Journal of the Autonomic Nervous System, 9 (1983) 399-409 Elsevier

399

Time delays in the human baroreceptor reflex

C o r n e l i u s B o r s t i a n d J o h n M. K a r e m a k e r
Department of Physiology, Universityof Amsterdam, Amsterdam (The Netherlands)

(Received May llth, 1983) (Revised version receivedJune 23rd, 1983) (Accepted July 12th, 1983)

Key words: arterial pressure - heart rate - atrioventricular conduction time baroreceptor reflex - nerve stimulation - carotid sinus nerve - cardiovascular control - reflex latency

Abstract
In 11 normotensive subjects with coronary artery disease, low intensity electrical stimulation of the carotid sinus nerves (CSN) was triggered by the R-wave in the electrocardiogram with an adjustable delay. The latent period was estimated between the start of CSN stimulation and the onset of the reflex-PP-interval prolongation and, during right atrial pacing, the onset of the reflex fall of diastolic arterial pressure and prolongation of the AV-interval. The latency to the reverse changes was determined after switching CSN stimulation off. The PP-interval changes started after a latency of 0.5-0.6 s. This latency was independent of the respiratory phase and it was independent of the directional change of the afferent activity. AV-interval changes started after about 1 s. When heart rate was fixed, arterial pressure changes started after 2 - 3 s. It is estimated that central processing of baroreceptor afferent activity may require 0.25 s in the human.

Introduction
In man, little information is available about the time delays involved in the reflex control by the arterial baroreceptors of arterial pressure, the SA node and the AV node. Electrical stimulation of the carotid sinus nerves (CSN) in patients with coronary heart disease [13], offered a unique opportunity to estimate these delays, i Present address: University Hospital Utrecht, Laboratory for Experimental Cardiology and Clinical Physiology, Catharijnesingel 101, P.O. Box 16250, 3500 CG Utrecht, The Netherlands. 0165-1838/83/$03.00 1983 Elsevier Science Publishers B.V.

400

because the impulse traffic in the baroreceptor afferent nerves could be altered abruptly in a well-defined and controlled manner. In the present study, all records that were obtained in a previous study on frequency limitation in the human baroreceptor reflex were reanalyzed [6]. Additional experiments were performed to measure the latency and time-course of the PP-interval prolongation produced by CSN stimulation with discrete 300 ms pulse trains. Cardiovascular response latencies were estimated for both activation and deactivation of the baroreceptor reflex by switching low intensity CSN stimulation on and off. Part of this work has been reported in preliminary form [3-5].

Materials and Methods

Patients

Eleven normotensive subjects with coronary heart disease (aged 44--68 years), were examined on 18 occasions 10-=65 months after implantation of a carotid sinus nerve stimulator (Angistat, medtronic) for therapeutic application o f CSN stimulation [13]. Invasive measurements and right atrial pacing were performed following diagnostic catheterization procedures, The subjects were in a stable clinical condition. All subjects gave informed consent. No ethical committee had been instituted at the time of the study.
Carotid sinus nerve (CSN) stimulation m the human

CSN stimulation was applied as described previously [5,6,13]. Briefly, a transmitter produces an amplitude-modulated radiofrequency wave that is transmitted with an antenna coil taped on the skin ovcx!ying an implanted receiver, The stimulus pulses are generated in the subcutaneous receiver and delivered bilaterally to the electrodes around the carotid sinus nerves. The modified stimulator was switched on or off with an adjustable delay (0-1100 ms) after the R-wave in the etectroeard~gram. Stimulus pulses (0.35 ms duration) were applied in 11 subjects at 40-200 Hz for 1-2 min [6], or in 4 subjects, with one discrete 300 ms lasting ~ train with 110 Hz intra-train frequency. Stimulation data at 20 Hz [6] were excluded from the present analysis because the reflex effects were considered to be too small [6] to determine reflex latencies. A distinct influence of the stimulation frequency on the latencies was never observed. As a result, in the range 40-200 Hz, the data were pooled. Stimulus intensity was 1-2 V (estimated from calibration in vitro, the in vivo voltage is imprecisely known due to the nature of the device [6]). Previously, several arguments have been presented that make it unlikely that the stimulus intensity reached the threshold for activation of chemoreceptor or tmanyelinated baroroceptor fibers [6,35]. It cannot be excluded that some chemoreceptor fibers were activated. Their contribution, however, to the reflex effects was probably ~ l e [6].
Measurements

