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Am J Physiol Regul Integr Comp Physiol 275: R541-R547, 1998;
0363-6119/98 $5.00
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Vol. 275, Issue 2, R541-R547, August 1998

Cholinesterase affects dynamic transduction properties from vagal stimulation to heart rate

Tsutomu Nakahara, Toru Kawada, Masaru Sugimachi, Hiroshi Miyano, Takayuki Sato, Toshiaki Shishido, Ryoichi Yoshimura, Hiroshi Miyashita, and Kenji Sunagawa

Department of Cardiovascular Dynamics, The National Cardiovascular Center Research Institute, Suita, Osaka, Japan

    ABSTRACT
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References

Recent investigations in our laboratory using a Gaussian white noise technique showed that the transfer function representing the dynamic properties of transduction from vagus nerve activity to heart rate had characteristics of a first-order low-pass filter. However, the physiological determinants of those characteristics remain to be elucidated. In this study, we stimulated the vagus nerve according to a Gaussian white noise pattern to estimate the transfer function from vagal stimulation to the heart rate response in anesthetized rabbits and examined how changes in acetylcholine kinetics affected the transfer function. We found that although increases in the mean frequency of vagal stimulation from 5 to 10 Hz did not change the characteristics of the transfer function, administration of neostigmine (30 µg · kg-1 · h-1 iv), a cholinesterase inhibitor, increased the dynamic gain from 8.19 ± 3.66 to 11.7 ± 4.88 beats · min-1 · Hz-1 (P < 0.05), decreased the corner frequency from 0.12 ± 0.05 to 0.04 ± 0.01 Hz (P < 0.01), and increased the lag time from 0.17 ± 0.12 to 0.27 ± 0.08 s (P < 0.05). These results suggest that the rate of acetylcholine degradation at the neuroeffector junction, rather than the amount of available acetylcholine, plays a key role in determining the dynamic properties of transduction from vagus nerve activity to heart rate.

systems analysis; Gaussian white noise; dynamic stimulation; rabbit

    INTRODUCTION
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References

ALTHOUGH THERE IS AN ABUNDANCE of literature regarding the vagal control of heart rate (HR), the determinants of the dynamic properties of transduction from vagus nerve activity to HR remain to be elucidated. Previous investigations using dynamic systems analysis have shown that HR minimally responds to changes in vagus nerve activity in the high-frequency range (>0.1 Hz); that is to say, the transfer function from vagal stimulation to HR response has low-pass filter characteristics (2, 6, 18, 19, 22, 26). Inasmuch as the characteristics of the transfer function represent the dynamic transduction properties relating vagus nerve activity to HR, a detailed analysis of the transfer function would likely enable an identification of the physiological determinants of these dynamic transduction properties.

Stimulation of the vagus nerve causes a cascade reaction involving the release of acetylcholine (ACh), which in turn leads to changes in the membrane ionic currents of the pacemaker cell (15). Characteristics of the rate-limiting step in the signaling pathway might be the main determinants of the dynamic transduction properties relating vagus nerve activity to HR. In studies on the rabbit sinoatrial node, it was shown that the diffusion of ACh markedly affected the time course of the muscarinic response (i.e., hyperpolarization) (23, 24). Furthermore, other observations (5, 13, 35) and mathematical models of underlying cellular mechanisms responsible for the changes in HR elicited by vagal stimulation predict that ACh concentration in neuroeffector junctions of the sinus node responds more slowly to changes in vagus nerve activity than does the membrane ionic currents to changes in ACh concentration (9-12, 22). Thus we hypothesized that the changes in ACh kinetics might critically affect the dynamic properties of transduction from vagus nerve activity to HR.

To examine this hypothesis, we modulated both the mean frequency of vagal stimulation and cholinesterase (ChE) activity, and evaluated the resulting changes in the transfer function from vagal stimulation frequency to HR response in anesthetized rabbits. The results suggested that ChE activity plays an important role in determining the dynamic properties of transduction from vagus nerve activity to HR.

