Autonomic cardiovascular control in conscious mice

Autonomic cardiovascular control was characterized in conscious, chronically catheterized mice by spectral analysis of arterial pressure (AP) and heart rate (HR) during autonomic blockade or baroreflex modulation of autonomic tone. Both spectra were similar to those obtained in humans, but at approximately 10x higher frequencies. The 1/f relation of the AP spectrum changed to a more shallow slope below 0.1-0.2 Hz. Coherence between AP and HR reached 0.5 or higher below 0.3-0.4 Hz and also above 2.5 Hz. Muscarinic blockade (atropine) or beta-adrenergic blockade (atenolol) did not significantly affect the AP spectrum. Atropine reduced HR variability at all frequencies, but this effect waned above 1 Hz. beta-Adrenergic blockade (atenolol) slightly enhanced the HR variability only above 1 Hz. alpha-Adrenergic blockade (prazosin) reduced AP variability between 0.05 and 3 Hz, most prominently at 0. 15-0.7 Hz. A shift of the autonomic nervous tone by a hypertensive stimulus (phenylephrine) enhanced, whereas a hypotensive stimulus (nitroprusside) depressed AP variability at 1-3 Hz; other frequency ranges of the AP spectrum were not affected except for a reduction below 0.4 Hz after nitroprusside. Variability of HR was enhanced after phenylephrine at all frequencies and reduced after nitroprusside. As with atropine, the reduction with nitroprusside waned above 1 Hz. In conclusion, in mice HR variability is dominated by parasympathetic tone at all frequencies, during both blockade and physiological modulation of autonomic tone. There is a limitation for further reduction but not for augmentation of HR variability from the resting state above 1 Hz. The impact of HR on AP variability in mice is confined to frequencies higher than 1 Hz. Limits between frequency ranges are proposed as 0.15 Hz between VLF (very low frequency range) and LF (low frequency range) and 1.5 Hz between LF and HF (high frequency range).     

Oxytocinergic regulation of cardiovascular function: studies in oxytocin-deficient mice

Oxytocin (OT) has been implicated in the cardiovascular responses to exercise, stress, and baroreflex adjustments. Studies were conducted to determine the effect of genetic manipulation of the OT gene on blood pressure (BP), heart rate (HR), and autonomic/baroreflex function. OT knockout (OTKO -/-) and control +/+ mice were prepared with chronic arterial catheters. OTKO -/- mice exhibited a mild hypotension (102 +/- 3 vs. 110 +/- 3 mmHg). Sympathetic and vagal tone were tested using beta(1)-adrenergic and cholinergic blockade (atenolol and atropine). Magnitude of sympathetic and vagal tone to the heart and periphery was not significantly different between groups. However, there was an upward shift of sympathetic tone to higher HR values in OTKO -/- mice. This displacement combined with unchanged basal HR led to larger responses to cholinergic blockade (+77 +/- 25 vs. +5 +/- 15 beats/min, OTKO -/- vs. control +/+ group). There was also an increase in baroreflex gain (-13.1 +/- 2.5 vs. -4.1 +/- 1.2 beats x min(-1) x mmHg(-1), OTKO -/- vs. control +/+ group) over a smaller BP range. Results show that OTKO -/- mice are characterized by 1) hypotension, suggesting that OT is involved in tonic BP maintenance; 2) enhanced baroreflex gain over a small BP range, suggesting that OT extends the functional range of arterial baroreceptor reflex; and 3) shift in autonomic balance, indicating that OT reduces the sympathetic reserve.     