We recorded the e l e c t r ~ d i o g r a m , intra, arterial blood pacing stimulus, a respiratory signal o b ~ n e d with a nose

atrial

Cs~

401 stimulus pulses as described earlier [6]. Invasive measurements were performed in 3 of 11 subjects. The cardiovascular responses to stimulation with 40-200 Hz [6] were used for analysis. Average plots of the diastolic arterial pressure and the AV-interval (pacing stimulus to R-wave or S-wave in the electrocardiogram) were constructed as described previously [5]. Arterial pressure was measured accurate to 1 mm Hg, and intervals were measured accurate to 2 ms. All data were expressed as percent change from control (mean value over 30 s prior to onset of stimulation). The latency to the onset of reflex changes was estimated by eye from ensemble average traces plotted with expanded time resolution. The temporal AV conduction time changes have been reported [5].

Estimation latency PP-interval changes The latency to the onset of PP-interval changes was estimated both according to Koepchen et al. [20] and with a similar method that employed the cusum method [26]. We determined the interval between the first stimulus pulse and the onset of the anticipated P-wave (St-P, interval), assuming the anticipated PP-interval In+ 1 to be equal to I n, the control PP-interval. With Koepchen's method, the average PP-interval increase was plotted versus the St-P, interval for class widths of 50 or 100 ms in the range 0-1.0 s. With the cusum method, we compared the actual In+ 1 with I n and computed for a given class of St-Pa intervals the excess count In+ a exceeded I n assuming the probability P(I,+ 1 > I n ) = 0.5. The cumulative distribution of this excess was plotted versus the St-P, interval in the range 0-1000 ms. If no trend was present in the PP-interval signal and if no systematic disturbance occurred [26], this distribution fluctuates randomly around zero when P(I n + 1 > In) = 0.5. The rationale for the non-parametric method was the large variation between subjects of the immediate PP-interval prolongation with CSN stimulation [6] and the pooled assessment of results obtained with continuous stimulation and single 300 ms pulse trains. Statistical analysis Results are presented as mean + standard deviation (S.D.) or standard error of the mean (S.E.M.). Student's t-test (two-tailed) was used to compare the means of two groups. P < 0.05 was considered to indicate a significant difference.

Results When the start of CSN stimulation was triggered by the ventricular depolarization, the cardiac cycle was prolonged instantaneously, as illustrated in Fig. 1.

Arterial pressure (n = 3)
During atrial pacing, 2-3 s elapsed before diastolic arterial pressure began to change after switching the stimulator on (Fig. 2, left) or ~off (Fig. 2, right).

402

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CSN STIMULATION
Fig. 1. Instantaneous RR-interval prolongation induced with R-wave-triggered continuous CSN stimulation (80 Hz). The electrocardiogram (ECG) was high-pass filtered to remove baseline instability.

PP-interoal (n = 11)

Fig. 3 shows that one 300 ms train of stimulus pulses produced a significant prolongation of the PP-interval after 0.55 s (P < 0.01). This effect outlasted the stimulus by about 6 s (Fig. 3, inset). The left panel in Fig. 4 summarizes the results in 11 subjects of switching C~N stimulation on. There was a slight tendency for the PP-interval In+ 1 to be longer than In, which may be ascribed to the commonly observed trend :of heart rate to slow gradually in the course of an experiment with a human subject. If the first stimulus pulse proceeded the anticipated P-wave by more than 0,55 s, a distinct excess (In+ 1 > In) was found (Fig. 4, left panel). Similarly, if the end of a stimula-

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CSN STIMULATION

Fig. 2. Relative fall of diastofi arterial pressure (~ of control value) in subjects W, R a n d M evoked by CSN stimulation during right atrial pacing (left panel). The control levels have an arbitrary position on the ordinate. The decrease of diastolic pressure started 2"3 s after the onset of CSN s d m ~ f i o n . After more than 1 rain of stimulation, the recovery of diastolic pressure began with the same delay after cessation of CSN stimulation (right panel). Each trace is the ensemble average of 6-14 responses to stimulation at 4 0 - ~ Hz. ~ e respouses were ~ l y i n t e v p 0 t a ~ to 0 ~ data ~ n t s at ~0.25 s intervals.