    MATERIALS AND METHODS
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References

Surgical preparations. Animal care was in accordance with institutional guidelines. Fourteen Japanese White rabbits weighing 2.4-3.0 kg were anesthetized using urethan (250 mg/kg iv) and alpha -chloralose (40 mg/kg iv) and mechanically ventilated with oxygen-enriched room air. Supplemental doses of anesthetics were given via the right femoral vein as necessary. Aortic pressure was monitored by means of a micromanometer catheter (model PC-340, 3F, Millar Instrument, Houston, TX) inserted via the left femoral artery. A catheter was inserted into the right femoral vein for the administration of drugs. The bilateral carotid sinus nerves and aortic depressor nerves were cut to eliminate the effects of the arterial baroreflex systems. We transected the bilateral sympathetic nerves at the level of the stellate ganglion to eliminate the possible interaction between the vagus and sympathetic nerves. Vagus nerves were sectioned bilaterally at the neck, where a pair of bipolar platinum electrodes was attached to the cardiac end of the sectioned right vagus nerve for stimulation. To prevent drying and to provide insulation, the stimulation electrodes and the nerve were immersed in a mixture of white petrolatum (Vaseline) and paraffin. Finally, a pair of bipolar stainless steel electrodes was sutured to the right atrium to record the cardiac electrogram for monitoring of HR. During all experiments, body temperature was maintained at 37°C with a heating pad.

Experimental procedures. The pulse duration of nerve stimulation was set at 2 ms. We adjusted the amplitude of vagal stimulation to yield an HR decrease of ~50 beats/ min at 5 Hz. This resulted in an amplitude ranging from 2.5 to 4.0 V (3.0 ± 0.9 V). To estimate the dynamic transduction properties, we stimulated the vagus nerve using a pulse train that was frequency modulated by a band-limited Gaussian white noise (2, 18, 19, 31). The instantaneous stimulation frequency was switched one time per second, yielding an input power spectrum that was fairly constant up to 0.5 Hz, decreased gradually to 1/10 at ~0.8 Hz, and attenuated sharply as the frequency increased to 1 Hz. We estimated the transfer function only up to 0.8 Hz, because the lack of input power above that frequency made estimation unreliable. The frequency range was nevertheless sufficient in spanning the physiological frequency range of vagal HR regulation (2, 18, 19).

In the first series of experiments (n = 6), we examined how changes in the mean frequency of the Gaussian white noise input vagal stimulation pattern affected the transfer function from vagal stimulation frequency to HR response. We set the mean stimulation frequency at either 5 or 10 Hz, with a standard deviation of frequency modulation of 2 Hz. We used different Gaussian white noise perturbation command sequences for different animals while keeping the statistical characteristics of the perturbation sequences, such as the mean frequency and standard deviation, unchanged. We also randomized the order of stimulation among the animals to reduce the likelihood of bias or systematic errors in our identification approach. After steady-state conditions were reached with each mean frequency change, we recorded both the vagal stimulation frequency and HR for 10 min.

In the second series of experiments (n = 8), we examined how the inhibition of ChE influenced the transfer function. After first recording the control HR response to dynamic vagal stimulation with Gaussian white noise (5 ± 2 Hz), we repeated the same protocol 15-20 min after initiation of continuous intravenous infusion of neostigmine at 30 µg · kg-1 · h-1 (Sigma, St. Louis, MO). This was the maximum dose, identified in preliminary experiments, beyond which hemodynamic instability ensued.

HR and vagal stimulation frequency were digitized at 200 Hz using a 12-bit analog-to-digital converter and stored on the hard disk of a dedicated laboratory computer system (NEC PC-98, Tokyo, Japan). We calculated the mean level of HR before vagal stimulation by averaging instantaneous HR for 10 s before the stimulation. The mean level of HR during vagal stimulation was calculated by averaging instantaneous HR over the time period (10 min).

Estimation of the transfer function. After applying an antialiasing filter, we resampled the input (vagal stimulation frequency)-output (HR) data pairs at 10 Hz and then segmented the data into eight 50%-overlapping segments of 1,024 data points each. For each segment, the linear trend was subtracted and a Hanning window was applied. We then performed a fast Fourier transformation to obtain the frequency spectrum of nerve stimulation frequency [N(f)] and of HR response [HR(f)]. The frequency resolution was 0.01 Hz.

