How does the vagus nerve influence heart rate

Klabunde Heart rate is normally determined by the pacemaker activity of the sinoatrial node SA node located in the posterior wall of the right atrium. This intrinsic firing rate decreases with age. Heart rate is decreased below the intrinsic rate primarily by activation of the vagus nerve innervating the SA node. This study provides more insight into the working of the baroreflex on heart rate.

One may now ask, how important is this PRC to the responsiveness of the sinoatrial node to its in vivo vagal input. In other words, in particular when looking at Figure 6 , what does this mean for the normally arriving vagal burst after a ventricular contraction? In the experiments stimulation was coupled to the atrial complex, since the heart rate is generated in the atrium, and coupling to the ventricular R-wave is inherently biased by possible timing differences due to the vagal and other - effects on AV-conduction.

The AV-conduction is slightly prolonged, the vagal burst occurs around the T-wave, i. The latency of ms which I found in my thesis work in awake rabbits from HR responses to carotid sinus nerve and depressor nerve stimulation, is slightly longer [ 44 ]. In our experiments in humans [ 45 ] we estimated still longer reflex times, extrapolating from electrical stimulation of carotid sinus nerves to heart rate responses 0.

However, in view of a number of uncertainties in those measurements, which have later been stressed by Eckberg and coworkers [ 46 ] this estimate might be over-cautious and therefore too long.

Therefore, although these are experiments in rabbits, the results have relevance for baroreflex functioning and related HRV in human physiology. A more elaborate discussion of this issue has been given in [ 48 ] and [ 45 ]. In the computation of baroreflex sensitivity BRS the original algorithm is to correlate the systolic pressures in the rising phase of a phenylephrine induced pressure rise to the durations of the succeeding beats [ 49 ].

At heart rates lower than 75 this should be the duration of the very beat where the systolic pressure was measured. HRV is known to diminish at higher HR, this is probably due to the vagal pulses coming too late for the ongoing beat to have their full effect, so it is delayed —with decrement- to the next beat. This also explains the increasing beat delay observed at higher heart rates in the systolic pressure to heart period correlation such as used in the running baroreflex sensitivity xBRS [ 50 ] or the phase delay between systolic pressure and heart period changes in Fourier analysis [ 1 ].

This delay need not necessarily be a sign of increasing sympathetic involvement in the baroreflex to heart rate response. As was shown above, even after bilateral vagotomy RSA was observed. In the literature this phenomenon has been attributed to direct stretch of the sinoatrial node [ 21 , 52 ]. It might equally well be due to cardiac stretch receptors synapsing with efferent autonomic nerves in the ganglionic plexus near the heart [ 7 , 53 ].

Whatever the exact cause of RSA in the resting situation, from physics we know that a minute disturbance may tip the balance in an unstable system; respiratory movement might be just that disturbance. This might also be an explanation for the extreme RSA that is sometimes observed in young persons, where HR may jump from around 60 to bpm and back in a few beats personal observation. All along this paper has been about the originator of heart rate, the sinus node, and how it reacts to vagal influences.

A number of basic issues related to known vagus nerve and sino-atrial node function should still be discussed. First of all, the delay time between arrival of acetylcholine at the end organ and the first measurable change of function in that organ. It is well-known that this delay after activation of the postganglionic muscarinic receptor is much longer than that at the nicotinic receptor like the ones in the ganglia and the neuromuscular junction. The latter one has delay times in the order of 0.

I was given the opportunity by Drs. Bouman and F. Bonke to re-analyze an archived copy of their experiments on vagus nerve stimulation in isolated rabbit sino-atrial node preparations [ 56 ].

They measured the sinoatrial node response to stimulation by trains of 25 Hz lasting a few seconds. The starts of a tetanic stimulation by Bouman and Bonke were like the one demonstrated in Figure 10 , where no reset but a gradual deviation from the unstimulated course would show.

Finally, the short- vs. An extensive review of the literature has been published in [ 58 ] ranging from the various types of muscarinic receptors in sinoatrial node tissue to the membrane channels involved in the translation of acetylcholine effect to changed membrane channel properties. It may be concluded that the hypothesis formulated above has a sufficiently sound basis in the known properties of the sinoatrial node, i.

Only the fast influence on HR of a vagal burst can be quickly undone from one heartbeat to the next, the slow response takes several beats to disappear. The cardiac vagus nerve fibers, serving as efferent pathway to the baroreflex, provide immediate adaptation of heart rate to changes in blood pressure. Therefore, the efferent cardiac vagal bursts, one per heartbeat, might be considered translations of the incoming baroreceptor afferent bursts that are caused by pulsatile stretch of the vessel wall at each heartbeat.

