Computer simulation of the synchronization of the sinoatrial central cell in response to periodic stimulation of the vagus nerve

The effect of periodic stimulation of the vagus nerve on the activity of the central cell of the sinoatrial node has been simulated. The regions of synchronization and desynchronization have been revealed, and the phase shift at different stimulation frequencies has been estimated. The positive chronotropic effect has been shown to occur at some frequencies of stimulation.     

Somatostatin as a modulator of vagal effects on heart rhythm]

In 11 experiments on anesthetised cats burst stimulation of peripheral cut end of right vagus nerve leads to synchronization of cardiac and vagus rhythms. Alterations of burst sequence frequency within definite limits has been synchronously reproduced by heart thus creating managed bradycardia possibility. Somatostatin (10(-8)-10(-9) M intravenously) decreases heart rate and inhibits total vagus chronotropic effect. Vagolytic effect of somatostatin caused a decrease of tonic component of the vagus chronotropic effect. On the other hand, somatostatin augmented the extent of the vagal synchronizing influences and caused enlargement of the ranges of managed bradycardia. The observed results testify to participation of the peptidergic mechanisms in genesis of vagal managed bradycardia.     

Motor reactivity of isolated heart of the grass-snake (Natrix natrix L.)

Stimulation of the vagus nerve with a volley of electric impulses changed the action of grass-snake heart producing a negative chronotropic and inotropic effect. The effect of vagal stimulation was not different from the effect of acetylcholine administration and it was absent in the presence of atropine and hexamethonium. It was not possible to demonstrate sympathetic nervous fibres in the stimulated segment of the vagus nerve and trials of finding a separate nerve increasing the heart rate were unsuccessful. Parasympathicotonic agents caused bradycardia and a fall in the amplitude of cardiac contractions, and in sufficiently high doses they arrested the heart in diastole. The action of muscarine-like agents was stronger than that of nicotine, and the anticholinergic action of tubocurarine was weaker than that of atropine. Catecholamines exerted a positive inotropic and chronotropic effect which was completely blocked by propranolol in some tests only.     

Hemodynamic changes during electrical stimulation of some bulbar cardiovascular structures

The effect of electrical stimulation was studied on the nucleus of the tractus solitarius, the nucleus cuneatus, and the dorsal motor nucleus of the vagus nerve, i.e., structures of the bulbar cardiovascular sector in which it has been postulated that impulses from the sinoaortic reflexogenic zone are relayed to the cardiovascular system. Stimulation of all the structures tested in acute experiments on cats under chloralose-Nembutal anesthesia evoked depressor responses of varied degree, the hemodynamic basis of which was a decrease in the cardiac output (CO). The effect of stimulation of the nucleus cuneatus on the development of the negative chronotropic effect was observed. The dorsal motor nucleus of the vagus nerve in cats is not the only or even the principal zone from which negative chronotropic influences are exerted on the heart.A. A. Bogomolets Institute of Physiology, Academy of Sciences of the Ukrainian SSR, Kiev. Translated from Neirofiziologiya, Vol.3, No.6, pp.631–636, November–December, 1971.     

The spectrogram of heart rate in cats following burst stimulation of the vagus nerve

Denervation of the heart (bilateral vagotomy and propranolol) in artificially ventilated cats didn't remove respiratory peaks on the spectrogram of heart rate, while burst stimulation of vagus nerve increased or decreased them several times by synchronization of the heart and vagus rhythms, which in its turn was observed under the bradycardia only. At the same time, the desynchronization of rhythms provoked severe sinus arrhythmia which had a distinct periodic character. Under these conditions, there were high non-respiratory peaks appearing at the spectrogram of the heart rate that indicated existence of two vagus chronotropic effects: a well known tonic one and special intracycle synchronizing effect correcting duration of every cardiac cycle.     

Dynamics of the vagus effect on the cardiac rhythm during blockade of various subtypes of M-cholinoreceptors in cats

While single vagus bursts were used in cats with an incremental time delay following P-wave of the ECG, two zones were identified within the cardiac cycle differing from each other by their chronotropic responses. At the initial (approximately 120-130 ms) part of the cardiac cycle, an increase in the P-stimulus interval evoked a "moderate" (+8-16%) increment of the chronotropic response up to its maximal amplitude. Further increase of that interval provoked an "abrupt" (-80-90%) decrease of the vagus response. Block of M1-(pirenzepine), M2-(metoctramine and gallamine) or M3-(DAMP) cholinoreceptors diminished vagally-induced minimal and maximal prolongation of the ECG P-P interval and decreased the amplitude of its alterations associated with varying the position of vagus stimulus within the cardiac cycle. The coefficient delineating magnitude of the vagus effect over a zone with "moderate" changes of the chronotropic response was decreased after blocking the M1- and M2-cholinoreceptors, whereas duration of that zone was shortened following blockade of the M1- and M3-receptors. Velocity of the original vagus response and the rate of its subsequent decline decreased following blockade of the M1- and M2-subtypes of cholinoreceptors.     