We ensemble averaged, over the eight segments, the power of the nerve stimulation [SN · N(f)], the HR response [SHR · HR(f)], and the cross power between them [SN · HR(f)]. Finally, we obtained the transfer function relating nerve stimulation frequency to HR response [H(f)] using the following equation
H(f) = <FR><NU>S<SUB>N ⋅ HR</SUB>(f)</NU><DE>S<SUB>N ⋅ N</SUB>(f)</DE></FR> (1)
The modulus [|H(f)|] and phase shift [theta (f)] of the transfer function were derived from its real part [HR(f)] and imaginary part [HI(f)] using the following equations
‖H(f)‖ = <RAD><RCD>H<SUB>R</SUB>(f)<SUP>2</SUP> + H<SUB>I</SUB> (f)<SUP>2</SUP></RCD></RAD> (2)
&thgr;(f) = tan<SUP>−1</SUP> <FR><NU>H<SUB>I</SUB> (f)</NU><DE>H<SUB>R</SUB>(f)</DE></FR> (3)
The modulus indicates the relative amplitude of HR change per unit change in nerve stimulation frequency and is expressed in units of beats per minute per hertz. We hereafter refer to the modulus as the gain of the transfer function. The phase shift is also a function of frequency and indicates, with respect to the input, a lag or lead in the output normalized by its corresponding frequency.

Because the transfer function from vagal stimulation frequency to HR response approximated a first-order low-pass filter with lag time (18), we parameterized the transfer function using the following equation
H(f) = <FR><NU>−K</NU><DE>1 + <FR><NU>f</NU><DE>f<SUB> c</SUB></DE></FR> <IT>j</IT></DE></FR> <IT>e</IT><SUP>−2&pgr;f <IT>j</IT>L</SUP>
<IT>j</IT> = <RAD><RCD>−1</RCD></RAD> (4)
where K is the estimated gain at zero frequency (and referred to hereafter as dynamic gain), f is the frequency, fc is the corner frequency at which the gain decreases by 3 dB from its steady-state value, and L is the lag time. L is defined as the time delay between the input and the output of the system without any distortion of the input signal (20). The negative sign in front of K in the equation results from the negative HR response to vagal stimulation.

To quantify the linear dependence of the HR response to nerve stimulation, we estimated the coherence function [Coh(f)] using of the following equation
Coh(f) = <FR><NU>‖S<SUB>N ⋅ HR</SUB>(f)‖<SUP>2</SUP></NU><DE>S<SUB>N ⋅ N</SUB>(f)S<SUB>HR ⋅ HR</SUB>(f)</DE></FR> (5)
After estimating the transfer functions, we used inverse Fourier transformation to determine the corresponding step response of HR to a 1-Hz nerve stimulation step input to easily visualize the system characteristics. The length of the calculated step response was 51.2 s. We derived the maximum step response by averaging the last 10 s of the estimated step response. The 90% rise time of the step response was also calculated relative to the maximum step response.

We calculated the time constant (tau ) and the rate constant (K) from fc using the following equations
&tgr; = <FR><NU>1</NU><DE>2&pgr;f<SUB> c</SUB></DE></FR> (6)
<IT>K</IT> = <FR><NU>1</NU><DE>&tgr;</DE></FR> (7)

Statistical analysis. We used Student's paired t-test for the statistical analysis of paired data. Differences were considered statistically significant if P < 0.05. All values are presented as means ± SD.

    RESULTS
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References

Effect of mean frequency on transfer function. Figure 1 shows typical recordings of vagal stimulation frequency as modulated by Gaussian white noise (Fig. 1, top) and associated HR responses (Fig. 1, bottom). HR changed in a fashion that was roughly reciprocal in relation to the stimulation pattern. Dynamic vagal stimulation at 5 ± 2 and 10 ± 2 Hz decreased the mean level of HR and mean aortic pressure relative to prestimulation values (P < 0.05) (Table 1). The mean level of HR during stimulation at 10 ± 2 Hz was lower than that at 5 ± 2 Hz (P < 0.01). In contrast, there was no significant difference between mean aortic pressures in response to vagal stimulations at 5 ± 2 and 10 ± 2 Hz.


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Fig. 1.   Representative recordings of vagal nerve stimulation (VNS) via band-limited Gaussian white noise (top) and associated heart rate (HR) responses (bottom). Stimulation at frequencies of 5 ± 2 Hz (A) and 10 ± 2 Hz (B) are shown.

