Biomedical subjects

J F Paton

Publications and source records attributed to J F Paton.

At least 37 records · Page 2Linked to original sources

PubMed2000

Characterizations of eupnea, apneusis and gasping in a perfused rat preparation.

In vivo mammalian preparations can exhibit eupnea, apneusis and gasping. In vitro mammalian preparations exhibit only a single invariant pattern, which appears identical to gasping. We characterized the patterns of ventilatory activity of a perfused heart-brainstem preparation of the juvenile rat. In this preparation, phrenic activity has a 'ramp-like' rise similar to eupnea in vivo. Peak phrenic activity declines and ultimately disappears in hypocapnia. In hypercapnia, both frequency and peak of phrenic bursts increase. In hypoxia, such increases are transient. The phrenic burst is terminated by electrical stimulation of the pontile 'pneumotaxic center' and, as in apneusis, is prolonged by lesions in this region. With severe hypoxia or ischemia, the 'ramp-like' phrenic activity is replaced by the 'decrementing' pattern of gasping. Variables of phrenic activity in gasping produced in hypoxia and ischemia are identical. We conclude that the perfused juvenile rat preparation exhibits patterns of eupnea, apneusis and gasping which are similar to in vivo mammalian preparations.

Animals↗

PubMed2000

Similarities in reflex control of laryngeal and cardiac vagal motor neurones.

We sought to test the hypothesis that laryngeal adductor and cardiac vagal motor neurones respond similarly to the activation of certain afferent inputs. Experiments were performed on a working heart-brainstem preparation of rat devoid of pulmonary stretch receptor feedback. Upper airway negative pressure receptors (UANPR), peripheral arterial chemoreceptors and receptors at the junction of the pharynx and oesophagus were stimulated selectively while recording heart rate, recurrent laryngeal, phrenic and hypoglossal motor outflows, subglottic pressure during constant translaryngeal airflow (as an index of laryngeal resistance), and single unit respiratory neurone activity. Stimulation of all three receptor types produced bradycardia, evoked discharges in the recurrent laryngeal and hypoglossal motor outflows during the post-inspiratory period and caused swallowing. Stimulation of pharyngoesophageal receptors and peripheral chemoreceptors evoked an increase in laryngeal resistance during the post-inspiratory phase indicative of laryngeal adductor motoneurone activation. Although this reflex response cannot be evaluated during UANPR stimulation, some post-inspiratory neurones were powerfully activated suggesting that UANPR probably drive laryngeal adductor muscles. Our data show that motor outflows controlling cardiac rate and laryngeal patency are concurrently activated by these sensory inputs. This may constitute the basis for a stereotyped defensive reflex response which maintains end expiratory lung volume, thus conserving oxygen in conditions of upper airway obstruction. Our observations lend further support to models of cardiorespiratory control which propose close coupling and shared central mechanisms for the regulation of the cardiovascular and respiratory systems.

Air Pressure↗

PubMed2000

Properties of solitary tract neurons receiving inputs from the sub-diaphragmatic vagus nerve.

