Inferior Cardiac Nerve Research Articles

Location of efferent sympathetic neurons and afferent neurons in spinal ganglia innervating the heart

Location and numbers of neurons associated with sympathetic innervation of the heart within the right stellate and accessory cervical ganglia, the spinal cord, and spinal ganglia were investigated using horseradish peroxidase retrograde axonal transport techniques in cats. The enzyme was applied to central sections of the anastomosis of the stellate ganglion with the vagus nerve, the inferior cardiac nerve, and the vagosympathetic trunk caudal to the anastomosis. Labeled neurons within the stellate ganglion were located close to the point of departure of the nerves and more thinly distributed in the accessory cervical ganglion. A group of labeled cells was found in the anastomosis itself. Preganglionic neurons associated with sympathetic innervation of the heat were detected at segmental levels T1–T5 in the spinal cord. Labeled neurons were diffusely located in the spinal ganglia, concentrated mainly at levels T2–T4.

Identification of serotonergic and sympathetic neurons in medullary raphe nuclei

The purpose of the present study was to identify midline medullary serotonin (5-HT) neurons and to determine if these neurons were distinct from previously identified sympathoinhibitory and sympathoexcitatory neurons. Identification of medullary 5-HT neurons was based on electrophysiological and pharmacological similarities to dorsal raphe 5-HT neurons. Sympathoinhibitory and sympathoexcitatory neurons were characterized by an irregular discharge pattern which was temporally related to inferior cardiac sympathetic nerve discharge (SND) and to the cardiac cycle. Sympathoinhibitory neurons increased their discharge rate and the discharge of sympathoexcitatory neurons decreased during baroreceptor reflex activation. A third type of neuron fired in an extremely regular fashion (as judged by interspike interval analysis), fired at a rate of 1.1 spikes/s and had spike durations of approximately 2 ms. The discharges of regularly firing neurons were not temporally related to SND and were not affected during baroreceptor reflex activation. Regularly firing neurons and sympathoinhibitory neurons could be antidromically activated by electrical stimulation of the intermediolateral cell column of the spinal cord. Axonal conduction velocity of sympathoinhibitory neurons (2.4 m/s) was significantly greater than that for regularly firing neurons (1.3 m/s). Regularly firing neurons were completely inhibited by low doses of the 5-HT 1A agonist 8-hydroxy-dipropylamino-tetralin (8-OH-DPAT) (i.e. 2 μg/kg, i.v.) while much higher doses of the drug failed to affect the discharges of sympathoinhibitory and sympathoexcitatory neurons. Microiontophoretic application of 5-HT and 8-OH-DPAT profoundly depressed the firing of regularly discharging neurons. Based on the striking similarities between regularly firing medullary neurons and dorsal raphe 5-HT neurons it is concluded that the regularly firing neurons were 5-HT-containing neurons. Furthermore, these medullary 5-HT neurons are distinct from sympathoinhibitory and sympathoexcitatory neurons.

Effect of bunazosin on cardiac sympathetic nerve activity in anesthetized rats.

The present study was undertaken to elucidate the effect of selective alpha-1 adrenoceptor antagonist, bunazosin, on sympathetic nerve activity in anesthetized rats. Intravenous administration of bunazosin (10 micrograms/kg) produced a reduction of mean arterial pressure with a significant decrease in heart rate. Accompanied with its hypotension and bradycardia, bunazosin caused a decrease in inferior cardiac nerve activity. On the other hand, renal nerve activity, which reflects vasoconstriction, was not significantly decreased by bunazosin. These findings suggest that bunazosin may possess an anti-tachycardic action resulting from the reduction of cardiac sympathetic nerve activity and that the sympathoinhibitory action of bunazosin may not contribute to its hypotensive action.

GABA-mediated inhibition of sympathoexcitatory neurons by midline medullary stimulation.