403

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Seconds

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Fig. 3. Reflex PP-interval prolongation (mean + S.E.M.) evoked by one discrete 300 ms pulse train of CSN stimulation delivered with a variable delay after the R-wave in the electrocardiogram. Abscissa: interval between first stimulus pulse and anticipated P-wave in the ECG (St-Pa). Ordinate: PP-interval prolongation in percentage of peak effect. Inset: the PP-interval was prolonged during about 6 s. Data are mean + S.E.M. for class width of 0.25 s in the first second and 0.5 s afterwards. In the inset the abscissa depicts time in seconds from the first pulse of the stimulus train.

tion p e r i o d exceeding I m i n p r e c e d e d the a n t i c i p a t e d P-wave b y m o r e than 0.55 s, an excess (I n +1 < In) was o b s e r v e d (Fig. 4, right panel). (The i n c r e m e n t in the 'excess' curve at 0.25 s in the right p a n e l of Fig. 4 was due to one subject.) Consequently, Fig. 4 shows that 0 . 5 - 0 . 6 s after the start or e n d of C S N stimulation, the PP-interval b e g a n to increase or decrease, respectively. The l a t e n c y was i n d e p e n d e n t of the c a r d i a c cycle length.

Influence of respiration (n = 4)
T h e m e a n r e s p i r a t o r y interval ranged f r o m 2.6 + 0.2 s ( + S.D.) to 3.7 + 0.6 s in the 4 subjects in w h o m single pulse trains were applied. The c a r d i a c cycle was p r o l o n g e d b y one 300 ms stimulus train, w h e t h e r delivered in i n s p i r a t i o n or expiration. T h e largest effect was evoked when the stimulus train started a b o u t 1.0 s in a d v a n c e of the a n t i c i p a t e d P-wave [3]. W h e n 300 ms pulse trains which s t a r t e d in the first 0.5 s o f the i n s p i r a t i o n were observed, the PP-interval p r o l o n g a t i o n b e g a n

4434
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1000 500 SS

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I l

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0

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Fig. 4. Cumulative distribution of the number of observations (upper trace) and of the excess number of times (lower trace) PP-interval ] ,+ t was longer than I n after s w i ~ r t 8 CSN stimulation ort (!eft p a m ~ or shorter than I n after switching stimulation off (ris~t pmml)~ When the first stimulus pal~e (St) preceded the anticipated P-wave (P=) in the-electrcmardiol~..m by > 0.55 s, the P P - ~ t was protot~ed (left panel). The same delay for PP-intervai shortenin8 was found after the last stimulus pulte (St') (right panel). The data in the left panel resulted from both continuous stimulation and single pulse train stimulation. The latter is shown separately in Fig. 3. The data in the right panel resuhed from continuous stimulation.

u.. (3

I00

INSPIRATION CSN STIMULATION

INSPIRATION
100

50 ~

EXCELS50 In1 >In F0 I I I

0.5 S t - P a INTERVAL Is]

10

,I O5
vSt-Pa INTERVAL (s]

~0

Fig. 5. Comparison of the reflex effect of one 300 ms s t ~ u l u s train startin8 in the first 0.5 s of the inspiration (left panel) with the PP-interval shortening that followed the same moment in the inspiration when no CSN stimulation was applied (right panel). See legend to Fig, 4. vSt, virtual first stimulus pulse.