Vagal afferents ascending from the gastrointestinal tract synapse on neurons in the nucleus of the solitary tract. Although these neurons constitute a significant proportion of solitary tract cells their firing behaviour and synaptic properties are not documented. Since gastrointestinal tract afferent termination sites overlap with regions mediating cardiorespiratory reflexes the possibility of convergence with afferents mediating cardiovascular and respiratory reflexes was proposed. Here we describe some electrophysiological and morphological properties of solitary tract neurons orthodromically driven from the subdiaphragmatic vagus nerves and assess possible convergent inputs from cardiorespiratory afferents. Whole-cell recordings of solitary tract neurons responding to electrical stimulation of the sub-diaphragmatic vagus nerves (0.1-1 ms; 1-10 V; 2-20 Hz) were made in a working heart-brainstem preparation of rat. Baroreceptors were stimulated by raising pressure in the aorta or carotid sinus, whereas aortic injection of sodium cyanide (0.05% solution 25-50 microl) was used to activate peripheral chemoreceptors. Phrenic nerve activity and heart rate were monitored continuously. Of 88 solitary tract neurons tested, 39 responded with an evoked excitatory synaptic potential following stimulation of the sub-diaphragmatic vagus nerves. Resting membrane potential and input resistance of sub-diaphragmatic vagus nerve driven solitary tract neurons were 53.2 +/- 0.5 mV and 291 +/- 17 Mohms, respectively (mean +/- S.E.M.). Response latencies to sub-diaphragmatic vagus nerve stimulation were divided into two groups: <20 ms (16.0 +/- 2 ms, n = 7; mean +/- S.E.M.) and >20 ms (77.3 +/- 5 ms, n = 32). One additional neuron displayed an evoked inhibitory postsynaptic potential (latency 175 ms). Nineteen neurons showed ongoing activity which consisted of either irregular single action potential firing (0.5-10 Hz; n = 12) or burst discharge (n = 7). Of 33 neurons tested, 17 showed spike frequency adaptation during injection of positive current, whereas 19 of 38 cells displayed rebound excitation following release from hyperpolarized potentials. There was no correlation between these properties and synaptic latencies. Ninety-one per cent of neurons tested displayed synaptic depression following paired pulse stimulation of the sub-diaphragmatic vagus nerve over intervals up to 500 ms. Stimulation of either baroreceptors (n = 31) or chemoreceptors (n = 36) failed to elicit a synaptic response in all sub-diaphragmatic vagus nerve-driven solitary tract neurons. Neurobiotin-labelled solitary tract neurons (n = 10) were from both latency groups and were located medial to the solitary tract at the level of area postrema, -0.3 mm to +1 mm from the obex. One cell was located in commissural subnucleus at midline, seven cells dorsal to the tractus solitarius and three ventral and medial to it. Soma sizes were 23 +/- 9.6 x 14 +/- 4.9 microm (range: 50 x 16 microm to 15 x 7 microm). The number of primary dendrites varied from three to five, secondary from one to eight and tertiary zero to four. Labelled axons were found in seven cells which ramified extensively in the solitary tract nucleus (n = 3) and/or branched extensively in the dorsal vagal motonucleus (n = 3) and/or projected towards the ventrolateral medulla (n = 3). We conclude that solitary tract neurons receiving signals from the sub-diaphragmatic vagus nerves (most likely from gastrointestinal tract structures) appear to be a distinct pool of neurons. There was a heterogeneity in terms of both their ongoing activity and projection targets but despite this, there were three consistent properties. First, sub-diaphragmatic vagus nerve evoked predominantly excitatory synaptic responses in solitary tract neurons; second, neurons exhibited lasting paired pulse depression following activation of sub-diaphragmatic vagus nerves; and third, sub-diaphragmatic vagus nerve-driven solitary tract neurons were

Afferent Pathways↗

PubMed2000

Somatic gene transfer: implications for cardiovascular control.

There is a great need for closer integration between physiologists and molecular biologists. These two research fields might soon form a single research discipline under the umbrella of molecular physiology. One of the areas where this interaction may be particularly fruitful is with somatic gene transfer using replication-deficient viral vectors. We applied this approach to study the central control of the cardiovascular system at the level of the nucleus of the solitary tract (NTS). We assess critically this new methodology as applied to experiments in an integrative environment (such as the whole animal). The usefulness of in vivo gene transfer is illustrated by an experiment where viral gene delivery helped to circumvent the problem imposed by an absence of a specific pharmacological blocker of the enzyme, endothelial nitric oxide synthase (eNOS). The pros and cons of using adenoviral vectors as opposed to conventional pharmacological approaches are discussed. We conclude that the use of adenoviruses to manipulate genes offers a new avenue for physiologists studying neuronal mechanisms in integrative models.

Adenoviridae↗

PubMed1999

Differential effects of angiotensin II on cardiorespiratory reflexes mediated by nucleus tractus solitarii - a microinjection study in the rat.