The present investigation determined whether the effects of electrical stimulation of depressor sites in midline medullary raphe nuclei were a result of inhibition of sympathoexcitatory medullospinal neurons in the rostral ventrolateral medulla of anesthetized cats. Electrical stimulation of the raphe inhibited inferior cardiac sympathetic activity. Microinjections of glutamate mimicked the effects of electrical stimulation. Electrical stimulation inhibited sympathoexcitatory neurons in the rostral ventrolateral medulla. The onset of the sympathoinhibition recorded from the inferior cardiac nerve (72 ms) was equal to the sum of the onset latency of the sympathoexcitatory response elicited from the rostral ventrolateral medulla (49 ms) plus the conduction time in the raphe to rostral ventrolateral sympathoinhibitory pathway (23 ms). Raphe stimulation excited a second set of neurons in the rostral ventrolateral medulla with an onset of 21 ms. Microiontophoretically applied bicuculline increased the discharge of sympathoexcitatory neurons and blocked the raphe-evoked inhibition. Iontophoretic glutamate excited sympathoexcitatory neurons but failed to antagonize raphe-elicited inhibition. These data suggest that neuronal elements in medullary raphe nuclei tonically inhibit sympathoexcitatory medullospinal neurons in the rostral ventrolateral medulla by activating closely adjacent gamma-aminobutyric acid (GABA) interneurons.

The effect of sevoflurane on somatically induced sympathetic reflexes.

The effects of various inspiratory concentrations of sevoflurane anesthetics on the sympathetic reflex responses evoked in the left inferior cardiac nerve branch following an electrical stimulation to the ipsilateral superficial peroneal nerve were investigated in cats. At a 2.0% inspiratory concentration of sevoflurane, two components of the somato-sympathetic reflexes with two different latencies were recorded. The early component was due to an activation of myelinated A afferent fibers (referred to as the A-reflex), while the late component was due to an activation of unmyelinated C afferent fibers (referred to as the C-reflex). The increase in the concentration of sevoflurane from 2.0% to 3.0% resulted in about 50% attenuation of both the A- and C-reflexes. A further increase in the concentration of sevoflurane to 4.0% resulted in further suppression of both reflexes.

Tonic descending inhibition of the spinal cardio-sympathetic reflex in the cat

Electrical stimulation of the left inferior cardiac nerve elicited a two-component reflex potential (spinal and supraspinal reflexes) in the ipsilateral white ramus T 3 from which recordings were made in chloralose-anaesthetised cats. Reversible interruption of all spinal pathways achieved by cooling the spinal cord at C 2/C 3 produced an enhancement of the spinal reflex and abolished the supraspinal reflex, the latter usually being the more prominent reflex potential prior to spinal cord block. The spinal cord block-induced increase in the amplitude of the spinal reflex was, however, less than the increase observed during stimulation of the somatic intercostal nerve T 4. Recordings of the afferent volley following cardiac nerve stimulation and analysis of the stimulus-reflex response relationship in neuraxis-blocked cats indicated that the spinal reflex as determined here was activated by Aδ afferent fibres. However, if stimulus strength was raised above C-fibre threshold, spinal cord block revealed in addition a late spinal reflex response. In some cases, the appearance of this late potential was accompanied by a secondary decline of the earlier spinal reflex potential, possibly indicating C-fibre-mediated afferent inhibition. Neither baroreceptor activation nor denervation had any effect on spinal reflex amplitudes. Pharmacologically, clonidine given i.v. to cats with a blocked neuraxis reduced the spinal reflex amplitudes to pre-block values, an action which could be antagonised by the subsequent administration of the α 2-adrenoceptor antagonist rauwolscine. When given to non-pretreated cats with intact neuraxis, however, neither rauwolscine nor its analog yohimbine were capable of inducing a persistent release from tonic inhibition. The results suggest that both purely visceral and somato-visceral reflexes are subject to tonic descending inhibition, but they do not support the hypothesis that a catecholamine is the responsible transmitter mediating this inhibition.

