Canio Polosa

Function of the ventrolateral medulla in the control of the circulation

The CNS control of the cardiovascular system involves the coordination of a series of complex neural mechanisms which integrate afferent information from a variety of peripheral receptors and produce control signals to effector organs for appropriate physiological responses. Although it is generally thought that these control signals are generated by a network of neural circuits that are widely distributed in the CNS, over the last two decades a considerable body of experimental evidence has accumulated suggesting that several of these circuits involve neurons found on or near the ventral surface of the medulla oblongata. Neurons in the VLM have been shown to be involved in the maintenance of vasomotor tone, in baroreceptor and chemoreceptor (central and peripheral) reflex mechanisms, in mediating the CIR and somatosympathetic reflexes and in the control of the secretion of vasopressin. These physiological functions of VLM neurons have been supported by neuroanatomical and electrophysiological studies demonstrating direct connections with a number of central structures previously implicated in the control of the circulation, including the IML, the site of origin of sympathetic preganglionic axons, and the SON and PVH, the site of origin of neurohypophyseal projecting axons containing AVP. Considerable suggestive evidence has also been obtained regarding the chemical messengers involved in transmitting information from VLM neurons to other central structures. There have been developments suggesting a role for monoamines and neuropeptides in mediating the neural and humoral control of SAP by neurons in the VLM. This review presents a synthesis of the literature suggesting a main role for VLM neurons in the control of the circulation.

Patterning of sympathetic preganglionic neuron firing by the central respiratory drive

The existence of a temporal relationship between the mass activity of sympathetic preor postganglionic nerves and that of the phrenic nerve has been described x,a. This finding demonstrates the existence of some form of coupling between the respiratory oscillator and the sympathetic preganglionic neurons (SPNs). Some of the coupling is done by mechanisms acting entirely within the CNS is. Gootman 1° and Gootman and Cohen 12 initiated a quantitative study of these central mechanisms by making an analysis of the phase relationship between the efferent activity of the whole splanchnic nerve and that of the phrenic nerve in vagotomized, paralyzed, thoracotomized, artificially ventilated cats. Their data show that the massed splanchnic activity started to increase during the early inspiratory phase, reached a maximum in midinspiration, after which it remained constant or declined slightly for the remainder of the inspiratory phase. During the early expiratory phase activity reached a minimum, after which it increased again to reach a plateau in the middle and late part of the expiratory phase. These authors suggested that this pattern of modulation could result from an interaction of brain stem phase-spanning respiratory neurons 6 and SPNs (or their antecedent neurons). However, mass recording does not allow the formulation of precise hypotheses concerning the mechanism of generation of the observed wave shape, because the latter may arise from the superposition of more than one firing pattern of the contributing units. For example, the inspiratory and expiratory peaks of the splanchnic neurogram could arise because the same units fire both in inspiration and expiration, or because some units fire in inspiration and others in expiration. On account of these limitations of the mass recording techniques, the present work, which is a logical extension of that of Gootman and Cohen 12 and of Mannard and Polosa 14, was undertaken. In the course of the latter study 14, the presence of a respiration-locked input was detected, by autocorrelation analysis of single SPN firing, in more than half of the SPNs studied. In the present study we have recorded the activity of single SPNs (or of a few units) simultaneously with that of the phrenic nerve, which we used as an index of the central respiratory cycle, in experimental conditions in which the main reflex loops that connect the respiratory to the

The relation between end-tidal CO2 and discharge patterns of sympathetic preganglionic neurons