However, this conversion is not one-to-one: already in the first transmission station, the nucleus tractus solitarii of the medulla oblongata, integration takes place with other incoming visceral and somatic afference [ 10 , 43 ].

In addition, the central interaction with respiration induces a partial blockade of vagal outflow during the inspiratory phase [ 10 , 43 , 59 ].

Consequently, the outgoing cardiac vagal traffic is not only a reflex response to the baroreceptive input signals. Moreover, the ganglionic cardiac plexus is not the simple textbook transmission station; ganglion cells themselves show subthreshold oscillations and, on top of that, incoming neural traffic from cardiac sensory neurons may alter their activity [ 7 ].

The combined effects of heart rate on the effectiveness of incoming vagal traffic, i. Parker et al. These observations have given credence to the corollary that heart periods should best be measured to account for vagal effects mainly in the resting condition and heart rates during exercise, looking at the effect of the sympathetics. A more elaborate discussion of the issue has been given earlier [ 61 ]. The issue raised by Yaniv et al. Pacemaker cells, when isolated in tissue culture, display widely varying intervals between firings [ 63 ].

Once the cells have replicated and form a syncytial-like tissue, the interval becomes stabilized. The postganglionic sympathetic and vagal fibers have an uneven distribution over that area, consequently the actual pacemaking region may shift with autonomic activity [ 56 ]. An example of that may be observed in Figure 9. Even more extreme might the sinoatrial node be blocked to such an extent, that a vagal escape occurs and the actual pacemaker shifts to another pacemaking area, like the AV-node, for one or more beats.

That did not occur in the present experiments, where care was taken not to go to extremes with vagal stimulation, but the phenomenon of vagal escape is well-known in physiological literature [ 66 , 67 ] and, of course, from clinical observations like in ophthalmic surgery [ 68 ] where manipulation of the eye can produce strong sinoatrial node inhibition, and the AV-node temporarily may take over pacemaking of the heart.

In this series of experiments, the importance of the Phase-Response Curve for understanding vagally induced phasic heart rate changes has been established, both for single burst and for beat-to-beat burst-like stimulation. The latter can be considered the normal in-vivo mode of operation in response to baroreceptor input due to the pulse wave upstroke, making vagal activity the most important contributor to HRV in the healthy, supine resting condition.

The experiments have also shown that the PRC is not a constant given, but a changing operator, depending on the prevailing condition of the sinoatrial node and immediately prior vagus nerve activity. Under conditions the response to a vagal burst may become unpredictable, when its timing in the cycle has become critical. In general, the HR-response to vagal activity shows two components: a fast one that may provoke large cycle changes from one beat to the next, and a slow one, that builds up with longer lasting activity.

The latter one also takes longer to subside, in small steps. The response to vagal stimulation is not only determined by the properties of primary pacemaking cells in the sinoatrial node, but also by the properties of the ganglion cells in the cardiac plexus and by the unequal distribution of their end-organ effects, leading to pacemaker shifts within the sino-atrial node or even to other areas, like the AV-node.

The existence of RSA, even after vagotomy, may be explained by integrating action of the cardiac autonomic plexus where vagal, sympathetic and cardio-sensory information come together. In the course of the experiments, stretched out over the years, many colleagues have helped directing the experimental set-up to its final shape, presented here. The technical support of Ms. Veltman and, later, Mr. Stok has been essential. The author has no relevant disclosures to make. The experiments have been carried out in the former Dept.

National Center for Biotechnology Information , U. J Clin Transl Res. John M. Author information Article notes Copyright and License information Disclaimer. E-mail: ln. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

This work is licensed under a Creative Commons Attribution 4. This article has been cited by other articles in PMC. Abstract Background and Aim: Analysis of heart rate variability HRV has recently become the playing field of mathematicians and physicists, losing its relation to physiology and the clinic. Methods: The response of HR to vagus nerve stimulation was tested after bilateral vagotomy in rabbits under anesthesia.

Results and Conclusions: Sensitivity of the sinoatrial node to the timing of vagal bursts in its cycle from protocol 1 explains most of the observations.

Relevance for patients: Measurement of heart rate variability HRV and baroreflex sensitivity BRS have become clinical tools in the cardiology clinic and in hypertension research. Keywords: sinoatrial node, vagotomy, phase response curve, respiratory sinus arrhythmia, baroreflex, cardiac autonomic plexus, cardiac baroreflex. Introduction Heart rate variability is, boldly put, the price paid by the blood pressure control system to obtain blood pressure stability.

