability. Heart rate decreased and HRV increased during stage 2 and slow wave sleep compared with the awake state with placebo. In REM sleep, similarly, heart rate increased above awake values and the values of HRV parameters fell back to awake levels. CONCLUSIONS: The results suggest that ERT increases vagal tone, but does not change cardiac vagal modulation. Changes in HRV suggest a strong vagal influence in non-REM and a sympathetic influence in REM sleep.

Nine months in space: effects on human autonomic cardiovascular regulation.

We studied three Russian cosmonauts to better understand how long-term exposure to microgravity affects autonomic cardiovascular control. We recorded the electrocardiogram, finger photoplethysmographic pressure, and respiratory flow before, during, and after two 9-mo missions to the Russian space station Mir. Measurements were made during four modes of breathing: 1) uncontrolled spontaneous breathing; 2) stepwise breathing at six different frequencies; 3) fixed-frequency breathing; and 4) random-frequency breathing. R wave-to-R wave (R-R) interval standard deviations decreased in all and respiratory frequency R-R interval spectral power decreased in two cosmonauts in space. Two weeks after the cosmonauts returned to Earth, R-R interval spectral power was decreased, and systolic pressure spectral power was increased in all. The transfer function between systolic pressures and R-R intervals was reduced in-flight, was reduced further the day after landing, and had not returned to preflight levels by 14 days after landing. Our results suggest that long-duration spaceflight reduces vagal-cardiac nerve traffic and decreases vagal baroreflex gain and that these changes may persist as long as 2 wk after return to Earth.

Human sympathetic and vagal baroreflex responses to sequential nitroprusside and phenylephrine.

We evaluated a method of baroreflex testing involving sequential intravenous bolus injections of nitroprusside followed by phenylephrine and phenylephrine followed by nitroprusside in 18 healthy men and women, and we drew inferences regarding human sympathetic and vagal baroreflex mechanisms. We recorded the electrocardiogram, photoplethysmographic finger arterial pressure, and peroneal nerve muscle sympathetic activity. We then contrasted least squares linear regression slopes derived from the depressor (nitroprusside) and pressor (phenylephrine) phases with 1) slopes derived from spontaneous fluctuations of systolic arterial pressures and R-R intervals, and 2) baroreflex gain derived from cross-spectral analyses of systolic pressures and R-R intervals. We calculated sympathetic baroreflex gain from integrated muscle sympathetic nerve activity and diastolic pressures. We found that vagal baroreflex slopes are less when arterial pressures are falling than when they are rising and that this hysteresis exists over pressure ranges both below and above baseline levels. Although pharmacological and spontaneous vagal baroreflex responses correlate closely, pharmacological baroreflex slopes tend to be lower than those derived from spontaneous fluctuations. Sympathetic baroreflex slopes are similar when arterial pressure is falling and rising; however, small pressure elevations above baseline silence sympathetic motoneurons. Vagal, but not sympathetic baroreflex gains vary inversely with subjects' ages and their baseline arterial pressures. There is no correlation between sympathetic and vagal baroreflex gains. We recommend repeated sequential nitroprusside followed by phenylephrine doses as a simple, efficientmeans to provoke and characterize human vagal and sympathetic baroreflex responses.

Human responses to upright tilt: a window on central autonomic integration.

1. We examined interactions between haemodynamic and autonomic neural oscillations during passive upright tilt, to gain better insight into human autonomic regulatory mechanisms. 2. We recorded the electrocardiogram, finger photoplethysmographic arterial pressure, respiration and peroneal nerve muscle sympathetic activity in nine healthy young adults. Subjects breathed in time with a metronome at 12 breaths min-1 (0.2 Hz) for 5 min each, in supine, and 20, 40, 60, 70 and 80 deg head-up positions. We performed fast Fourier transform (and autoregressive) power spectral analyses and integrated low-frequency (0.05-0.15 Hz) and respiratory-frequency (0. 15-0.5 Hz) spectral powers. 3. Integrated areas of muscle sympathetic bursts and their low- and respiratory-frequency spectral powers increased directly and significantly with the tilt angle. The centre frequency of low-frequency sympathetic oscillations was constant before and during tilt. Sympathetic bursts occurred more commonly during expiration than inspiration at low tilt angles, but occurred equally in expiration and inspiration at high tilt angles. 4. Systolic and diastolic pressures and their low- and respiratory-frequency spectral powers increased, and R-R intervals and their respiratory-frequency spectral power decreased progressively with the tilt angle. Low-frequency R-R interval spectral power did not change. 5. The cross-spectral phase angle between systolic pressures and R-R intervals remained constant and consistently negative at the low frequency, but shifted progressively from positive to negative at the respiratory frequency during tilt. The arterial baroreflex modulus, calculated from low-frequency cross-spectra, decreased at high tilt angles. 6. Our results document changes of baroreflex responses during upright tilt, which may reflect leftward movement of subjects on their arterial pressure sympathetic and vagal response relations. The intensity, but not the centre frequency of low-frequency cardiovascular rhythms, is modulated by the level of arterial baroreceptor input. Tilt reduces respiratory gating of sympathetic and vagal motoneurone responsiveness to stimulatory inputs for different reasons; during tilt, sympathetic stimulation increases to a level that overwhelms the respiratory gate, and vagal stimulation decreases to a level below that necessary for maximal respiratory gating to occur.