1. The effect of microinjecting angiotensin II (ANGII) into the nucleus of the solitary tract (NTS) on both baroreceptor and peripheral chemoreceptor reflexes was compared. 2. Experiments were performed in a working heart-brainstem preparation of rat. Baroreceptors were stimulated by raising perfusion pressure and chemoreceptors were activated with aortic injections of sodium cyanide (0.025 %, 25-75 microl). Reflex changes in phrenic nerve activity and heart rate were measured after bilateral NTS microinjection (50 nl) of ANGII (0.5-5000 fmol). 3. NTS microinjection of 5 fmol ANGII elicited a transient (28.2 +/- 6 s; mean +/- s.e.m.) bradycardia (-18 +/- 3 beats min-1), and decreased phrenic nerve activity cycle length and amplitude (P < 0.05). At higher doses of ANGII a similar respiratory response was seen but heart rate changes were inconsistent. 4. The baroreceptor reflex bradycardia was depressed significantly by NTS microinjections of ANGII (5-5000 fmol) in a dose-dependent manner with the reflex gain decreasing from 1.7 +/- 0.16 to 0.66 +/- 0.1 beats min-1 mmHg-1 (P < 0.01) at 5000 fmol. Although the chemoreceptor reflex bradycardia was depressed at a low dose of ANGII (5 fmol), all higher doses (50-5000 fmol) produced a dose-dependent potentiation of the reflex bradycardia (maximally +64 +/- 8 %). The respiratory component was unaffected. The effects of ANGII on both reflexes were blocked by an ANGII type 1 (AT1) receptor antagonist, losartan (20 microM). 5. The potentiating action of ANGII on the chemoreceptor reflex cardiac response was abolished by a neurokinin type 1 (NK1) receptor blocker (CP-99,994, 5 microM) but this had no effect on the baroreceptor reflex. 6. AT1 receptors in the NTS can depress the baroreceptor reflex bradycardia which is independent of NK1 receptors. The ANGII effect on the cardiac component of the chemoreceptor reflex is bi-directional being inhibited at low concentrations and potentiated at higher concentrations; the latter involves NK1 receptors and presumably results from release of substance P.

Angiotensin II↗

PubMed1999

Differential effects of angiotensin II in the nucleus tractus solitarii of the rat--plausible neuronal mechanism.

1. Cellular mechanisms of the actions of angiotensin II (ANGII) within the nucleus of the solitary tract (NTS) were studied using rat brain slices in 78 neurones recorded in the whole-cell configuration. Twenty-nine per cent of cells had an on-going activity and with only one exception these cells responded to tractus solitarii (TS) stimulation with a monophasic excitatory postsynaptic potential (EPSP). In approximately half of the silent cells, TS stimulation evoked an EPSP-inhibitory postsynaptic potential (IPSP) complex. 2. The ANGII (200 or 1000 nM) effect on TS-evoked EPSPs depended on the cell subpopulation. In cells with on-going activity, ANGII (1000 nM) increased evoked EPSP amplitude by +70 +/- 13 % (means +/- s.e.m., n = 5) but reduced it (200 and 1000 nM) in silent cells where both evoked EPSPs and IPSPs were present. ANGII either increased TS-evoked IPSP conductances in cells where they were detectable or revealed an evoked IPSP (200 nM ANGII: IPSP conductance increased from 70 +/- 29 to 241 +/- 34 pS; n = 11). All ANGII effects were prevented by the ANGII type 1 (AT1) receptor blocker losartan. Since 200 nM ANGII did not increase responses to iontophoretically applied GABA, the effect of ANGII on TS-evoked IPSPs may occur presynaptically. 3. The neurokinin type 1 (NK1) receptor antagonist CP-99,994 (5 microM) blocked the ANGII-induced increase in EPSPs but had no effect on TS-evoked IPSP potentiation by ANGII. 4. Thus, ANGII can potentiate both inhibitory and excitatory synaptic transmission within different subpopulations of NTS neurones. Potentiation of evoked EPSPs, but not of IPSPs, involves activation of NK1 receptors. The balance of these actions of ANGII could be reflex specific: for the baroreflex circuitry the inhibitory action might predominate while the peripheral chemoreceptor reflex may be facilitated due to enhanced excitatory transmission.

Angiotensin II↗

PubMed1999

Differential effects of apamin on neuronal excitability in the nucleus tractus solitarii of rats studied in vitro.