Slow cardioacceleration mediated by noncholinergic transmission in the stellate ganglion of the cat

In C1-spinal, pentobarbital-anaesthetized or anemically decerebrated cats, the preganglionic input to the acutely decentralized right stellate ganglion was stimulated with 10- to 30-s strains at 20-40 Hz. Electrical stimulation consistently produced an increase in heart rate in the presence of blocking doses of hexamethonium and atropine or after depletion of acetylcholine from the preganglionic axons by prolonged low frequency stimulation in the presence of hemicholinium. The increase in heart rate had a delayed slow onset, lasted several minutes, and was abolished by propranolol or by section of the inferior cardiac nerve. The magnitude and duration of the heart rate increase were related to intensity, frequency, and duration of preganglionic stimulation. The response to stimulation of a given white ramus was progressively attenuated, and eventually irreversibly lost, during prolonged continuous stimulation of that ramus, while the response to stimulation of a different unstimulated ramus was unchanged. We conclude that the slow cardioacceleration results from a slow and prolonged excitation of postganglionic neurons by a noncholinergic transmitter released by the preganglionic axons.

5-HT 2 receptor agonists increase spontaneous sympathetic nerve discharge

The selective 5-HT 2 agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) produced a marked increase in spontaneous sympathetic nerve discharge recorded from the inferior cardiac nerve in chloralose anesthetized cats. DOI (0.01–1.0 mg/kg i.v.) increased sympathetic nerve discharge to a maximum of 1750% of control values. The increase in sympathetic nerve discharge produced by DOI was reversed by the 5-HT 2 antagonists ketanserin and LY 53857. In addition, pretreatment with ketanserin, but not prazosin, completely prevented the increase in sympathetic nerve discharge produced by DOI. These data are discussed in relationship to the role of serotonin in the regulation of activity in central sympathetic pathways.

Postsynaptic adrenoceptor-mediated vasoconstriction in coronary and femoral vascular beds.

This study examined the response to intra-arterial norepinephrine and sympathetic nerve stimulation on perfusion pressure of cannulated dog femoral and left circumflex coronary arteries perfused at constant flow rates. Sympathetic nerve stimulation was delivered through the decentralized inferior cardiac nerve and the lumbar sympathetic chain; beta-adrenergic blockade was maintained with propranolol. In the coronary artery, the vasoconstrictor response to norepinephrine was blunted by alpha 1-adrenergic blockade with prazosin but was abolished by alpha 2-adrenergic blockade with rauwolscine, indicating postsynaptic alpha 2-adrenoceptor-mediated vasoconstriction. In the femoral artery, prazosin decreased norepinephrine-induced vasoconstriction by 20-40%; the subsequent addition of rauwolscine completely abolished vasoconstriction, indicating that both alpha 1- and alpha 2-adrenoceptors contributed to vasoconstriction. Sympathetic nerve stimulation produced frequency-dependent increases of perfusion pressure in both coronary and femoral vascular beds. Prazosin caused approximately 50% reduction in the vasoconstrictor response of the coronary vascular bed and approximately 30% reduction in the femoral bed. The addition of rauwolscine completely blocked the response to sympathetic nerve stimulation in coronary and femoral vascular beds. These studies demonstrate that postsynaptic alpha 2-adrenoceptor-mediated mechanisms participate in vasoconstriction in response to both exogenous norepinephrine and sympathetic nerve stimulation in the canine coronary and femoral vascular beds.

Analysis of reflex activity in cardiac sympathetic nerve induced by myelinated phrenic nerve afferents

Electrical stimulation of the phrenic nerve afferents evoked excitatory responses in the right inferior cardiac sympathetic nerve in chloralose-anaesthetized cats. The reflex was recorded in intact and spinal cats. The latency and threshold of the volley recorded from the phrenic nerve as well as of the cord dorsum potentials evoked by electrical stimulation of the phrenic nerve indicated that group III afferents were responsible for this reflex. The phrenicocardiac sympathetic reflex recorded in intact cats was followed by a silent period. The maximum amplitude of the reflex discharges was 800 μV, the latency was 83 ms and the central transmission time 53 ms. Duration of the silent period lasted up to 0.83 s. In spinal cats the reflex was recorded 5.5–8 h after spinalization. The maximum amplitude of the spinal reflex discharges ranged from 22 to 91 μV and the latency from 36 to 66 ms.