Applicability of recent methods used to estimate spontaneous baroreflex sensitivity to resting mice

Short-term blood pressure (BP) variability is limited by the arterial baroreflex. Methods for measuring the spontaneous baroreflex sensitivity (BRS) aim to quantify the gain of the transfer function between BP and pulse interval (PI) or the slope of the linear relationship between parallel BP and PI changes. These frequency-domain (spectral) and time-domain (sequence) techniques were tested in conscious mice equipped with telemetric devices. The autonomic relevance of these indexes was evaluated using pharmacological blockades. The significant changes of the spectral bandwidths resulting from the autonomic blockades were used to identify the low-frequency (LF) and high-frequency (HF) zones of interest. The LF gain was 1.45 +/- 0.14 ms/mmHg, with a PI delay of 0.5 s. For the HF gain, the average values were 2.0 +/- 0.19 ms/mmHg, with a null phase. LF and HF bands were markedly affected by atropine. On the same 51.2-s segments used for cross-spectral analysis, an average number of 26.4 +/- 2.2 slopes were detected, and the average slope in resting mice was 4.4 +/- 0.5 ms/mmHg. Atropine significantly reduced the slopes of the sequence method. BRS measurements obtained using the sequence technique were highly correlated to the spectral estimates. This study demonstrates the applicability of the recent methods used to estimate spontaneous BRS in mice. There was a vagal predominance in the baroreflex control of heart rate in conscious mice in the present conditions.     

Capsaicin increases modulation of sympathetic nerve activity in rats: measurement using power spectral analysis of heart rate fluctuations

We assessed the sympatho-vagal activities of the heart after administration of capsaicin by measuring the power spectral analysis in rats. There were major two frequency components of heart rate variability, which we defined as high (1.0 Hz <, HF) and low (LF, < 1.0 Hz) frequency components. Vagal blockade by atropine abolished the high frequency component, and lowered the amplitude of the low frequency component. On the other hand, under conditions of sympathetic blockade by propranolol, the low frequency component was reduced. Combined vagal and sympathetic blockade abolished all heart rate fluctuations. We analyzed the low and high frequency components by integrating the spectrum for the respective band width. The rats administered capsaicin had a higher heart rate and sympathetic nervous system index (LF/HF) than the control group of rats. These results suggest that power spectral analysis is an effective and noninvasive method for detecting subtle changes in autonomic activity in response to the intake of foods or drugs.     

Evaluation of baroreflex control of heart rate in renovascular hypertensive mice

The objective of the present study was to evaluate the baroreflex and the autonomic control of heart rate (HR) in renovascular hypertensive mice. Experiments were carried out in conscious C57BL/6 (n = 16) mice 28 days after a 2-kidney 1-clip procedure (2K1C mice) or a sham operation (sham mice). Baroreflex sensitivity was evaluated by measuring changes in heart rate (HR) in response to increases or decreases in mean arterial pressure (MAP) induced by phenylephrine or sodium nitroprusside. Cardiac autonomic tone was determined by use of atropine and atenolol. Basal HR and MAP were significantly higher in 2K1C mice than in sham mice. The reflex tachycardia induced by decreases in MAP was greatly attenuated in 2K1C mice compared with sham mice. Consequently, the baroreflex sensitivity was greatly decreased (2.2 +/- 0.4 vs. 4.4 +/- 0.3 beats x min(-1) x mmHg(-1)) in hypertensive mice compared with sham mice. The reflex bradycardia induced by increases in MAP and the baroreflex sensitivity were similar in both groups. Evaluation of autonomic control of HR showed an increased sympathetic tone and a tendency to a decreased vagal tone in 2K1C mice compared with that in sham mice. 2K1C hypertension in mice is accompanied by resting tachycardia, increased predominance of the cardiac sympathetic tone over the cardiac vagal tone, and impairment of baroreflex sensitivity.     