We demonstrated previously that microinjection of the calcium-dependent potassium channel antagonist, apamin, into the nucleus tractus solitarius (NTS) in vivo potentiated the baroreceptor reflex mediated bradycardia but attenuated the cardiopulmonary reflex. The latter result was surprising since, intuitively, potassium channel blockade would be expected to increase neuronal excitability leading to reflex potentiation. The aim of this in vitro study was to investigate possible neuronal mechanisms to explain our in vivo observations. Transverse brainstem slices of rat were cut at the level of area postrema and recordings were made from 36 NTS neurones in whole-cell mode. The neurones were classified into three groups, based on their response to apamin (10 nM). Each group had a similar resting membrane potential (RMP; -55 +/- 1 mV; n = 36) and input resistance (404 +/- 20 M omega; n = 36). (1) In 15/36 neurones, apamin decreased the number of spikes evoked during injection of positive current by 37 +/- 6%; this was associated with a concomitant fall in input resistance of 12 +/- 2% (P < 0.05). Stimulation of the ipsilateral tractus solitarius evoked EPSP-IPSP complexes in nine of the 12 neurones tested; the inhibitory components were increased in amplitude, at a holding potential of -46 mV, from -1.7 +/- 0.4 to -3.2 +/- 0.6 mV (P < 0.01) in the presence of apamin, while the EPSPs were unaffected. All three of these effects were bicuculline (10 microM) sensitive. (2) In 8/36 neurones, apamin increased the number of spikes evoked during injection of positive current by 27 +/- 8%, but affected neither RMP nor input resistance. Only one of five neurones tested demonstrated a synaptically evoked EPSP-IPSP complex. The remaining four neurones displayed a single evoked EPSP, the amplitudes of which were unaffected by apamin. (3) In the remaining neurones (13/36), apamin affected neither responsiveness to positive current injection, RMP, nor input resistance. Six of 12 neurones demonstrated synaptically evoked EPSP-IPSP complexes; at a holding potential of -46 mV, apamin increased the IPSP component from -2.6 +/- 1 to -3.6 +/- 0.8 mV (P < 0.05), while the EPSPs were unaffected. In conclusion, apamin can both increase and decrease NTS neuronal excitability: the former reflecting blockade of channels on the recorded neurone; the latter may possibly result from an increase in GABA release by interneurones impinging onto the recorded neurone. The possibility of a differential distribution of apamin-sensitive channels in sub-populations of NTS neurones subserving different reflexes is discussed.

Action Potentials↗

PubMed1999

Reflex response and convergence of pharyngoesophageal and peripheral chemoreceptors in the nucleus of the solitary tract.

The pharynx is a common conduit for the passage of both ingested material and respiratory gases and may receive a dual control from medullary structures regulating deglutition and respiration. We sought both to compare the pattern of reflex response following stimulation of pharyngoesophageal and peripheral chemoreceptors and to assess whether these afferents converge in the nucleus of the solitary tract. In an arterially perfused working heart-brainstem preparation of mature rat, pharyngoesophageal receptors were stimulated by distension of the pharyngeal-oesophageal junction, whereas chemoreceptors were activated by sodium cyanide solution. In peripheral studies we recorded electromyographic activity from genioglossus, mylohyoideus and the lower thoracic oesophagus as well as hypoglossal, laryngeal and phrenic motor discharge. Sub-glottal pressure was also measured at constant airflow. In central studies, nucleus of the solitary tract neurons were recorded with blind whole-cell techniques. In peripheral studies spontaneous irregular electromyographic discharges (cycle length 99+/-26 s) occurred sequentially in genioglossus and mylohyoideus muscles (during the inter-phrenic nerve activity interval) and subsequently the oesophagus; these were accompanied by post-inspiratory discharges in both hypoglossal and laryngeal motor nerves and an atropine-sensitive bradycardia (-39+/-5 beats/min). Components of the reflex response elicited following stimulation of both pharyngoesophageal receptors and chemoreceptors were qualitatively similar and included: (i) expiratory-related increases in laryngeal pressure; (ii) sequential electromyographic discharge in genioglossus, mylohyoideus muscles and oesophagus; (iii) post-inspiratory burst discharge in hypoglossal, recurrent and superior laryngeal motor nerves; and (iv) an atropine-sensitive bradycardia (-38 to -95 beats/min). The chemoreceptor reflex-evoked responses were abolished after sinoaortic denervation. Of 135 whole-cell recordings of nucleus of the solitary tract neurons, 31 received a synaptic input from pharyngoesophageal receptors (22 excitatory and nine inhibitory). Cells excited by pharyngoesophageal receptor stimulation were either "spontaneously" bursting, which occurred during the inter-phrenic nerve activity interval (cycle length 79+/-22 s; n=9), or non-bursting (n=13). Of the 22 nucleus of the solitary tract neurons excited by pharyngoesophageal receptor stimulation, 77% received a convergent excitatory synaptic input from chemoreceptors (eight bursting and nine non-bursting neurons). Thus, stimulation of pharyngoesophageal receptors and chemoreceptors evoked common reflex response components including activation of hypoglossal, laryngeal adductor, cardiac vagal motoneurons and swallowing. Moreover, some excitatory pharyngoesophageal and chemoreceptors inputs typically converged on nucleus of the solitary tract neurons. The possibility that this convergence manifests a defensive reflex reaction is discussed.