                              
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Table 1.   Effect of dynamic vagal stimulation on mean levels of HR and MAP

Figure 2 shows the transfer function obtained at stimulation frequencies of 5 ± 2 and 10 ± 2 Hz. The gain plot (Fig. 2, top), phase plot (Fig. 2, middle), and coherence (Fig. 2, bottom) are shown. Characteristics of the gain and phase plots match what is known as a first-order low-pass filter with lag time. At the lowest frequencies, the phase shift was nearly out of phase (i.e., -pi radians) and decreased further as frequency increased. The coherence was >0.8 in the frequency range from 0.01 to 0.3 Hz, indicating strong linearity between vagal stimulation and HR response in this frequency range. The gains and phase shifts of the transfer functions and coherences obtained at the two levels of stimulation frequency were not remarkably different. Consequently, there were no significant differences between the parameters characterizing the respective transfer functions, as summarized in Table 2.


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Fig. 2.   Averaged transfer function from vagal stimulation frequency to HR change obtained at stimulation frequencies of 5 ± 2 Hz (A) and 10 ± 2 Hz (B) (pooled data; n = 6). Gain (top), phase shift (middle) and coherence function (Coh, bottom) are shown. Note that gain and frequency axes are logarithmically scaled. Solid lines, mean values; broken lines, mean + SD values; bpm, beats/min.

                              
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Table 2.   Effect of changes in mean frequency of vagal stimulation on parameters of transfer function relating dynamic vagal stimulation to HR

The corner frequencies of HR response to vagal stimulation at 5 ± 2 and 10 ± 2 Hz were 0.10 ± 0.05 and 0.11 ± 0.04 Hz, respectively (Table 2). This means that HR responded mainly to changes in vagus nerve activity in frequencies <0.1 Hz. According to Eqs. 6 and 7, defined in MATERIALS AND METHODS, we calculated the time constants from these corner frequencies and estimated the rate constants. There were no significant differences in the time constants (1.8 ± 0.7 vs. 1.7 ± 0.7 s) or the rate constants (0.66 ± 0.30 vs. 0.70 ± 0.28 s-1) derived for the two conditions of mean stimulation frequency.

Effect of neostigmine on transfer function. Figure 3 shows typical recordings of vagal stimulation frequency (Fig. 3, top) and associated HR responses (Fig. 3, bottom) before and during infusion of neostigmine (30 µg · kg-1 · h-1 iv). Neostigmine decreased the mean level of HR both before and during dynamic vagal stimulation (P < 0.01) (Table 3). In contrast, although neostigmine showed a tendency to decrease mean aortic pressure before vagal stimulation, the change did not reach statistical significance. Neither were decreases in mean aortic pressure elicited by vagal stimulation affected by neostigmine.


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Fig. 3.   Representative recordings of VNS via band-limited Gaussian white noise (top) and associated HR responses (bottom) before (control, A) and during infusion of neostigmine (30 µg · kg-1 · h-1 iv, B).

                              
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Table 3.   Effect of neostigmine infusion (30 µg · kg-1 · h-1 iv) on mean levels of HR and MAP

Figure 4 shows the effect of neostigmine on the transfer function from vagal stimulation frequency to HR response. The gain plot (Fig. 4, top), phase plot (Fig. 4, middle), and coherence (Fig. 4, bottom) are shown. As summarized in Table 4, neostigmine increased the dynamic gain from 8.19 ± 3.66 to 11.7 ± 4.88 beats · min-1 · Hz-1 (P < 0.05) and decreased the corner frequency from 0.12 ± 0.05 to 0.04 ± 0.01 Hz (P < 0.01). Neostigmine increased the lag time from 0.17 ± 0.12 to 0.27 ± 0.08 s (P < 0.05), suggesting a prolongation of the latency of onset of the HR response to vagal stimulation. However, neostigmine did not significantly affect the coherence.


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Fig. 4.   Averaged transfer function from vagal stimulation frequency to HR change before (A) and during infusion of neostigmine (30 µg · kg-1 · h-1 iv, B) (pooled data, n = 8). Gain (top), phase shift (middle), and Coh (bottom) are shown. Solid lines, mean values; broken lines, mean + SD values.

                              
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Table 4.   Effect of neostigmine infusion (30 µg · kg-1 · h-1 iv) on parameters of transfer function relating dynamic vagal stimulation to HR

Neostigmine significantly prolonged the time constants estimated from the corner frequencies of the HR response to vagal stimulation from 1.5 ± 0.6 to 4.1 ± 0.9 s (P < 0.01). It also decreased the estimated rate constants from 0.75 ± 0.28 to 0.25 ± 0.05 s-1 (P < 0.01). The rate constants were in good agreement with those obtained from experimental and theoretical studies (4, 5, 10-13, 17, 24).