Cardiac sympathetic nerve stimulation does not attenuate dynamic vagal control of heart rate via alpha-adrenergic mechanism

Complex sympathovagal interactions govern heart rate (HR). Activation of the postjunctional beta-adrenergic receptors on the sinus nodal cells augments the HR response to vagal stimulation, whereas exogenous activation of the presynaptic alpha-adrenergic receptors on the vagal nerve terminals attenuates vagal control of HR. Whether the alpha-adrenergic mechanism associated with cardiac postganglionic sympathetic nerve activation plays a significant role in modulation of the dynamic vagal control of HR remains unknown. The right vagal nerve was stimulated in seven anesthetized rabbits that had undergone sinoaortic denervation and vagotomy according to a binary white-noise signal (0-10 Hz) for 10 min; subsequently, the transfer function from vagal stimulation to HR was estimated. The effects of beta-adrenergic blockade with propranolol (1 mg/kg i.v.) and the combined effects of beta-adrenergic blockade and tonic cardiac sympathetic nerve stimulation at 5 Hz were examined. The transfer function from vagal stimulation to HR approximated a first-order, low-pass filter with pure delay. beta-Adrenergic blockade decreased the dynamic gain from 6.0 +/- 0.4 to 3.7 +/- 0.6 beats x min(-1) x Hz(-1) (P < 0.01) with no alteration of the corner frequency or pure delay. Under beta-adrenergic blockade conditions, tonic sympathetic stimulation did not further change the dynamic gain (3.8 +/- 0.5 beats x min(-1) x Hz(-1)). In conclusion, cardiac postganglionic sympathetic nerve stimulation did not affect the dynamic HR response to vagal stimulation via the alpha-adrenergic mechanism.     

Effects of the cold pressor test on cardiac autonomic control in normal subjects

The cold pressor test (CPT) triggers in healthy subjects a vascular sympathetic activation and an increase in blood pressure. The heart rate (HR) response to this test is less well defined, with a high inter-individual variability. We used traditional spectral analysis together with the non-linear detrended fluctuation analysis to study the autonomic control of HR during a 3-min CPT. 39 healthy young subjects (23.7+/-3.2 years, height 180.4+/-4.7 cm and weight 73.3+/-6.4 kg) were divided into two groups according to their HR responses to CPT. Twenty subjects have a sustained increase in HR throughout the test with reciprocal autonomic interaction, i.e. increase in sympathetic activity and decrease vagal outflow. In the 19 remainders, HR decreased after an initial increase, with indication of involvement of both sympathetic and vagal outflow. Baseline evaluation of the subjects revealed no difference between the two groups. Nevertheless, a higher sympathetic activity at the skin level during CPT was present in the group with decreased HR. Further studies are needed to explain why healthy subjects react differently to the CPT and if this has potential clinical implications.     

Capsaicin Increases Modulation of Sympathetic Nerve Activity in Rats: Measurement Using Power Spectral Analysis of Heart Rate Fluctuations

We assessed the sympatho-vagal activities of the heart after administration of capsaicin by measuring the power spectral analysis in rats. There were major two frequency components of heart rate variability, which we defined as high (1.0 Hz<, HF) and low (LF, <1.0 Hz) frequency components. Vagal blockade by atropine abolished the high frequency component, and lowered the amplitude of the low frequency component. On the other hand, under conditions of sympathetic blockade by propranolol, the low frequency component was reduced. Combined vagal and sympathetic blockade abolished all heart rate fluctuations. We analyzed the low and high frequency components by integrating the spectrum for the respective band width. The rats administered capsaicin had a higher heart rate and sympathetic nervous system index (LF/HF) than the control group of rats. These results suggest that power spectral analysis is an effective and noninvasive method for detecting subtle changes in autonomic activity in response to the intake of foods or drugs.     