Animals↗

PubMed1999

5-HT(4) receptors in nucleus tractus solitarii attenuate cardiopulmonary reflex in anesthetized rats.

We determined whether the cAMP-protein kinase A (PKA) pathway modulation of the cardiopulmonary reflex was caused by activation of 5-HT(4) receptors at the level of the nucleus tractus solitarii (NTS) of the anesthetized rat. NTS microinjection of 5-methoxytryptamine (5-MeOT, 2.25 pmol, n = 13), a 5-HT-receptor agonist, attenuated the cardiopulmonary reflex-evoked bradycardia and tachypnea. Microinjection of RS-39604 (4.5 pmol, n = 6), a selective 5-HT(4)-receptor antagonist, blocked the attenuating effect of 5-MeOT. NTS microinjection of 8-bromoadenosine 3', 5'-cyclic monophosphate (8-BrcAMP, 9 nmol, 45 nl, n = 10), a membrane-permeant analog of cAMP, significantly attenuated the reflex bradycardia and tachypnea. Rp-adenosine 3',5'-cyclic monophosphorothioate (4.5 nmol, n = 6), a cAMP-dependent PKA inhibitor, had no effect on the cardiopulmonary reflex when microinjected into the NTS alone but when given before a microinjection of either 8-BrcAMP (n = 6) or 5-MeOT (n = 6) blocked the attenuating effect on the reflex-evoked bradycardia. Thus stimulation of 5-HT(4) receptors within the NTS depresses the reflex bradycardia components of the cardiopulmonary reflex via a cAMP-dependent PKA pathway.

5-Methoxytryptamine↗

PubMed1998

Angiotensin II receptors within the nucleus of the solitary tract mediate the developmental attenuation of the baroreceptor vagal reflex in pre-weaned rats.

This study tested the hypothesis that baroreceptor vagal reflex (BVR) attenuation in developing rats, which occurs between postnatal ages (P) of 10 to 20 days old, is due to a central action of angiotensin II (Ang II). In urethane or halothane anaesthetised mature (P > 45) or pre-weaned rats (P14-18), BVR sensitivity was estimated as the ratio between the fall in heart rate and the increase in arterial pressure induced by i.v. phenylephrine. An Ang II AT1 receptor antagonist, losartan, was administered intra-venously (i.v.) or microinjected into brainstem structures. In pre-weaned rats BVR sensitivity was increased significantly by losartan (5 mg/kg; urethane anaesthesia: p < 0.01; halothane anaesthesia: p < 0.05) while a larger dose (10 mg/kg) was ineffective in mature animals. In pre-weaned rats, microinjection of losartan (500 pmol) into the nucleus tractus solitarii (NTS) but neither area postrema nor subjacent nuclei, reversibly increased the sensitivity of BVR (+89 +/- 19%; p < 0.01, n = 12). Microinjection of losartan (500 or 1500 pmol) into the NTS of mature rats did not change the BVR. An AT2-antagonist, PD123-319 did not restore the BVR sensitivity in pre-weaned rats. Thus, AT1 receptors located within the NTS play a pivotal role in the developmental attenuation of the BVR in pre-weaned rats.

Age Factors↗

PubMed1998

Coupling of sympathetic and somatic motor outflows from the spinal cord in a perfused preparation of adult mouse in vitro.

1. The relationship between sympathetic and somatic motor outflows from thoraco-lumbar spinal cord was investigated in a novel arterially perfused trunk-hindquarters preparation of adult mouse. 2. Ongoing activity was present in both somatic motor (obturator, sciatic or femoral nerves) and sympathetic outflows (either renal nerve or abdominal sympathetic chain). Sympathetic activity was rhythmic with bursts frequencies of 0.6-2.2 Hz. No obvious rhythmic activity was found in the somatic motor outflow. There were periods during which sympathetic and somatic motor activity were correlated. 3. Addition of NMDA (20-80 microM) to the perfusate elicited repetitive burst discharges in the somatic motor outflow which were sometimes rhythmic. The frequency of these burst discharges/rhythmic activity varied between preparations but in all cases increased with increasing NMDA concentration. 4. NMDA induced burst discharges in the sympathetic outflow. This bursting activity was of the same frequency as the somatic motor outflow and the two were coupled as revealed by correlation analysis. Periods of coupling persisted for up to 3 min. 5. Administration of hexamethonium (300 microM), to block sympathetic ganglionic transmission, had no effect on the somatic motor activity but severely attenuated sympathetic nerve discharge. 6. The thoraco-sacral cord therefore has the neuronal machinery necessary for generating and coupling activity in somatic motor and sympathetic outflows. Our findings indicate a dynamic control over the degree of coupling. We discuss that the synchronization of these neural outflows reflects either coupling between two independent mechanisms or the presence of a common synaptic driver impinging on both somatic motor and sympathetic neurones.