Selective pharmacological blocking of synaptic transmission through the parasympathetic ganglia: Effects on the cardiovascular system

In acute experiments on rats and dogs, compounds IEM-1556 and IEM-1678, the blockers of transmission through the parasympathetic ganglia, reduced the negative chronotropic effect of stimulation of the vagus nerve (VN), while practically not changing the heart rate (HR). In chronic experiments on dogs, these compounds increased the HR, substantially reduced the respiratory heart arrhythmia, did not change the arterial blood pressure (AP), and reduced the chronotropic effects of VN stimulation. IEM-1556 exerted more strong and long-lasting blocking effects on vagal heart control than IEM-1678 did, but in anesthetized animals could evoke a drop in the AP. Acetylcholine, if administered during the action of the above compounds, inhibited heart activity. It is concluded that both IEM-1678 and IEM-1556 are selective parasympatholytics (although IEM-1556 may produce a side effect). The above compounds block synaptic transmission through the intracardiac parasympathetic ganglia and do not affect neuro-effector transmission in the heart.Neirofiziologiya/Neurophysiology, Vol. 28, No. 2/3, pp. 151–159, March–June, 1996.     

The dynamics of the chronotropic effect of a single vagal stimulus in cats under the action of met-enkephalin and neurotensin]

Following a burst of pulses applied to the vagus nerve with progressively incremental delay after the P wave of the ECG, the narrow zone of the cardiac cycle was identified where even a small shift of the vagal burst position evoked an abrupt alteration of the chronotropic effect magnitude. Met-enkephalin potentiated the phase-dependent vagal chronotropic effect, whereas neurotensin moved its limits toward the initial part of the P-P interval.     

Characteristics of the phase-dependent vagus effects in the heart of the frog Rana temporaria and of the cod Gadus morhua

In experiments on the heart of the cod Gadus morhua and frog Rana temporaria in situ, studies have been made of changes in the heart rate induced by stimulation of the vagal nerve by single brief bursts delivered at various intervals after P wave of the ECG. Certain differences were found in changes of the heart rate between these animals. In the cod, maximum chronotropic effect was equal to 65% of the duration of initial cardiac cycle, the latency of this effect being equal to 290 ms; in the frog, corresponding figures were 12-13% and approximately 940 ms. The duration of negative chronotropic effect in the heart of the cod was equal to 700 ms, that of the frog--to 2.700 ms. Functional role of these differences is discussed in relation to the problem of the development of parasympathetic regulation of the heart rate in phylogenesis of vertebrates.     

Controlled sinus arrhythmia during burst stimulation of the vagus nerve

In experiments on anesthesized cats and rats the desynchronization of the heart rate and burst stimulation of the vagus brought about severe sinus arrhythmia. Analysis of the functional dependence between the P--S interval (atrial wave of the ECG--moment of vagus stimulation) and the P--P interval showed periodical alterations in pacemaker sensitivity to the effect of the vagus during each cardiac cycle. It is supposed that natural vagus arrhythmia is the result of discoordination between heart automacy and efferent vagus bursts of central origin.     

Peptidergic modulation of the vagal effect on heart rhythm]

In 20 experiments on anesthetised cats burst stimulation of peripheral cut end of right vagus nerve leads to synchronisation of cardiac and vagus rhythms. Inhibitory effect of dalargin was caused by a decrease of tonic component while secretin would selectively inhibit synchronizing component. The observed results testify to existence of selective peptidergic modulation of vagus influence on the cardiac rhythm.     