Central and peripheral mechanisms underlying gastric distention inhibitory reflex responses in hypercapnic-acidotic rats

We have observed that in chloralose-anesthetized animals, gastric distension (GD) typically increases blood pressure (BP) under normoxic normocapnic conditions. However, we recently noted repeatable decreases in BP and heart rate (HR) in hypercapnic-acidotic rats in response to GD. The neural pathways, central processing, and autonomic effector mechanisms involved in this cardiovascular reflex response are unknown. We hypothesized that GD-induced decrease in BP and HR reflex responses are mediated during both withdrawal of sympathetic tone and increased parasympathetic activity, involving the rostral (rVLM) and caudal ventrolateral medulla (cVLM) and the nucleus ambiguus (NA). Rats anesthetized with ketamine and xylazine or α-chloralose were ventilated and monitored for HR and BP changes. The extent of cardiovascular inhibition was related to the extent of hypercapnia and acidosis. Repeated GD with both anesthetics induced consistent falls in BP and HR. The hemodynamic inhibitory response was reduced after blockade of the celiac ganglia or the intraabdominal vagal nerves with lidocaine, suggesting that the decreased BP and HR responses were mediated by both sympathetic and parasympathetic afferents. Blockade of the NA decreased the bradycardia response. Microinjection of kainic acid into the cVLM reduced the inhibitory BP response, whereas depolarization blockade of the rVLM decreased both BP and HR inhibitory responses. Blockade of GABA(A) receptors in the rVLM also reduced the BP and HR reflex responses. Atropine methyl bromide completely blocked the reflex bradycardia, and atenolol blocked the negative chronotropic response. Finally, α(1)-adrenergic blockade with prazosin reversed the depressor. Thus, in the setting of hypercapnic-acidosis, a sympathoinhibitory cardiovascular response is mediated, in part, by splanchnic nerves and is processed through the rVLM and cVLM. Additionally, a vagal excitatory reflex, which involves the NA, facilitates the GD-induced decreases in BP and HR responses. Efferent chronotropic responses involve both increased parasympathetic and reduced sympathetic activity, whereas the decrease in BP is mediated by reduced α-adrenergic tone.     

Effect of autonomic blockers on heart period variability in calves: evaluation of the sympathovagal balance

This study was designed to validate the measures of heart period variability for assessing of autonomic nervous system control in calves. Eight calves received an injection of either 0.5 mg/kg atenolol (sympathetic tone blockade), 0.2 mg/kg atropine sulfate (parasympathetic tone blockade), 0.5 mg/kg atenolol + 0.2 mg/kg atropine sulfate (double autonomic blockade) or saline. In the time-domain, we calculated the mean instantaneous heart rate (HR), mean of RR intervals (MeanRR), standard deviation of RR intervals (SDRR) and that of the difference between adjacent intervals (RMSSD). In the frequency-domain, the power of the spectral band 0-1 Hz (TPW), the power of the 0-0.15 Hz band (LF), that of the 0.15-1 Hz band (HF), and the LF/HF ratio were considered. The net vago-sympathetic effect (VSE) was calculated as the ratio of MeanRR in a defined situation to MeanRR during the double blockade. Atenolol injection had no effect on cardiac activity, whereas atropine induced large modifications which were moderated when atenolol was administered at the same time. VSE, HR, MeanRR and RMSSD were found to be valid indicators of the parasympathetic tone of calves because of large variations due to the drug and low individual variations. No measure reflected the sympathetic tone.     

Early autonomic malfunction in normotensive individuals with a genetic predisposition to essential hypertension

One of the primary pathologies associated with hypertension is a complex autonomic dysfunction with evidence of sympathetic hyperactivity and/or vagal withdrawal. We investigated the possibility for early detection of essential hypertension on the basis of the analysis of heart rate (HR) and blood pressure fluctuations, which reflect autonomic control. Young adult normotensive offspring of one hypertensive parent (KHT; n = 12) and normotensive offspring of two normotensive parents (YN; n = 14) participated in this study. ECG, continuous blood pressure, and respiration were recorded during steady-state conditions and under various autonomic challenges. Time-frequency decomposition of these signals was performed with the use of a continuous wavelet transform. The use of the wavelet transform enables the extension of typical HR variability analysis to non-steady-state conditions. This time-dependent spectral analysis of HR allows time-dependent quantification of different spectral components reflecting the sympathetic and parasympathetic activity during rapid transitions, such as an active change in posture (CP). During an active CP from the supine to standing position, KHT demonstrated a significantly greater increase in the low-frequency fluctuations in HR than YN, indicating enhanced sympathetic involvement in the HR response to CP, and a reduced alpha-index, indicating decreased baroreceptor sensitivity. On recovery from handgrip, vagal reactivation was more sluggish in KHT. These results indicate the early existence of malfunctions in both branches of autonomic control in individuals at increased risk of hypertension.     