Open in a separate window. Figure 1. Blood pressure control by the fast vagally mediated baroreflex. In the second beat systolic blood pressure is increased red line by an increased stroke volume; the baroreceptors react by more afferent impulses, resulting in more efferent vagal activity, which is delaying the upcoming beat by longer hyperpolarizing the sinus node.

Consequently, the next diastolic pressure is not as much increased as the grey lines suggests but already more or less stabilized. Figure adapted from [ 2 ] and [ 3 ]. Figure 2. Schematic overview of the stimulation protocols. Single burst stimulation: burst in one cardiac cycle only at a variable delay D from start of the cycle.

Beat-to-beat stimulation: one burst of stimuli at a variable delay D in each cardiac cycle. The delay is kept constant until a steady state is reached.

In one particular cycle S the strength of the stimulus burst is changed, either by decreasing 2b2 or increasing 2b3 the number of pulses in the burst. Tetanic stimulation; in one particular cycle pulses are suppressed 2c1 or the frequency is increased 2c2 for an adjusted period, starting at a variable delay D from the beginning of the cycle. Figure 3. P-P cycle recording of the first seconds of the series; the numbers show the delay settings in ms for each stimulation.

Note the small respiratory sinus arrhythmia. Phase response curve of the combined results. X-axis: delay D setting Figure 2a.

Impulse response curve. X-axis: time between the start of the burst and the occurrence of a P-wave for that run. Materials and Methods The experiments have been carried out over a period from to , in accordance with prevailing law at the time and code of ethics in animal experimentation Declaration of Helsinki, the UFAW handbook on the care and management of laboratory animals [ 18 ] , under supervision of the veterinary staff of the Jan Swammerdam Institute where the experiments have been conducted.

Figure 4. Cycle durations in response to a strong stimulus 8 pulses, Hz, 0. A sharp transition between delays 91 and 93 ms is observable. Figure 5. Phase response curves at different baseline P-P cycle durations layout as in Figure 3. The various curves have been smoothed by a 5-point averaging filter.

Figure 6. Responses to one burst of 4 pulses in each cycle 15 ms interval, 0. Upper black curve shows successive P-P cycles; each dot represents one cycle. At a delay setting of ms, around secs in the experiment, the cycle durations become more and more unstable at progressively longer delays. Layout as in 6b. Blue squares give the duration of the pre-test P-P cycle. In the test cycle the burst is halved to only 2 pulses, red triangles give the resulting duration of the test cycle.

More and more cycle shortening is observed. Note: adapted scales in 6d. Figure 7. Responses to increases of only one stimulus burst in beat-to-beat stimulation. Drawn red lines give the undisturbed interval durations on beat-to-beat stimulation. Squares: duration of test interval, triangles: next interval. Resting heart period around ms.

Figure 9. Stretch of the recording from the experiment with beat-to-beat stimulation in fig. Top: surface ECG, AC: atrial complex from catheter electrode, below: trigger pulse started by atrial depolarization, schematic indication of 4 stimuli. Figure 8. Results 3. Beat-to-beat stimulation In these experiments considerably lower stimulus intensities for the stimulus burst in each cardiac cycle had to be applied than in the previous protocols.

Beat-to-beat stimulation with suddenly increased stimulus strength This experiment is, as it were, the mirror of the previous one, and the results can very well be interpreted as such. Unsolicited results In the present experiments, where both vagi have been cut, one would expect a stable baseline of heart rate, devoid of the fast beat-to-beat variations, if these were only vagally mediated.

Discussion The main objective of this study was to investigate how the physiological properties of the vagus nerve-sinoatrial node complex in vivo translate changes in cardiac vagal activity into heart rate variability.

The baroreflex, hrv and timing of vagal bursts This study provides more insight into the working of the baroreflex on heart rate. Respiratory sinus arrhythmia and the vagus nerve As was shown above, even after bilateral vagotomy RSA was observed. The sinus node under vagal control All along this paper has been about the originator of heart rate, the sinus node, and how it reacts to vagal influences. Figure Recording from an experiment by L.

Bonke: micro-electrode in rabbit sinoatrial node cell SN while the attached vagus nerves were stimulated. AC: atrial complex, recorded from the crista terminalis. At the rightmost up-arrow 25 Hz vagus nerve stimulation started.

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