Animals↗

PubMed1998

Comparison of cardiorespiratory reflexes in NK1 receptor knockout, heterozygous and wild-type mice in vivo.

Neurokinin-1 receptors (NK1) are present within the nucleus of the solitary tract, a nucleus which plays a vital role in cardiovascular and respiratory homeostasis. We compared the efficacy of the baroreceptor and pulmonary chemoreflexes between NK1 knockout, heterozygous and wild-type urethane-anaesthetised mice. The magnitude of the baroreceptor reflex mediated bradycardia, induced by a phenylephrine induced pressor response, was significantly greater in NK1 knockout mice (P < 0.001) compared to heterozygous and wild-type animals. In comparison, administration of an NK1 antagonist, CP-99,994 (1.5 mg/kg i.v.) to wild-type animals, had no significant effect on baroreceptor reflex performance. In contrast to the baroreceptor reflex, there were no significant differences in the magnitude of the reflex evoked falls in heart rate, arterial pressure, or respiratory depression between the three groups of mice when the pulmonary chemoreflex was evoked with right atrial injections of phenylbiguanide. It is concluded that the baroreceptor reflex pathway over-compensates for the lack of NK1 receptors in knockout mice. Plausible mechanisms accounting for the enhanced baroreceptor reflex responsiveness in NK1 knockout animals are discussed.

Animals↗

PubMed1998

Convergence properties of solitary tract neurones driven synaptically by cardiac vagal afferents in the mouse.

1. Cardiac vagal receptors are chemically and/or mechanically sensitive but it is unknown if this information is preserved centrally within the nucleus of the solitary tract (NTS). The present study had two aims: first, to investigate qualitatively whether both mechanically and chemically sensitive cardiac vagal encoding were preserved within the NTS, and second, to determine the patterns of convergence from other cardiorespiratory afferents to NTS neurones receiving cardiac vagal inputs. 2. The extracellular activity of single NTS neurones was investigated during stimulation of both chemically and mechanically sensitive cardiac vagal receptors in a working heart-brainstem preparation of mouse. Chemically sensitive cardiac receptors were stimulated using intra-left ventricular injections of either veratridine (1-3 microg kg-1), bradykinin (0.25-1 microg) or prostaglandin E2 (100-200 ng), whereas the left ventricle was distended to activate cardiac mechanoreceptors. 3. Forty-three NTS neurones were activated both synaptically by electrical stimulation of the ipsilateral vagus nerve (latency, 35 +/- 3 ms), and by intra-left ventricular injection of veratridine and also, in some cases, by bradykinin and/or PGE2. These NTS neurones were delineated into two populations based on their response to left ventricular distension and convergence properties. Left ventricular distension-insensitive neurones (n = 30) were excited by stimulation of carotid body chemoreceptors (81 %) but not arterial baroreceptors (3 %; i.e. n = 1 neurone), whereas distension-sensitive cells (n = 13) were activated mainly by baroreceptors (86 %) rather than peripheral chemoreceptors (14 %; i.e. n = 1 neurone). 4. The data reveal two distinct populations of NTS neurones receiving cardiac vagal inputs: (a) cells responsive to veratridine stimulation only, and (b) neurones activated by both veratridine and mechanical stimuli. The specific convergence pattern of baroreceptors and chemoreceptors to these cardioreceptive NTS neurones is discussed in relation to a common afferent modality integration within the NTS.

Afferent Pathways↗

PubMed1998

Cardiorespiratory reflexes in mice.