Quantitative evaluation of ontogenetic change in heart rate and its autonomic regulation in newborn mice with the use of a noninvasive piezoelectric sensor

A reliable basal heart rate (HR) measurement in freely moving newborn mice was accomplished for the first time by using a novel noninvasive piezoelectric transducer (PZT) sensor. The basal HR was approximately 320 beats/min at postnatal day (P)0 and increased with age to approximately 690 beats/min at P14. Contribution of autonomic control to HR was then assessed. Sympathetic blockade with metoprolol significantly reduced basal HR at both P6 (-236 +/- 23 beats/min; mean +/- SE) and P12 (-105 +/- 8 beats/min), but atropine was without effect, indicating the predominant tonic adrenergic stimulation and absence of vagal control for basal HR in newborn mice. In contrast to stable basal HR during 5-min recording, HR measured by ECG (ECG-HR) was markedly decreased because of the restraint stress of attaching ECG electrodes, with accompanying freezing behavior. ECG-HR lowered and further decreased gradually during 5 min (slow cardiodeceleration) at P0-P3 and rapidly decreased and gradually recovered within 5 min (transient bradycardia) at P9-P14. The response was not uniform in P4-P8 mice: they showed either of these two patterns or sustained bradycardia (9-29%), and the number of mice that showed transient bradycardia increased with age (30-100%) during the period. Studies with autonomic blockade suggest that the slow cardiodeceleration and transient bradycardia are mediated mainly by withdrawal of adrenergic stimulation and phasic vagal activation, respectively, and the autonomic control of HR response to restraint stress is likely to change from the withdrawal of adrenergic stimulation to the phasic vagal activation at different stages during P4-P8 in individual mice. The PZT sensor may offer excellent opportunities to monitor basal HR of small animals noninvasively.     

Power spectral analysis of heart rate variability for assessment of diurnal variation of autonomic nervous activity in miniature swine.

BACKGROUND AND PURPOSES: The purpose of the study was to document diurnal variation of autonomic nervous functions by use of power spectral analysis of heart rate (HR) variability. METHODS: To clarify characteristics of power spectral analysis of HR variability, electrocardiogram (ECG), blood pressure (BP), and respiratory (Resp) waveform simultaneously were recorded. RESULTS: Two major spectral components were examined at low (LF)- and high (HF)-frequency bands for HR variability. Coherence between HR and Resp variabilities and HR and BP variabilities was maximal at approximately 0.14 and 0.03 Hz, respectively. On the basis of these data, two frequency bands of interest--LF (0.01 to 0.07 Hz) and HF (0.07 to 1.0 Hz)--were defined. Autonomic blockade studies indicated that the parasympathetic system mediated the HF and LF components, whereas the sympathetic system mediated only the LF component; HR had a diurnal pattern. The LF and HF bands in the dark phase tended to be higher than those in the light phase. The LF-to-HF ratio had a diurnal pattern similar to that of the HR. CONCLUSION: Parasympathetic nervous activity in miniature swine may be predominant in the dark phase. The characteristics of power spectra and diurnal variations of autonomic nervous functions are almost the same as those of humans. Therefore, miniature swine may be a useful animal model for future biobehavioral and pharmacotoxicologic studies.     