Figure 5 shows the calculated step response of HR to a 1-Hz vagal stimulation step input before and during infusions of neostigmine. Neostigmine increased the maximum step response of HR from 7.94 ± 3.98 to 11.4 ± 4.22 beats/min (P < 0.05) and prolonged the 90% rise time from 4.40 ± 1.74 to 8.31 ± 4.15 s (P < 0.01).


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Fig. 5.   Step response of HR calculated from transfer function obtained before (control, A) and during infusion of neostigmine (30 µg · kg-1 · h-1 iv, B). Neostigmine increased maximum response and prolonged time period required for maximum response. Solid lines, mean values; broken lines, mean - SD values.

    DISCUSSION
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References

We showed that an increase in the mean frequency of vagal stimulation did not change the transfer function from vagal stimulation frequency to HR response, whereas neostigmine markedly affected it. These results suggest that the dynamic properties of transduction from vagus nerve activity to HR are affected by the rate of ACh degradation rather than by the amount of available ACh.

It is well established that the muscarinic response to static vagal stimulation depends on stimulation frequency and the activity of acetylcholinesterase (1, 3, 25, 27, 28). In this study, we found that decreases in the mean level of HR elicited by dynamic vagal stimulation were dependent on mean stimulation frequency and potentiated by neostigmine. In a previous report, a conceptual framework was proposed wherein the operating HR is determined through a sigmoidal relationship between autonomic nervous activity and HR (18). Although this framework predicts that an increase in the mean frequency of vagal stimulation decreases HR, thereby lowering the gain of the transfer function (2, 18), it is conceivable that, in this study, the shift of operating points caused by increases in the mean stimulation frequency from 5 to 10 Hz might not be large enough to noticeably change the gain. By contrast, neostigmine increased the gain despite the fact that the mean HR level during dynamic vagal stimulation at 5 ± 2 Hz with neostigmine was similar to that during vagal stimulation at 10 ± 2 Hz without neostigmine (157 ± 16 vs. 157 ± 31 beats/min). Thus, in the case of neostigmine, a shift in the HR operating point alone cannot account for the observed alteration in the HR response to dynamic vagal stimulation.

Neostigmine increased the gain and decreased the corner frequency of the transfer function, reflecting an enhanced yet slowed HR response to vagal stimulation in the time domain (Fig. 5). Because neostigmine not only slows the degradation of ACh but also activates ACh receptors on cardiac ganglion cells producing ACh release (1), the augmented HR response might have resulted from an increase in the amount of ACh released per vagal stimulus. Indeed, in this study, neostigmine evoked slight (~10%) bradycardia with bilateral vagus nerve transection. These results might be a manifestation of the neostigmine-induced release of ACh from the cholinergic nerve terminals. However, if the effects of neostigmine were ascribed solely to the increase in the amount of ACh released per vagal stimulus, neostigmine should increase the amplitude of the steady-state response to vagal stimulation without affecting the 90% rise time of the response.

We evaluated the time required to reach steady state of the calculated HR response to vagal stimulation in terms of the 90% rise time, lag time included. Prolongation by neostigmine of the lag time, however, was relatively quite small. The increase in rise time by neostigmine therefore primarily reflects the slow dynamic nature of the step response. In fact, neostigmine increased the time constants estimated from the corner frequencies of the transfer function (1.5 ± 0.6 vs. 4.1 ± 0.9 s) and decreased the rate constants by ~70% (0.75 ± 0.28 vs. 0.25 ± 0.05 s-1). These values are in good agreement with the previously estimated rate constants of ACh degradation at the sinoatrial node (4, 5, 10-13, 17, 24). Although the mechanism of increased lag time by neostigmine is unclear, neostigmine seems to affect the HR response to vagal stimulation primarily through inhibition of ACh degradation by ChE.

Intravenously administered neostigmine could affect the transmission properties at the nerve ganglia as well as at the neuroeffector junction of the sinus node. We therefore cannot uniquely identify the site of action of neostigmine. Cholinergic transmission in the autonomic ganglia, however, is known to be as quick as that at the neuromuscular junction of skeletal muscle (~1 ms) (4, 7, 14, 30). Thus the delay associated with cholinergic transmission in the ganglia is by far smaller than the time constants of the muscarinic receptor-mediated cardiac response and of the HR response to vagal stimulation in this study. Accordingly, it is conceivable that the alteration by neostigmine of the transfer function from vagal stimulation frequency to HR response might be mainly attributable to the modulation of ACh degradation within the neuroeffector junction of the sinus node.