The various transgenic strains of mice make this species an attractive experimental model. We compared qualitatively some cardiorespiratory reflexes in two different preparations of mouse: in vivo urethane anaesthetised and a working heart-brainstem preparation (WHBP). Cardiorespiratory reflexes were evoked by stimulating baroreceptors, pulmonary vagal C fibres and cardiac receptors in both preparations, while peripheral chemoreceptors were also stimulated in the WHBP. In anaesthetised mice, activation of baroreceptors, pulmonary C fibres and cardiac receptors evoked an atropine-sensitive bradycardia (range: 21-414 bts/min) and depressed ventilation. A reflex fall in arterial pressure was also observed during pulmonary C fibre and cardiac receptor stimulation. Similar reflex bradycardia (range 81-164 bts/min) and respiratory responses were observed in the WHBP following stimulation of baro-, pulmonary C fibre and cardiac receptors. Additionally, sodium cyanide stimulation of peripheral chemoreceptors in the WHBP produced an atropine-sensitive bradycardia and increased respiratory frequency and amplitude. Thus, the cardiorespiratory reflex responses elicited in the mouse are similar to those reported in other species. It is concluded that the qualitatively similar reflex performances between the in vivo anaesthetised mouse and the WHBP make the latter an adequate model for studying central mechanisms controlling the cardiorespiratory system.

Anesthesia↗

PubMed1998

Importance of neurokinin-1 receptors in the nucleus tractus solitarii of mice for the integration of cardiac vagal inputs.

Unmyelinated vagal afferents from the heart terminate within the nucleus tractus solitarii (NTS) located in the dorsomedial medulla. The neurotransmitter and postsynaptic receptors mediating information from cardiac vagal receptors to the NTS are unknown. This study determined the effects of neurokinin-1 (NK1) receptor blockade on: (i) the reflex response evoked following aortic root injection of either veratridine (1-3 microg/kg) or bradykinin (80-300 ng/kg) to stimulate cardiac receptors in in vivo anaesthetized mice; and (ii) the evoked synaptic response of cardioreceptive NTS neurons following both intraleft-ventricular injection of veratridine or bradykinin, and electrical stimulation of the ipsilateral vagus nerve in an arterially perfused working heart-brainstem preparation of mouse. Administration of CP-99,994 (0.75-1.5 mg/kg i.v.), a specific NK1 antagonist, attenuated significantly the evoked reflex bradycardia and depressor response following cardiac receptor (n = 6), but not pulmonary chemoreflex stimulation in vivo. From extracellular recordings of cardioreceptive NTS neurons, CP-99,994 reduced reversibly the total number of evoked spikes, peak firing frequency and response duration evoked by intraventricular injections of veratridine (n = 5) or bradykinin (n = 5). The number of evoked action potentials following electrical stimulation of the vagus nerve was also reduced. In five whole cell recordings of NTS neurons, both the evoked depolarization following cardiac receptor stimulation, and the peak amplitude and duration of vagus nerve-evoked EPSPs were reduced by CP-99,994; synaptic inputs from both peripheral chemoreceptors or pulmonary C-fibres were unaffected. These data support a selective involvement of NK1 receptors in the transmission of cardiac vagal afferent inputs to NTS neurons integrating cardiorespiratory information.

Afferent Pathways↗

PubMed1998

K+ channel blockade in the NTS alters efficacy of two cardiorespiratory reflexes in vivo.

We investigated the role of potassium conductances in the nucleus of the solitary tract (NTS) in determining the efficacy of the baroreceptor and cardiopulmonary reflexes in anesthetized rats. The baroreceptor reflex was elicited with an intravenous injection of phenylephrine to evoke a reflex bradycardia, and the cardiopulmonary reflex was evoked with a right atrial injection of phenylbiguanide. Microinjection of two Ca-dependent potassium channel antagonists (apamin and charybdotoxin) into the NTS potentiated the baroreceptor reflex bradycardia. This may reflect the increased neuronal excitability observed previously in vitro with these blockers. In contrast, the Ca-dependent potassium channel antagonists attenuated the cardiopulmonary reflex, whereas voltage-dependent potassium channel antagonists (4-aminopyridine and dendrotoxin) attenuated both the baro- and cardiopulmonary reflexes when microinjected into the NTS. The possibility that the reflex attenuation observed indicates a predominant distribution of certain potassium channels on gamma-aminobutyric acid interneurons is discussed.

4-Aminopyridine↗

PubMed1998

Pattern of cardiorespiratory afferent convergence to solitary tract neurons driven by pulmonary vagal C-fiber stimulation in the mouse.