Short-term and long-term blood pressure and heart rate variability in the mouse

Knowledge on murine blood pressure and heart rate control mechanisms is limited. With the use of a tethering system, mean arterial pressure (MAP) and pulse interval (PI) were continuously recorded for periods up to 3 wk in Swiss mice. The day-to-day variation of MAP and PI was stable from 5 days after surgery. Within each mouse (n = 9), MAP and PI varied by 21+/-6 mm Hg and 17+/-4 ms around their respective 24-h averages (97+/-3 mm Hg and 89+/-3 ms). Over 24-h periods, MAP and PI were bimodally distributed and clustered around two preferential states. Short-term variability of MAP and PI was compared between the resting (control) and active states using spectral analysis. In resting conditions, variability of MAP was mainly confined to frequencies <1 Hz, whereas variability of PI was predominantly linked to the respiration cycle (3-6 Hz). In the active state, MAP power increased in the 0.08- to 3-Hz range, whereas PI power fell in the 0.08- to 0.4-Hz range. In both conditions, coherence between MAP and PI was high at 0.4 Hz with MAP leading the PI fluctuations by 0.3-0.4 s, suggesting that reflex coupling between MAP and PI occurred at the same frequency range as in rats. Short-term variability of MAP and PI was studied after intravenous injection of autonomic blockers. Compared with the resting control state, MAP fell and PI increased after ganglionic blockade with hexamethonium. Comparable responses of MAP were obtained with the alpha-blocker prazosin, whereas the beta-blocker metoprolol increased PI similarly. Muscarinic blockade with atropine did not significantly alter steady-state levels of MAP and PI. Both hexamethonium and prazosin decreased MAP variability in the 0.08- to 1-Hz range. In contrast, after hexamethonium and metoprolol, PI variability increased in the 0.4- to 3-Hz range. Atropine had no effect on MAP fluctuations but decreased those of PI in the 0.08- to 1-Hz range. These data indicate that, in mice, blood pressure and its variability are predominantly under sympathetic control, whereas both vagal and sympathetic nerves control PI variability. Blockade of endogenous nitric oxide formation by N(G)-nitro-L-arginine methyl ester increased MAP variability specifically in the 0.08- to 0.4-Hz range, suggesting a role of nitric oxide in buffering blood pressure fluctuations.     

Wavelet analysis of instantaneous heart rate: a study of autonomic control during thrombolysis

Myocardial infarction (MI) is known to elicit activation of the autonomic nervous system. Reperfusion, induced by thrombolysis, is thus expected to bring about a shift in the balance between the sympathetic and vagal systems, according to the infarct location. In this study, we explored the correlation between reperfusion and the spectral components of heart rate (HR) variability (HRV), which are associated with autonomic cardiac control. We analyzed the HR of patients during thrombolysis: nine anterior wall MI (AW-MI) and eight inferoposterior wall MI (IW-MI). Reperfusion was determined from changes in ST levels and reported pain. Reocclusion was detected in four patients. HRV was analyzed using a modified continuous wavelet transform, which provided time-dependent versions of the typically used low-frequency (LF) and high-frequency (HF) peaks and of their ratio, LF/HF. Marked alterations in at least one of the HRV parameters was found in all 18 reperfusion events. Patterns of HRV, compatible with a shift toward relative sympathetic enhancement, were found in all of the nine reperfusion events in IW-MI patients and in three AW-MI patients. Patterns of HRV compatible with relative vagal enhancement were found in six AW-MI patients (P < 0.001). Significant changes in HRV parameters were also found after reocclusion. Time-dependent spectral analysis of HRV using the wavelet transform was found to be valuable for explaining the patterns of cardiac rate control during reperfusion. In addition, examination of the entire record revealed epochs of markedly diminished HRV in two patients, which we attribute to vagal saturation.     

Power spectral analysis of heart rate variability for assessment of diurnal variation of autonomic nervous activity in guinea pigs.