In 11 Nembutal-anesthetized, vagotomized, thoracotomized, paralyzed and artificially ventilated cats, the electrical activity of 32 single sympathetic preganglionic neurons (SPNs), dissected from the cervical nerve was recorded at various end-tidal CO2 levels, together with the activity of the phrenic nerve. Seven of these neurons were insensitive to CO2 changes, within a range of end-tidal CO2 values from 1;0 to 10;0%. All 7 had a background firing pattern without respiratory modulation, even at the highest CO2 levels tested, i.e., had the same firing frequency in both phases of the phrenic nerve activity cycle. Seventeen units were silent at low CO2 levels, began to discharge at particular CO2 levels (on the average, at 2.3% CO2) and increased their firing frequency (on the average, by 0.9 spikes/sec/% CO2) as end-tidal CO2 was raised above the threshold level. Their background discharge pattern was characterized by firing only in the inspiratory phase of the phrenic nerve activity cycle. Three units had firing which was CO2-independent within a range of low CO2 concentrations and which increased as CO2 concentration was increased above this range. These units fired throughout the phrenic nerve activity cycle but had their peak frequency in inspiration. Five units had a firing frequency which was highest at low CO2 and which decreased with increasing CO2 levels. These units had their peak frequency in expiration. These results show that the output of this SPN population is strongly influenced by CO2 within the range of concentrations tested. The finding that sensitivity to CO2 changes is a property only of SPNs with respiratory-modulated firing pattern suggests that the CO2-dependent input is relayed to these SPNs via the respiratory center; A comparison of data obtained under hypocapnic conditions with data obtained in previous studies in normocapnic cats with mid-cervical spinal cord transections suggests that brain stem inspiratory neurons represent a major excitatory input to this SPN pool.

Aortic baroreceptor reflex pathway: a functional mapping using [3H]2-deoxyglucose autoradiography in the rat

The organization of pathways within the central nervous system which are activated by aortic baroreceptor input was studied in the urethane anesthetized rat using the 2-deoxyglucose method. [3H]2-deoxyglucose was administered i.v. while either the aortic nerve was electrically stimulated or aortic baroreceptors were physiologically activated by pulse increases in arterial pressure in animals with bilateral denervation of the carotid sinus. Autoradiographs of transverse sections of the central nervous system were developed and analyzed for changes in metabolic activity in discrete regions compared to control animals, as indicated by the density of the photographic emulsion. Electrical stimulation of the aortic nerve resulted in all animals in an increase in the uptake of deoxyglucose in a number of sites throughout the central nervous system, primarily ipsilateral to the site of stimulation. In the brainstem, structures previously implicated in cardiovascular reflexes were labeled. These included the nucleus of the solitary tract, the solitary tract, the dorsal motor nucleus of the vagus, and the nucleus ambiguus. In addition, the inferior olivary nucleus, the parabrachial nuclei and the ventrolateral reticular formation showed increased labeling. In the hypothalamus, increased labeling was observed only in the paraventricular and supraoptic nuclei.

Fast inhibitory postsynaptic potentials and responses to inhibitory amino acids of sympathetic preganglionic neurons in the adult cat

Intracellular recordings were obtained from sympathetic preganglionic neurons (SPNs) of the intermediolateral nucleus (IML) in slices of upper thoracic spinal cord of the anesthetized cat. A total of 44 neurons was studied. Single shock stimulation of an area of white matter dorsolateral to the IML, close to the recording electrode (< 0.5 mm), evoked fast IPSPs with rise time of 3.8 ms and 1/2 decay time of 14.7 ms (n = 12). In 17 other cells only fast EPSPs were recorded but, after suppression of the EPSPs by the excitatory amino acid receptor antagonists CNQX (20 microM) and APV (100-250 microM), fast IPSPs were unmasked. The IPSP reversed polarity at -63 mV (-67 mV in the presence of CNQX and APV). The reversal potential shifted to a less negative value when the extracellular chloride concentration was reduced. The IPSP was reversibly abolished by the GABAA receptor antagonist bicuculline in 32% of the cells, by the glycine receptor antagonist strychnine in 47% of the cells and by the combination of the two in 21% of the cells. The IPSP was abolished by TTX (0.5 microM), had constant latency and showed no failures during high frequency stimulation. The IPSP presumably resulted from the excitation of inhibitory axons and/or inhibitory neuron somata with monosynaptic connections to the SPN. Glycine and GABA (1-3 mM) produced hyperpolarization associated with decreased membrane resistance. Sixty-nine percent of cells responded to both agonists, 19% to glycine only and 12% to GABA only. The GABAB agonist baclofen (5 microM) had no effect.(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of superior laryngeal nerve stimulation on the respiratory rhythm: phase-resetting and aftereffects