405 after about 0.6 s (Fig. 5, left panel). Inspiration itself evoked the opposite effect after about the same delay (Fig. 5, right panel). Thus, stimulus trains starting in early inspiration evoked reflex inhibition of the SA node after about 0.6 s.
A V-interval (n = 3)

From ensemble average plots of the AV-interval [5], it was estimated that the AV-interval changes after a latent period between 0.8 and 1.4 s in subject M (n = 3), between 0.9 and 1.6 s in subject R (n = 9). In subject W, both the PP-interval and AV-interval did not change significantly, whereas mean arterial pressure decreased by 9.8 + 0.9% ( + S.E.M.) (P < 0.001) after 1 min of stimulation. After i.v. administration of atropine sulphate (0.04 mg/kg) in subject R, both the chronotropic and dromotropic effects started after approximately 3 s.
Discussion

The principal findings are: (a) a latent period of 2-3 s for diastolic arterial pressure changes during atrial pacing; (b) a latent period of 0.5-0.6 s for PP-interval changes (3 s after cholinergic block); and (c) a latency between 0.9 and 1.4 s for AV-interval changes (3 s after cholinergic block).
C S N stimulation in the human

In a previous paper [6], the nature of the activated fibers in the carotid sinus nerve has been discussed in detail. It was concluded that the reflex effects of low intensity stimulation have to be ascribed to activation of the largest myelinated baroreceptor afferents. Hence, CSN stimulation is an appropriate method for establishing the delays involved in baroreflex control of the human circulation, because: (a) the afferent impulse traffic can be increased or decreased stepwise; and (b) the transducer delay of the receptors is negligible [17] compared to the total delay of the entire reflex arc.
Peripheral resistance

The initial fall of diastolic arterial pressure during atrial pacing can be attributed largely to the reflex release of sympathetic vasoconstrictor tone [13,31,33]. We observed a 2-3 s latency for diastolic pressure changes after both activating and deactivating the baroreceptor reflex. The 2-3 s latency corresponds closely to values reported in animal studies [19,29], and to the 2.5 s latency observed recently with neck suction [11]. In the latter study, however, heart rate was not fixed and Fig. 1 demonstrates that a prolonged cardiac cycle results in a drop in diastolic arterial pressure.
S A node

Baroreflex control of heart rate is predominantly affected by modulation of vagal tone [19,24,29]. Previously published estimates of the reflex latency range from 0.2 s

406

[8] to an extreme of 9.2 s [26], but most authors report values ~<0.6 s [1,2,9,11,27]. The present estimate of 0.55 + 0.05 s (+class width in Fig. 4) is based on 1357 measurements and corresponds closely to estimates by Bevegard et al. [2] and Picketing and Davies [27]. With neck suction, however, Eckberg arrived at an estimate of 0.24 s [9].

Influence of respiratory phase

During spontaneous breathing at a rate of about 20/min, the reflex effect of 300 ms stimulus trains did not seem to be delayed more when the trains were delivered during inspiration. Although baroreflex slowing of the SA node was of shorter duration when a brief burst of CSN stimulation was delivered in inspiration, the interaction of respiratory and baroreflex influences resembled an additive more than a gating mechanism [3]. Comparable findings were reported by Eckberg et al. [12] with neck suction in young volunteers who breathed at a rate of 24 breaths/rain. However, inspiratory inhibition of baroreflex responsiveness was found at rates of 12 breaths/min and less [12]. The complete inspiratory inhibition commonly observed in experimental animals [21,25,28,30] might be related to the often low central respiratory rate during anesthesia. The respiratory gating hypothesis [21,25,28] has been reviewed recently by Spyer [30], who concluded that there is no 'all-or.none' respiratory 'gate' in the baroreceptor-cardiac reflex.

Asymmetry in the baroreceptor-cardiac reflex

The present results fail to show a distinct indication of asymmetry as to the latency of the response to switching CSN stimulation on or off (Fig. 4). Katona and Barnett [18] reported a 200 ms difference in the reflex excitation and inlfibifion of cardiac vagal motoneurons in the cat. The same difference was observed in the reflex PP-interval prolongation and shortening with neck suction and neck pressure in the human [11].