Cardioacceleration produced by close intra-arterial injection of neurotensin into the stellate ganglion of the cat

The effect on heart rate of close i.a. injection of neurotensin (NT), substance P (SP), and vasoactive intestinal peptide (VIP) into the decentralized right stellate ganglion was tested in anaesthetized spinal cats. These peptides are present in the stellate ganglion and may mediate the stellate ganglion cell excitation underlying a previously described slow cardioacceleration evoked by preganglionic stimulation during block of cholinergic transmission. NT (Tyr11-NT) at doses of 25-200 micrograms produced increases in heart rate of 10-125 beats/min (bpm) and of slow time course. At the dose of 100 micrograms, NT produced a cardioacceleration of 56 +/- 8.4 bpm (mean +/- SEM, n = 13) with an onset latency of 23 +/- 4 s, a slow rise to peak (rise time 62 +/- 4.5 s), and a half decay of 167 +/- 14 s. A cardioacceleration of comparable magnitude (78 +/- 3.8 bpm) caused by close i.a. administration of acetylcholine (100 micrograms, n = 13) had an onset latency of 2 +/- 1 s, a fast rise to a sharp peak (rise time 3 +/- 1 s), and a half decay of 23 +/- 4 s. The analogues, Phe11-NT and Trp11-NT, as well as the stereoisomer, D-Tyr11-NT, had no effect on heart rate when injected at doses up to 400 micrograms. The NT-evoked cardioacceleration was blocked by propranolol or by section of the inferior cardiac nerve and may therefore be attributed to prolonged excitation of stellate ganglion cells. Administration of hexamethonium and atropine was without effect on the NT response.(ABSTRACT TRUNCATED AT 250 WORDS)

Cat diencephalic neurons with sympathetic nerve-related activity.

In a companion paper, we demonstrated that hypothalamic or medial thalamic lesions attenuate the reduction in inferior cardiac postganglionic sympathetic nerve discharge (SND) produced by decerebration in the anesthetized cat [Huang et al., Am. J. Physiol. 254 (Regulatory Integrative Comp. Physiol. 23): R249-R256, 1988]. This raised the possibility that these diencephalic regions contain the cell bodies of neurons that contribute to SND. The current study tested this possibility in cats anesthetized with alpha-chloralose. Spike-triggered averaging of inferior cardiac SND revealed the existence of two types of hypothalamic and medial thalamic neurons with sympathetic nerve-related activity. Recordings were made from the soma-dendritic region of these neurons, since an inflection often appeared on the rising phase of the unit action potential. The activity of type 1 neurons was synchronized to an aperiodic spikelike event in SND, whereas that of type 2 neurons was synchronized to a 2- to 6-Hz rhythmic component. Some of the type 2 neurons but none of the type 1 neurons had cardiac-related activity. Microstimulation at type 1 and type 2 unit recording sites increased SND. Our results are consistent with the possibility that hypothalamic and medial thalamic neurons contribute to the rhythmic and aperiodic components of SND in the anesthetized cat.

Diencephalic regions contributing to sympathetic nerve discharge in anesthetized cats.

We reported that the forebrain is responsible for a significant component (38%) of inferior cardiac postganglionic sympathetic nerve discharge (SND) in baroreceptor-denervated cats anesthetized with alpha-chloralose [Huang et al., Am. J. Physiol. 252 (Regulatory Integrative Comp. Physiol. 21): R645-R652, 1987]. The current study was initiated to assess the contribution of various diencephalic regions to the forebrain-dependent component of SND in this preparation. For this purpose, the reductions in inferior cardiac SND and blood pressure produced acutely by midbrain transection at stereotaxic plane A3 in nonlesioned control cats were compared with those in cats in which diencephalic lesions were made with radio-frequency current. Lesions of the anterior medial hypothalamus including the paraventricular nucleus failed to attenuate the decreases in SND and blood pressure produced by midbrain transection. In contrast, the effects of midbrain transection were significantly attenuated by lesions of the lateral hypothalamus (including medial forebrain bundle), posterior medial hypothalamus, or the medial thalamus. We conclude that both the hypothalamus and medial thalamus contribute to SND in anesthetized cats.