Neuromodulation of the cardiac vagus: comparison of neuropeptide Y and related peptides

Neuropeptide Y (NPY), a putative co-transmitter in noradrenergic sympathetic nerves of the cardiovascular system, inhibits the negative chronotropic action of the cardiac vagus. In the present study, peptides related to NPY were tested for potency in producing this effect. In bilaterally vagotomized, anaesthetised dogs, the increase in pulse interval caused by electrical stimulation of the peripheral stump of the right vagus was measured before and after intravenous administration of peptide. The effects of doses of NPY were compared with those of equimolar doses of peptide YY (PYY), and of avian and human pancreatic polypeptides (APP and HPP). PYY inhibited the vagal action more effectively than did NPY. APP and HPP, however, caused no change in strength of vagal action at the doses used. The response to a second injection of NPY, given soon after the injection of APP or HPP, was not significantly different from the original. Thus no evidence was obtained for a competitive inhibition of the action of NPY by either pancreatic polypeptide. A C-terminal hexapeptide fragment of human pancreatic polypeptide was also tested. Like APP and HPP, it neither inhibited the cardiac vagus nor blocked the action of NPY. The order of potency obtained here (PYY greater than NPY much greater than APP, HPP, CFPP) can be expected to be of use in efforts to distinguish the active site(s) of the NPY molecule, and to characterise the receptors involved in these modulatory effects.     

Verapamil potentiates vagally mediated sinoatrial chronotropic responses in dogs

A brief burst of electrical stimuli delivered to the vagus nerve during the cardiac cycle elicits a triphasic cardiac chronotropic response. The cardiac cycle length initially increases, then briefly decreases, and subsequently increases again. We studied the effects of a calcium channel blocking agent, verapamil, on these responses to vagal stimulation during sinoatrial nodal rhythm in anesthetized, open-chest dogs. Verapamil increased the basal cardiac cycle length only slightly; however, the primary cardioinhibition was accentuated approximately 40% (from 396 to 555 ms) by verapamil. Neither the acceleratory phase of this triphasic response nor the secondary cardioinhibition was significantly affected by verapamil. These results indicate that verapamil potentiates the initial action of acetylcholine at the sinoatrial node when the vagus is activated with brief stimuli.     

Effects of calcium channel antagonists on the vagally mediated cardiac chronotropic response in dogs

A brief electrical stimulation of the vagus nerve may elicit a triphasic response comprising (i) an initial prolongation of the same or the next cardiac cycle, (ii) a return of the subsequent cardiac cycle to about the level prior to vagal stimulation, and (iii) a secondary prolongation of cardiac cycle length that lasts several beats. We compared the effects of two calcium channel antagonists, verapamil and nifedipine, on this triphasic response to vagal stimulation in chloralose-anesthetized, open-chest dogs. In the absence of vagal stimulation, nifedipine (doses of 10, 40, and 50 micrograms/kg for a total dose of 100 micrograms/kg, i.v.) and verapamil (two doses of 100 micrograms/kg each, i.v.) increased the cardiac cycle length (A-A interval) by 16% (429 +/- 20 to 496 +/- 21 ms) and 29% (470 +/- 33 to 605 +/- 54 ms), respectively. Nifedipine (100 micrograms/kg total) attenuated the initial vagally mediated prolongation of the A-A interval, from 474 +/- 19 to 369 +/- 42 ms above the basal A-A interval. Following the initial prolongation of the vagal effect, other A-A intervals were not affected. In contrast, verapamil potentiated the vagally mediated initial prolongation in cardiac cycle length at the first dose administered (100 micrograms/kg) from 492 +/- 17 to 561 +/- 14 ms, but other increases in dosages had no further effect. Thus these two calcium channel antagonists have different effects on the sinoatrial chronotropic responses caused by brief vagal stimulation.     

Increase of cardiodepressant activity in medium incubating the posterior pituitary lobe in situ during vagal nerve stimulation in rat.

Previous studies have indicated that there is a cardiodepressant factor in the medium incubating the posterior pituitary lobe in situ. The cardiodepressant activity of the medium incubating the posterior pituitary lobe before and during stimulation of the vagus nerves was tested on isolated auricles of the right heart atrium of a two-day-old rat. It was found that the medium incubating the posterior pituitary lobe collected before stimulation decreased the contraction rate of the auricle by 34%, while that collected during the intermittent stimulation of the central ends of the cut vagus nerves caused a decrease of the auricle contractions frequency by 52%. The addition of cholinergic, serotoninergic, histaminergic receptor blockers or prostaglandin synthetase into Ringer-Lock's solution bathing the auricle has no effect on the changes of the contraction rate caused by the incubation medium.     