The effect of brief superior laryngeal nerve stimulation on the respiratory rhythm was investigated in midcollicular decerebrate, unanesthetized, artificially ventilated, paralysed, vagotomized and debuffered cats. Stimulus trains (50 ms, 200 Hz) delivered during inspiration (I) with intensities exceeding a threshold value, that was inversely related to the phase of the cycle, terminated I and shortened the following expiration (E) (irreversible I termination). Stimulus trains given during I with intensities just below this threshold value produced a transient suppression of I followed by resumption of activity, resulting in a slight prolongation of both I and the following E (reversible I termination). Stimulation during E produced a phase-dependent prolongation of E, but did not affect the next I. Phase-resetting curves were constructed by measuring the changes in respiratory cycle duration produced by stimuli given at phases throughout the cycle. A single stimulus produced aftereffects that lasted several cycles. The aftereffects were investigated by delivering stimuli at a fixed delay from cycle onset every n cycles (n is an integer). Certain combinations of delay, stimulus intensity, and n, resulted in (1) a variable combination of reversible and irreversible I terminations, rather than a consistent response, and (2) an increase in cycle duration. The stimulus aftereffects, that can last up to 9 cycles, may account for previously described unpredictability in the response of the respiratory oscillator to a given stimulus.

Properties of the inspiration‐related activity of sympathetic preganglionic neurones of the cervical trunk in the cat.

1. The experiments reported here have examined some temporal characteristics of the inspiration‐related sympathetic discharge of the cat in control conditions and during forcing of the respiratory oscillator into marked deviations from its natural frequency. The purpose of these experiments was to establish whether or not the relation of sympathetic to phrenic nerve activity shows properties consistent with the hypothesis that the inspiration‐related sympathetic discharge is driven by a neural oscillator, independent of, but coupled and stably entrained to, the brain‐stem respiratory oscillator. 2. The electrical activity of the whole cervical sympathetic trunk (n = 26) or of small strands of the cervical trunk containing single units (n = 20) and of the phrenic nerve was recorded in pentobarbitone‐anaesthetized, paralysed, artificially ventilated, sino‐aortic denervated cats. Most of the cats were bilaterally vagotomized. 3. The onset of the inspiratory burst of the sympathetic preganglionic neurones had a fixed delay from the onset of the phrenic nerve burst. The level of activity within the burst, in whole cervical trunk recording, reached a maximum in early inspiration and then was maintained at approximately this level for the rest of inspiration (twenty‐two out of twenty‐six cats). In four cats the activity level increased throughout the burst. Individual sympathetic preganglionic neurones displaying inspiration‐related burst firing were characteristically recruited in early inspiration and thereafter maintained an approximately constant firing frequency for the rest of inspiration. 4. Electrical stimulation of afferents in the superior laryngeal nerve during various phases of the respiratory cycle caused equivalent, phase‐dependent, resetting patterns of both phrenic nerve and inspiration‐related sympathetic discharge. 5. In cats with intact vagus nerves, entrainment of the brain‐stem respiratory oscillator to the frequency of the respiratory pump was used to change the frequency of the former, within limits, by changing the frequency of the latter. Over the range of frequencies tested, the pump‐to‐phrenic delay varied as a function of frequency, while the delay between phrenic and sympathetic burst onset was essentially independent of frequency. 6. In hyperthermic, hypocapnic cats phrenic nerve burst frequency increased up to about 300 bursts/min from a value of 15 bursts/min in normothermia‐normocapnia. At all frequencies within this range the sympathetic burst maintained a delay, with respect to the phrenic burst, which was essentially independent of frequency.(ABSTRACT TRUNCATED AT 400 WORDS)