Cardiac sympathetic afferent input onto neurons in nucleus ventralis posterolateralis in cat thalamus

Neurons receiving cardiac sympathetic afferent input were studied in the nucleus ventralis posterolateralis (VPL) of the cat thalamus. Animals were anesthetized with urethan-chloralose. Units in the VPL were classified into 3 classes; low-threshold mechanoreceptive (LTM), nociceptive specific (NS) and wide dynamic range (WRD) units. Units driven by electrical stimulation of the left inferior cardiac nerve (ICN) were not included in the population of LTM units, but 43.5% of NS units and 68.8% of WDR units were excited by this stimulation. Units exclusively responsive to caridiac sympathetic afferents were found. Both NS and WDR units were located in the shell region of the caudal VPL. NS units responsive to cardiac afferents had a circumscribed cutaneous receptive field in the area corresponding to tactile dermatomes C 5–T 13. WDR units receiving cardiac sympathetic afferent input had at least a part of their receptive fields in the same area. These results thatthe shell region of the caudal VPL constitutes a thalamic link in a cardiac pain pathway, and that cardiac and cutaneous pain systems share a common projection locus in the VPL.

Spinal segmental preganglionic outflow to cervical sympathetic trunk and postganglionic cardiac sympathetic nerves

The aim of this study was to verify in which spinal cord segments the preganglionic neurones projecting to the cervical sympathetic trunk or converging onto the somata of the postganglionic cardiac sympathetic neurones are located in cats. The thoracic while rami T 1 to T 5 were electrically stimulated and the evoked responses were recorded in the cervical sympathetic trunks and postganglionic cardiac nerves. The responses were mostly evoked by electrical stimulation of group B preganglionic fibres. The maximum amplitude of evoked responses in the cervical sympathetic trunk was obtained when the T 2 white ramus was stimulated and decreased gradually when followed by the stimulation of T 1, T 3, T 4 and T 5 white rami. In most cases the maximum amplitude of evoked responses in the left inferior cardiac nerve, right inferior cardiac nerve and left middle cardiac nerve was obtained when the T 3 white ramus was stimulated. The size of the responses decreased when more cranial and caudal white rami were stimulated. It was found that the somata of the postganglionic neurones of the right and left inferior cardiac nerves were placed in the right and left stellate ganglion, respectively. Somata of the postganglionic neurones with axons in the left middle cardiac nerve were mainly located in the left middle cervical ganglion and some in the left stellate ganglion.

Sympathetic alterations after midline medullary raphe lesions.

The present study was designed to determine the functional importance of the midline medullary raphe nuclei in the autonomic regulation of the cardiovascular system in the anesthetized cat. Baroreceptor and somatosympathetic reflexes as well as the effects of electrical stimulation of vagal afferents and pressor and depressor sites in the hypothalamus and spinal trigeminal tract were determined before and after midline medullary lesions that extended from 2 to 7 mm rostral to the obex. Midline medullary lesions failed to affect baroreceptor reflexes as judged by the lack of effect on the sympathoinhibition associated with the pressor response to phenylephrine and the degree of slow-wave locking of sympathetic activity to the cardiac cycle. However, the lesion did significantly increase spontaneous sympathetic activity recorded from the inferior cardiac nerve. Blood pressure and heart rate were not altered by midline lesions. In addition, the computer-summed sympathoexcitatory response to electrical stimulation of somatic afferents in the sciatic nerve and the sympathoinhibitory response to stimulation of vagal afferent fibers were not affected by midline lesions. In contrast, the decrease in blood pressure and inhibition of sympathetic nerve activity elicited by electrical stimulation of the spinal trigeminal tract were completely abolished by the lesion. Depressor responses evoked from the anteroventral third ventricle region of the hypothalamus but not pressor responses elicited from the posterior hypothalamus were eliminated following midline medullary lesions. Finally, the sympathoinhibitory actions of the serotonin antagonist methysergide were blocked by medullary raphe lesions. These data indicate that neural elements in the medial medullary area function to provide a tonic inhibition of sympathetic nerve activity that is of nonbaroreceptor origin. Depressor responses evoked from the anterior hypothalamus and the spinal trigeminal tract also are mediated through this area of the medulla. Finally, the data support our contention that medullary serotonergic neurons have a sympathoexcitatory function.