Postnatal development of chronotropic responses to chemical and electrical stimulation of adrenergic nerve endings in the sinoatrial node of the heart of the albino rat

The positive chronotropic response to stimulation of adrenergic nerve endings in the sinoatrial node was studied in isolated atria from the hearts of rats of different ages. Dimethylphenylpiperazinium (DMPP) was used for chemical stimulation and transmural stimulation of the sinoatrial node region as electrical stimulation; in both cases noradrenaline is released from the nerve endings. With both stimulation methods, postnatal development was recorded in two phases. In the first phase, positive chronotropic responses are markedly increased and attained the maximum at the age of 14 days on using DMPP and of 24 days on using electrical stimulation. In the second phase, positive chronotropic responses diminish and at the age of about 45 days, with both stimulation methods, they become reduced to adult level. The first developmental phase can be attributed to an increase in the noradrenaline content of the nerve endings and the release of a larger amount of the transmitter during stimulation, together with an increase in the noradrenaline sensitivity of the cells of the sinoatrial node. It is not clear why positive chronotropic responses decrease in the second phase, when the noradrenaline content of the myocardial tissue continues to rise and pacemaker sensitivity to noradrenaline is not reduced.     

Vagal innervation of guinea pig bronchial smooth muscle

We isolated the guinea pig right bronchus with the vagus nerves intact and evaluated the changes in isometric tension of the smooth muscle in response to nerve stimulation. Brief (10-s) trains of electrical field stimulation or vagus nerve stimulation caused a biphasic contraction: the "first phase" sensitive to atropine and the "second phase" sensitive to capsaicin. The two phases could be dissociated by adjusting the stimulus intensity; greater stimulus intensities (pulse durations or voltage) were required to evoke the capsaicin-sensitive phase. When stimulated at 30-min intervals, the magnitude of both phases of the contractions declined over a 2-h period of repeated stimulation; however, this was prevented by indomethacin. Stimulation of the left vagus nerve resulted in a monophasic contraction of the right bronchus, with little evidence of a capsaicin-sensitive phase. Blocking neurotransmission through the bronchial ganglion, as monitored by intracellular recording techniques, abolished the first-phase contraction but had no effect on the capsaicin-sensitive phase. Selective blockade of muscarinic M1 receptors had no effect on vagus nerve-mediated contractions. The results demonstrate that the left and right vagus nerves carry preganglionic fibers to the right bronchial ganglion. The right but not the left vagus nerve also carries capsaicin-sensitive afferent fibers that, when stimulated, result in a persistent contraction of the right bronchus. Finally, we provide functional and electrophysiological evidence supporting the hypothesis that capsaicin-sensitive afferent neurons communicate with postganglionic motoneurons within the bronchus.     

Integration of the effects of a single stimulus applied to the vagus nerve on the right and the left, in the rabbit heart

It was reported by the literature that a train stimulation, simultaneously delivered on the two vagi, resulted in a decrement of the negative chronotropic effect, when it was compared to the sum of the effects obtained by the stimulation of the two nerves, separately. Our data indicate that the size of the chronotropic effect obtained by the simultaneous application on the two vagi of a single supraliminar stimulus, randomly applied within the P-P cycle, in rabbits, can be equal, higher or lower than the sum of the same stimulation separately delivered to the two nerves. The results could depend upon the different amount of acetylcholine released during stimulation. The hypothesis is put forward that different patterns of the neuro-cardiac junction regulation might be activated according to the quantity of released neuromediator.     

Neuroinhibition in the regulation of emesis

Elucidation of an inhibitory system in the regulation of emesis is presented in this report. Emesis preceded by retching, can be induced in the dog by appropriate electrical stimulation of abdominal vagus nerves at the supradiaphragmatic level. Failure to produce retching or emesis by electrical stimulation of the cervical vagus trunk suggests either that the abdominal vagal emetic afferent does not course in the cervical vagus or that fibers inhibitory to emesis are present. This report presents evidence for afferent fibers inhibitory to retching and emesis in the cervical vagus. Retching and emesis resulting from stimulation of the supradiaphragmatic vagus can be prevented by either transection of the cervical vagus or simultaneous stimulation of the cervical vagus trunk. In addition, retching and emesis occur with stimulation of a fine nerve bundle dissected from the cervical vagus trunk. That the afferent pathway inhibitory to retching and emesis involves pulmonary afferents is suggested by the observation that hyperventilation occurs with stimulation of the cervical vagus trunk.Research supported by U.S.P.H.S. Grant No. FR05339-07     

Parasympathetic regulation of cardiac rhythm in delta sleep-inducing peptide deficiency

The effect of delta-sleep peptide (DSP) deficiency on the parasympathetic regulation of the heart rate was studied on 35 rabbits. It was established that the injection of an-serum (titer-1:2000-1:3000) leads to the attenuation of parasympathetic influences: heart rate increase in freely behaving animals and a decrease in negative chronotropic effect with direct vagus irritation. Antiserum, like DSP, administration causes practically no damage of the myocardial ultrastructure.