In most cases, including this study, the low-pass filter characteristics of the HR response were derived by modulating the vagal stimulation frequency without taking into account the phase-dependent sensitivity of the sinus node to vagal inputs (16) (i.e., nonsynchronized vagal stimulation protocol). In contrast, Mokrane et al. (22) found, using a synchronized vagal stimulation protocol, that the transfer function was characterized by a combination of a low-pass filter with a corner frequency of 0.065 Hz and an all-pass filter. Their results suggest that at least two ACh-dependent components, a slow component and a fast component, are involved in the vagal control of HR. Furthermore, the authors predicted that the low-pass filter characteristics of ACh concentration at the sinus node would affect the filter characteristics of the HR response to vagal stimulation. Inhibition of ChE would decrease the corner frequency of the low-pass filter characteristics of ACh kinetics, thereby decreasing that of the transfer function from vagal stimulation frequency to HR response. Thus their theoretical prediction was in line with our experimental observations. With regard to the corner frequency of the low-pass filter characteristics of the HR response to nonsynchronized modes of vagal stimulation, the values for the rabbit (0.12-0.15 Hz) (18, 26) and the dog (0.15 Hz) (2) are higher than those obtained from the cat (0.05 Hz) (6). The present data are in good agreement with those obtained from previous rabbit experiments (18, 26). The differences in corner frequencies among various animal species may be due to differences in the concentration of acetylcholinesterase strongly influencing the rate of ACh degradation.

Clinically, ChE inhibitors, such as neostigmine, coupled with anticholinergic drugs are used to reverse muscle relaxation at the end of surgery (21, 29). In a mathematical modeling study, Dexter et al. (12) demonstrated that the combination of a ChE inhibitor and an anticholinergic drug decreased the amplitude of the high-frequency HR variation corresponding to respiratory sinus arrhythmia. A more recent study on humans supported this prediction (32). These results suggest that the rate of ACh degradation would be of importance in synchronous changes in ACh concentration in sinus node neuroeffector junctions with high-frequency variations in vagus nerve activity (8). Similarly, the slowing of ACh degradation by ChE inhibition would provide a mechanism for explaining our experimental observation that neostigmine decreased the corner frequency of the transfer function from vagal stimulation frequency to HR response; in other words, neostigmine administration resulted in a loss of vagally mediated high-frequency fluctuations in HR.

Because anesthesia affects neural regulation of the cardiovascular system (33, 34), there remains the possibility that anesthesia affected the results to some degree. However, because we cut the efferent pathways of both sympathetic and vagal systems, the effect of anesthetics on the central nervous system should have little effect on the present results.

In summary, we found that neostigmine markedly changed the transfer function from vagal stimulation frequency to HR response. The experimental observation that neostigmine decreased the corner frequency of the transfer function supports the notion that the low-pass filter characteristics of the transfer function might result from the filter characteristics of ACh kinetics. Because the transfer function may thus represent the characteristics of the rate-limiting step in the signal transduction pathway elicited by vagal stimulation, our findings may predict that the process of ACh degradation is the rate-limiting step in vagal control of HR. Whether or not such an interpretation is indeed true, it is rather clear from our study that ChE activity plays an important role in determining the dynamic properties of transduction from vagus nerve activity to HR.

    ACKNOWLEDGEMENTS

This study was supported by a Research Grant for Cardiovascular Diseases (6A-4, 7A-1, 7C-2, 9C-1) from the Ministry of Health and Welfare of Japan, by a grant from the Science and Technology Agency of the Encourage System of Center of Excellence, and by a grant from the Sankyo Foundation of Life Science.

    FOOTNOTES

Address for reprint requests: K. Sunagawa, Dept. of Cardiovascular Dynamics, The National Cardiovascular Center Research Institute, 5-7-1 Fujishirodai, Suita, Osaka 565-8565, Japan.

Received 2 September 1997; accepted in final form 27 April 1998.

    REFERENCES
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References

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Am J Physiol Regul Integr Compar Physiol 275(2):R541-R547
0002-9513/98 $5.00 Copyright © 1998 the American Physiological Society



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