Characterization of the very late cardiosympathetic A-reflex in high-mesencephalic cats

In unanaesthetized mid-collicular decerebrate cats, stimulation of low-threshold afferents running in the inferior cardiac nerve can evoke in renal nerve a long-latency reflex response, which is able to reduce or overcome the inhibition developing after the late response. The spatial and temporal summation have great importance in generating this very late response (VLR). Increasing the stimulus intensity and the frequency of the impulses, using short trains or a previous A + C tetanic stimulation of the segmental inputs considerably increased the chance of the VLR overcoming the late inhibition.

Lateral tegmental field neurons of cat medulla: a source of basal activity of ventrolateral medullospinal sympathoexcitatory neurons.

We tested the hypothesis that neurons of the lateral tegmental field (LTF) of the cat medulla exert their sympathoexcitatory actions over a pathway that includes rostral ventrolateral medullospinal neurons innervating the spinal intermediolateral nucleus (IML). Thirty-one LTF neurons with sympathetic nerve-related activity [as demonstrated with spike-triggered averaging of inferior cardiac postganglionic sympathetic nerve discharge (SND)] were antidromically activated by microstimulation of the rostral ventrolateral medulla (VLM). The threshold current required to elicit the longest latency antidromic response was increased when the stimulating microelectrode was moved to more dorsal or medial sites in the rostral medulla. This observation suggests that the axons of LTF neurons projected to the rostral VLM. The firing rate of LTF neurons with sympathetic nerve-related activity was decreased during baroreceptor reflex activation. This observation is consistent with the view that these neurons subserved a sympathoexcitatory function. Twenty-five VLM neurons with sympathetic nerve-related activity were synaptically activated by microstimulation of the LTF. The modal onset latency of synaptic excitation (25.6 +/- 2.6 ms) compared favorably with the difference (31 ms on the average) between the firing times of LTF and VLM neurons relative to the peak of the cardiac-related sympathetic nerve slow wave. The firing rate of these VLM neurons decreased during baroreceptor reflex activation. Of nine VLM neurons tested, seven were antidromically activated by microstimulation of the second thoracic (T2) IML. These data are consistent with the view that LTF neurons are a source of the basal discharge of VLM-spinal sympathoexcitatory neurons. Sixteen VLM neurons with sympathetic nerve-related activity were antidromically activated by microstimulation of both the LTF and the T2 IML. In some cases, LTF stimulation activated an axonal branch rather than the main axon. This was demonstrated using time-controlled collision of the VLM neuronal action potentials initiated by LTF and T2 IML stimulation. These data raise the possibility that individual VLM neurons influence SND by actions mediated at both spinal and supraspinal levels.

Electrophysiological evidence for the modular organization of the reticular formation: sympathetic controlling circuits

Cross-correlation analysis revealed that the discharges of cat medullary reticular neurons located in the recording field of a single microelectrode were synchronized on a time scale of a few ms. The incidence of short time scale interactions was significantly greater when both members of a neuronal pair had activity temporally related to postganglionic inferior cardiac sympathetic nerve discharge than when only one member had sympathetic nerve-related activity. The data support the view that the reticular formation is organized into functionally distinct modules that are potentially interactive.

Longitudinal distribution of negative cord dorsum potentials following stimulation of afferent fibres in the left inferior cardiac nerve

Cord dorsum potentials were recorded along the spinal cord following electrical stimulation of afferent fibres of the left inferior cardiac nerve in chloralose anaesthetized cats. The potentials were more pronounced in spinal than in intact cats. Afferent fibres which generated cord dorsum potentials in the cervical spinal cord were localized mainly in T 2 and T 3 and to a smaller extent in C 8 and T 1 dorsal roots. The responses consisted of two waves: with short (7.0 ms; N3 wave) and long (56 ms; N4 wave) latency to the onset of potentials. N3 and N4 waves were generated by group III and group IV afferent fibres, respectively. The N3 wave was maximal at C 8 and T 1 spinal cord level and could be detected at least 5–6 segments rostrally from the level of afferent input responsible for its generation. The N4 wave could be detected at least 4 segments rostrally from its afferent fibre input. We conclude that afferent fibres from the left inferior cardiac nerve activate neurones in the cervical spinal cord. The implications of such finding are discussed.