We established characteristics of power spectral analysis of heart rate variability, and assessed the diurnal variations of autonomic nervous function in guinea pigs. For this purpose, an electrocardiogram (ECG) was recorded for 24 hr from conscious and unrestrained guinea pigs using a telemetry system. There were two major spectral components, at low frequency (LF) and high frequency (HF) bands, in the power spectrum of HR variability. On the basis of these data, we defined two frequency bands of interest: LF (0.07-0.7 Hz) and HF (0.7-3.0 Hz). The power of LF was higher than that of HF in the normal guinea pigs. Atropine significantly reduced power at HF. Propranolol also significantly reduced power at LF. Furthermore, the decrease in the parasympathetic mechanism produced by atropine was reflected in a slight increase in the LF/HF ratio. The LF/HF ratio appeared to follow the reductions of sympathetic activity produced by propranolol. Autonomic blockade studies indicated that the HF component reflected parasympathetic activity and the LF/HF ratio seemed to be a convenient index of autonomic balance. Nocturnal patterns, in which the values of heart rate in the dark phase (20:00-06:00) were higher than those in the light phase (06:00-20:00), were observed. However, the HF, LF and the LF/HF ratio showed no daily pattern. These results suggest that the autonomic nervous function in guinea pigs has no clear circadian rhythmicity. Therefore, this information may be useful for future studies concerning the autonomic nervous function in this species.     

Exercise training augments the dynamic heart rate response to vagal but not sympathetic stimulation in rats

We examined the transfer function of autonomic heart rate (HR) control in anesthetized sedentary and exercise-trained (16 wk, treadmill for 1 h, 5 times/wk at 15 m/min and 15-degree grade) rats for comparison to HR variability assessed in the conscious resting state. The transfer function from sympathetic stimulation to HR response was similar between groups (gain, 4.2 ± 1.5 vs. 4.5 ± 1.5 beats·min(-1)·Hz(-1); natural frequency, 0.07 ± 0.01 vs. 0.08 ± 0.01 Hz; damping coefficient, 1.96 ± 0.55 vs. 1.69 ± 0.15; and lag time, 0.7 ± 0.1 vs. 0.6 ± 0.1 s; sedentary vs. exercise trained, respectively, means ± SD). The transfer gain from vagal stimulation to HR response was 6.1 ± 3.0 in the sedentary and 9.7 ± 5.1 beats·min(-1)·Hz(-1) in the exercise-trained group (P = 0.06). The corner frequency (0.11 ± 0.05 vs. 0.17 ± 0.09 Hz) and lag time (0.1 ± 0.1 vs. 0.2 ± 0.1 s) did not differ between groups. When the sympathetic transfer gain was averaged for very-low-frequency and low-frequency bands, no significant group effect was observed. In contrast, when the vagal transfer gain was averaged for very-low-frequency, low-frequency, and high-frequency bands, exercise training produced a significant group effect (P < 0.05 by two-way, repeated-measures ANOVA). These findings suggest that, in the frequency domain, exercise training augments the dynamic HR response to vagal stimulation but not sympathetic stimulation, regardless of the frequency bands.     

Baroreflex sensitivity, blood pressure buffering, and resonance: what are the links? Computer simulation of healthy subjects and heart failure patients.

The arterial baroreflex buffers slow (<0.05 Hz) blood pressure (BP) fluctuations, mainly by controlling peripheral resistance. Baroreflex sensitivity (BRS), an important characteristic of baroreflex control, is often noninvasively assessed by relating heart rate (HR) fluctuations to BP fluctuations; more specifically, spectral BRS assessment techniques focus on the BP-to-HR transfer function around 0.1 Hz. Skepticism about the relevance of BRS to characterize baroreflex-mediated BP buffering is based on two considerations: 1) baroreflex-modulated peripheral vasomotor function is not necessarily related to baroreflex-HR transfer; and 2) although BP fluctuations around 0.1 Hz (Mayer waves) might be related to baroreflex BP buffering, they are merely a not-intended side effect of a closed-loop control system. To further investigate the relationship between BRS and baroreflex-mediated BP buffering, we set up a computer model of baroreflex BP control to simulate normal subjects and heart failure patients. Output variables for various randomly chosen combinations of feedback gains in the baroreflex arms were BP resonance, BP-buffering capacity, and BRS. Our results show that BP buffering and BP resonance are related expressions of baroreflex BP control and depend strongly on the sympathetic gain to the peripheral resistance. BRS is almost uniquely determined by the vagal baroreflex gain to the sinus node. In conclusion, BP buffering and BRS are unrelated unless coupled gains in all baroreflex limbs are assumed. Hence, the clinical benefit of a high BRS is most likely to be attributed to vagal effects on the heart instead of to effective BP buffering.     