Centraldelay
The time delay of 0.5-0.6 s for the reflex SA node response provides a basis for a rough estimate of the central processing time for vagally m ~ t e d baroreflex heart rate control in the human. The following extrapolations on afferent and efferent conduction times stem from studies in dogs. From increased arterial pressure to increased nerve activity at the site of the electrode requires about 20 ms [17]. From the electrode along the glossopharyngeal nerve to the nucleus tractus solitarii takes about 5 ms [16]. On the efferent side, along the cardiac vagal fibers to the right atrium takes about 55 ms (conduction velocity 7 m / s ) [19-25], and the time required to reduce the discharge rate of the SA node and postpone the P-wave is in the order of 170 ms [23,24]. Thus, there remains 0.25-0.35 s for the central delay, wl-~iehis appreciabtylonger than found in the anesthetized dog (usually l O O m s [20,22,2'3]). AneSthesia,

407 however, is known to modify reflex vagal heart rate control [19,32]. The functional implication of this estimate would be that, in the human, many interneurons are involved in central processing of baroreceptor information. A complex network of interneurons would be in accordance with the low-pass filtering properties observed earlier [16], and with the sparseness of bulbar and suprabulbar neurons with a cardiac rhythm [16,30].

Comparison between neck suction and CSN stimulation

The 0.24 s latency obtained with neck suction [9] is appreciably smaller than most estimates reported previously [1,2,27], and the findings of the present study (Figs. 3 and 4). The origin of the difference is unclear. Electrical stimulation, however, is expected to produce shorter latencies than neck suction because of temporal facilitation and the absence of the receptor delay. There is no doubt that baroreceptors in the carotid sinus are stimulated by neck suction, but a suction chamber that does not encircle the neck [9,11,12] may have effects other than increasing carotid transmural pressure. The possibility of bradycardia following intubation is a wellknown risk in anesthesiology. It has not been established whether or not other receptors in the neck (e.g. tracheal receptors) are activated by suction at - 3000 mm H g / s [10]. In our opinion, Eckberg's technique, which imposes asymmetrical suction with respect to the front and back of the neck, needs validation in this respect. Selective carotid sinus denervation ought to abolish any PP-interval response to neck suction in the conscious animal.

A V node
The latency for changes in AV-conduction time (between 0.9 and 1.4 s) was slightly longer than for SA node changes, as was noted in animals [24]. Atropine modified the reflex dromotropic and chronotropic changes in a similar way, the delays became 3 s and the changes were small and sluggish [5], in accordance with animal studies [24].

Comparison of vagally and sympathetically mediated effects

In the anesthetized animal, vagal activity to the heart alters within about 100 ms after the start of CSN stimulation, and sympathetic activity alters after 150-300 ms [30]. The different latencies for vagally and sympathetically mediated effects in the human, ~< 1 s and 2-3 s, respectively, are probably due to different conduction velocities in the efferent pathways and different neuroeffector delays. Conduction velocity in efferent cardiac vagal fibers is about 7 m / s [19-25,30], whereas in muscle sympathetic fibers it is about 1 m / s [14]. Inhibition of muscle sympathetic activity by CSN stimulation or neck suction was observed after a latency of 1-2 s [14,34,35]. The lag time between liberation of noradrenaline and the resulting effector response exceeds the short neuroeffector delay of acetylcholine by approximately 1 s [15,24]. Thus, the distinctly different latencies for baroreflex modulation of heart rate and

408

blood pressure have to be attributed predominantly to the properties of the two different efferent parts of the reflex arc. In addition, parasympathetic effects have a short time constant (a few seconds), whereas sympathetic responses have relatively long time constants (about 10 s) [19,24]. The functional consequence of these different temporal response patterns is that shortly after a brief baroreceptor stimulus, the heart rate response is determined by the reflex blood pressure fall rather than by the original stimulus [7].

Aekno~~ts
The assistance of Professor L.N. Bouman, Professor A.J, Dunni_ng, Professor J. Wagner and H. de Best is gratefully acknowledged. The authors thank professor W. de Jong for commenting on the manuscript, and Mrs. W. van Eijsden for typing the manuscript.

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