The central integration of signals from pulmonary vagal C-fibers (or type-J receptors) with those arising from cardiac, peripheral chemoreceptor, and baroreceptor afferents to neurons within the nucleus of the solitary tract (NTS) was studied in an arterially perfused working heart-brain stem preparation of adult mouse. Pulmonary vagal C-fibers were excited by right atrial injection of phenylbiguanide (PBG) while cardiac receptors were stimulated by left ventricular injection of veratridine (1-3 micrograms/kg) or mechanically by distension of the left ventricle (20-50 microl perfusate) using an indwelling cannula. Carotid body chemoreceptors were activated by aortic injection of Na cyanide, whereas baroreceptors were stimulated by increasing arterial perfusion pressure. Stimulation of pulmonary C-fibers and cardiac, chemo-, and baroreceptors all produced a reflex bradycardia (23-133 bpm). Central respiratory activity, as recorded from the phrenic nerve, was depressed by stimulating pulmonary C-fibers and cardiac and baroreceptors but enhanced in amplitude and frequency during chemoreceptor stimulation. Twenty-seven NTS neurons were excited and three were inhibited after pulmonary C-fiber stimulation displaying decrementing discharges with a peak firing frequency of up to 42 Hz (15 +/- 2.2 Hz, mean +/- SE) that lasted for 8.8 +/- 0.9 s. These responses occurred <1 s from the end of the PBG injection that was within the pulmonary circulation time. None of these cells responded to increases in right atrial pressure. All cells excited by PBG were also driven synaptically after electrical stimulation of the ipsilateral cervical vagus nerve at a latency of 32.9 +/- 3.2 ms (range 20-62 ms). None of these neurons had ongoing activity related to central respiratory activity. Convergence from cardiorespiratory afferents to 21 neurons driven by pulmonary C-fibers was tested. Twenty-five percent of cells were selectively excited by chemical stimulation of cardiac receptors alone, 19% were driven by peripheral chemoreceptors, and 38% responded to both cardiac and chemoreceptor activation. In contrast, only 13% of the cells activated by PBG injection responded to stimulation of baroreceptors and only 6% to cardiac mechanoreceptor stimulation. None of these neurons were activated by increasing right atrial pressure. The data indicate a high proportion of afferent convergence from pulmonary C-fibers, cardiac receptors, and peripheral chemoreceptors in the NTS. However, these neurons appear not to integrate inputs from cardiovascular mechanoreceptors. The significance of the data is discussed in relation to pathological disease states such as pulmonary congestion and cardiac failure.

Afferent Pathways↗

PubMed1998

Convergence properties of solitary tract neurons responsive to cardiac receptor stimulation in the anesthetized cat.

The convergence pattern of cardiac receptors, pulmonary C-fibers, carotid chemoreceptor, and baroreceptor afferents onto neurons within the nucleus of the solitary tract (NTS) was studied in the anesthetized (pentobarbitone sodium, 40 mg/kg,) paralyzed and artificially ventilated cat. Extra- and intracellular recordings were made from NTS neurons while stimulating both cardiac receptors by aortic root injections of veratridine (1-3 micrograms/kg) and pulmonary C-fibers by a right atrial injection of phenylbiguanide (10-20 micrograms/kg). The ipsilateral carotid body was stimulated by using arterial injection of CO2-saturated bicarbonate solution, whereas inflation of the ipsilateral carotid sinus was used to activate baroreceptors. The ipsilateral cardiac vagal branch, cervical vagus, and carotid sinus nerves were stimulated electrically (1 Hz, 0.2-1 ms, 1-35 V). In 78 NTS neurons recorded either extracellularly (n = 47) or intracellularly (n = 31), electrical stimulation of the cardiac branch of the vagus nerve evoked synaptic potentials (spikes and/or excitatory postsynaptic potentials) with an onset latency between 4 and 220 ms. Some neurons displayed both short and long latency inputs(15.5 +/- 1.8 and 160.0 +/- 8.5 ms; n = 14). Of these 78 neurons, 24 responded to veratridine stimulation of cardiac receptors (i.e., cardioreceptive neurons) by exhibiting an augmenting-decrementing discharge of 37 +/- 4 s in duration with a peak frequency of 30 +/- 5 Hz. Convergence from other cardiorespiratory receptors was noted involving either carotid chemoreceptors (n = 7) or pulmonary C-fibers (n = 4) or from both carotid chemoreceptors and pulmonary C-fibers (n = 6). In contrast, only one cardioreceptive NTS neuron was activated by distension of the carotid sinus. Recording sites recovered were confined to the medial NTS at the level of the area postrema and extended caudally into the commissural subnucleus. Our results indicate a convergence of carotid chemoreceptor and pulmonary C-fiber afferent inputs to cardioreceptive NTS neurons. With the paucity of baroreceptor inputs to these neurons it is suggested that sensory integration within the NTS may reflect regulatory versus defensive or protective reflex control.

Afferent Pathways↗