Cardiovascular control by medullary surface chemoreceptors

The cardiovascular and respiratory effects of superfusion of the ventral surface of the medulla with acid hypercapnic or alkaline hypocapnic solutions have been studied in anaesthetized, paralyzed, artificially ventilated cats. Peripheral chemoreceptor and baroreceptor denervation was achieved by section of carotid sinus, aortic and cervical vagus nerves. Systemic arterial and central venous pressure, hindquarters blood flow, heart rate and phrenic nerve activity were recorded. Acid hypercapnic (pH 6.8, pCO2 85 mm Hg) superfusion caused increases in systemic arterial pressure, phrenic nerve activity and heart rate, and a decrease in hindquarters blood flow. Alkaline hypocapnic (pH u.i, pCO2 less than 10 mmHg) superfusion caused opposite effects. These experiments indicate a significant role of the chemoreceptors of the ventral surface of the medulla in cardiovascular control.

Effect of preganglionic stimulation on neuropeptide-like immunoreactivity in the stellate ganglion of the cat

In pentobarbital-anesthetized cats, treated with hexamethonium and atropine, 40 Hz stimulation of the preganglionic input to the decentralized right stellate ganglion caused cardioacceleration. When the 40-Hz stimulation is maintained for 2 h, this cardioacceleration was progressively attenuated and eventually irreversibly lost. At this time, neurotensin-like and leucine-enkephalin-like immunoreactivity associated with intraganglionic fibers and presumptive axon terminals was also lost. Preganglionic 40 Hz stimulation for 2 h did not change substance P-like, somatostatin-like, vasoactive intestinal peptide-like and corticotropin-releasing factor-like immunoreactivity in the stellate ganglion. A 40-Hz 2-h stimulation of the intact stellate ganglion output caused no change of the neuropeptide immunoreactivity pattern. These findings suggest that neurotensin and leucine-enkephalin are released by sympathetic preganglionic axon terminals and that the releasable pool of these peptides is depleted by prolonged preganglionic stimulation. The association of peptide depletion with loss of the cardioacceleration, evoked by stimulation of the input to the stellate ganglion in the presence of cholinergic antagonists, suggests the possibility that peptides are involved in the non-cholinergic mechanism of ganglionic transmission mediating the cardioacceleration.

Effect of post-impulse depression on background firing of sympathetic preganglionic neurons

(1) Many of the preganglionic neurons responsible for sympathetic tone in the cat exhibit a characteristic irregular background spike activity with a low repetition rate. The properties of this activity, described by the interspike interval histogram, can be explained as the result of the responses of the neurons to random synaptic imputs. (2) Serial interspike interval correlation was used to show that additive post-impulse depression in preganglionic neurons does not enter into the timing of typical low-rate, irregular background firing. However, if cells are accelerated by anitdromic tetanization, a depressive recovery process accumulates to cause a prolonged silent period after driving of the cells has ceased. If cells are accelerated, by the action of their synaptic inputs, to rates higher than their usual basal rates, serial post-impulse depressions overlap, and summate to cause a temporal interaction between neighboring pulses which is observable by serial interval correlation. (3) By observing the effect of antidromic responses occurring at various intervals after a background spike, we showed that the time course of the summative part of post-impulse depression is shorter than the interspike intervals typically encountered in background firing. (4) At higher-than-basal levels of sympathetic activity, occurring spontaneously or during antidromic stimulation, successive post-impulse recovery periods overlap and sum to impart a negative correlation of serial interspike intervals. At the levels of sympathetic activity existing in waking animals, the damping effect of cumulative post-impulse depression is probably an important factor in stabilizing sympathetic tone.