Sudden cardiac death thirty years ago and at present. The role of autonomic disturbances in acute myocardial infarction revisited

The most common cause of sudden cardiac death is ventricular fibrillation (VF). In addition to the status, size and location of the ventricular focus, a major pathogenic mechanism triggering VF is autonomic dysbalance (disturbance). This term refers to a wide range of reflex changes in the ratio of sympathetic to vagal ventricular activation over time, occurring immediately after coronary artery occlusion at the onset of acute myocardial infarction (AMI). Another trigger of VF is autonomic disturbance due to emotional stress. Experimental and clinical research into autonomic disturbances associated with coronary artery occlusion and emotional stress was given considerable attention as early as some 30 years ago when researchers were already searching for ways of inhibiting autonomic disturbances using predominant sympathetic and vagal activation by beta-blockers (BB) and atropine, respectively. The aim of our paper is to compare results obtained 30 years ago with current status of experimental and clinical research into SCD prevention. Another aim is to identify questions that have remained unanswered to date; answers to these outstanding questions could help further reduce the risk of SCD.     

Cyclosporine attenuates the autonomic modulation of reflex chronotropic responses in conscious rats

Cyclosporine A (CyA), an immunosuppressant drug, has been shown to attenuate the baroreflex control of heart rate (HR). This study investigated whether or not the CyA-induced baroreflex dysfunction is due to alterations in the autonomic (sympathetic and parasympathetic) control of the heart. We evaluated the effect of muscarinic or beta-adrenergic blockade by atropine and propranolol, respectively, on reflex HR responses in conscious rats treated with CyA (20 mg x kg(-1) x day(-1) dissolved in sesame oil) for 11-13 days or the vehicle. Baroreflex curves relating changes in HR to increases or decreases in blood pressure (BP) evoked by phenylephrine (PE) and sodium nitroprusside (NP), respectively, were constructed and the slopes of the curves were taken as a measure of baroreflex sensitivity (BRS(PE) and BRS(NP)). Intravenous administration of PE and NP produced dose-related increases and decreases in BP, respectively, that were associated with reciprocal changes in HR. CyA caused significant (P < 0.05) reductions in reflex HR responses as indicated by the smaller BRS(PE) (-0.97 +/- 0.07 versus -1.47 +/- 0.10 beats x min(-1) x mmHg(-1) (1 mmHg = 133.322 Pa)) and BRS(NP) (-2.49 +/- 0.29 versus -5.23 +/- 0.42 beats x min(-1) x mmHg(-1)) in CyA-treated versus control rats. Vagal withdrawal evoked by muscarinic blockade elicited significantly lesser attenuation of BRS(PE) in CyA compared with control rats (40.2 +/- 8.0 versus 57.7 +/- 4.4%) and abolished the BRS(PE) difference between the two groups, suggesting that CyA reduces vagal activity. CyA also appears to impair cardiac sympathetic control because blockade of beta-adrenergic receptors by propranolol was less effective in reducing reflex tachycardic responses in CyA compared with control rats (41.6 +/- 4.2 versus 59.5 +/- 4.5%). These findings confirm earlier reports that CyA attenuates the baroreceptor control of HR. More importantly, the study provides the first pharmacological evidence that CyA attenuates reflex chronotropic responses via impairment of the autonomic modulation of the baroreceptor neural pathways.