Central mechanisms I: plasticity of central pathways.

Cough is the most common symptom for which individuals seek medical attention and spend health-care dollars. Despite the burden induced by cough, the current treatments for cough are only partially effective. Delineating the sites and mechanisms in the cough central network for changes in the cough reflex could lead to new therapeutic strategies and drug target sites for more effective treatments. The first synaptic target in the CNS for the cough-related sensory input is the second-order neurons in the nucleus tractus solitarius (NTS); these neurons reorganize the primary sensory information into a coherent output. The NTS neurons have been shown to undergo neuroplasticity under a variety of conditions, such as respiratory disorders, stress, and exposures to environmental pollutants. The NTS contains a rich innervation of substance P immunoreactive nerve terminals, suggesting that substance P might be important in altered cough reflex response. This chapter summarizes our current findings on the role of substance P in enhanced cough reflex as well as the potential NTS targets for the action of substance P.

Regional hemodynamic effects of antihypertensive renomedullary lipids in conscious rats.

Renomedullary tissue has been proposed to exert an antihypertensive endocrine-like action. The antihypertensive polar renomedullary lipids (APRL) and neutral renomedullary lipids (ANRL) are potential mediators of this action. We evaluated the blood pressure and regional hemodynamic responses to APRL administered peripherally (i.v.) and to the central nervous system (CNS) in normal rats and rats with sinoaortic deafferentation (SAD) to remove baroreflex buffering. Rats were chronically instrumented with Doppler flow probes for measurement of mesenteric, renal, and hind-quarter vascular resistance, with arterial pressure and intravenous catheters, and with lateral cerebroventricular cannuli for intracerebroventricular (i.c.v.) administration. Intravenous APRL (0.01 to 1.0 micrograms) produced a dose-dependent decrease in blood pressure, tachycardia, and dilation of all vascular beds studied. The dose-response relationships were shifted to the left in SAD animals. APRL administered i.c.v. had no effect on intact or SAD rats. Pressor and regional vasoconstrictor responses to norepinephrine, angiotensin, and vasopressin were markedly reduced in SAD animals during constant infusion of APRL. In a second group of conscious SAD animals instrumented for blood pressure and heart rate measurements, intravenous ANRL (500 micrograms) decreased both arterial pressure (-45 +/- 16 mm Hg) and heart rate (-50 +/- 16 bpm). When given i.c.v., however, ANRL (10-100 micrograms) had no significant effect on resting blood pressure or heart rate. These studies suggest that APRL and ANRL produce no significant cardiovascular effects that are mediated through the CNS. However, both lipids are potent depressor agents, and APRL exhibits a strong peripheral vasodilator action and nonspecifically reduces reactivity to vasoconstrictor agents.

Comparative central and peripheral antihypertensive mechanisms of urapidil and prazosin.

The central effects of urapidil were investigated in conscious rats with sinoaortic denervation. Intraventricular urapidil administration (40 to 100 micrograms) produced a transient depressor response followed by a pressor response coupled with tachycardia. In comparison, intraventricular prazosin administration (2.5 to 5.0 micrograms) produced only a prolonged depressor effect. The effect of intravenously administered urapidil (3 mg/kg) on arterial pressure, heart rate, and mesenteric, renal, and hindquarter resistances was then compared with that of prazosin (0.5 mg/kg) in conscious rats with sinoaortic denervation, instrumented with pulsed Doppler flow probes. Both agents caused similar significant decreases in arterial pressure and vascular resistances, but urapidil decreased renal resistance significantly more than did prazosin. Prazosin increased heart rate, whereas no change was found with urapidil. Prazosin blocked the pressor and regional constrictor effects of intravenously administered norepinephrine more effectively than urapidil.

Lung C-fiber CNS reflex: role in the respiratory consequences of extended environmental tobacco smoke exposure in young guinea pigs.

Environmental tobacco smoke (ETS) exposure harms the respiratory health of children and is associated with an increased risk of asthma and sudden infant death syndrome (SIDS). The mechanisms by which ETS causes these effects are not understood. We hypothesized that one mechanism is an upregulation of the lung C-fiber central nervous system (CNS) reflex responses, which would result in exaggerated reflex responses of apnea, bronchoconstriction, and mucous hypersecretion. The purpose of this work is to highlight evidence obtained in an animal model of postnatal ETS exposure supporting the hypothesis and present data suggesting that actions of the neuropeptide substance P in the nucleus tractus solitarius (NTS) may contribute. Exposing young guinea pigs to sidestream smoke, the surrogate for ETS, for 5 weeks during the equivalent of human childhood, increased the excitability of afferent lung C fibers and NTS neurons in the CNS reflex pathway and prolonged the expiratory apnea. The findings suggest that an increased excitability of NTS neurons that can augment reflex output may contribute to respiratory symptoms in children exposed to ETS. Besides ETS exposure, substance P can also excite NTS neurons and augment lung C-fiber CNS reflex responses. Others have shown that substance P synthesis in lung C fibers is upregulated by another environmental stimulant, allergen. Thus, an upregulation of the substance P system at NTS synapses could contribute to the increased NTS excitability and enhanced reflex responses to lung C-fiber stimulation, providing a potential mechanism to help explain the association of ETS exposure with respiratory symptoms and SIDS.

Pulmonary congestion enhances responses of lung rapidly adapting receptors to cigarette smoke in rabbit.

We examined the effects of low-nicotine cigarette smoke, pulmonary venous congestion, and their combination on the activity of rapidly (RAR) and slowly adapting receptors (SAR) in anesthetized rabbits. Pulmonary venous congestion was achieved by inflating a balloon in the left atrium to increase left atrial pressure. We examined smoke effects on RARs (averaged over 15 breaths) at baseline left atrial pressure and at subthreshold and suprathreshold increases in left atrial pressure. At baseline, smoke significantly increased RAR activity from 12.1 +/- 4.2 to 16.2 +/- 4.2 impulses/breath (P < 0.05). At subthreshold increases in left atrial pressure (2.9 +/- 0.6 mmHg), smoke produced larger increases in RAR activity (12.3 +/- 3.3 to 22.5 +/- 4.1 impulses/breath; P < 0.05). Suprathreshold increases in left atrial pressure (9.2 +/- 1.1 mmHg) alone increased RAR activity from 10.9 +/- 3.2 to 19.8 +/- 5.9 impulses/breath (P < 0.05). Smoke had no additional effect (22.3 +/- 4.8 impulses/breath; P > 0.05). There was, however, a transient increase in RAR activity (1st 3 breaths of smoke) under all three conditions. Of nine SARs examined, only two were stimulated by smoke. We conclude that in the rabbit smoke-induced stimulation of RARs is augmented by mild pulmonary venous congestion. of RARs is augmented by mild pulmonary venous congestion.

Exposing guinea pigs to ozone for 1 wk enhances responsiveness of rapidly adapting receptors.

Acute exposure to ozone causes changes in breathing pattern and lung function which may be caused in part by stimulation of rapidly adapting receptors (RARs). The consequences of repeated daily ozone exposure on RAR responsiveness are unknown, although ozone-induced changes in pulmonary function diminish with repeated exposure. Accordingly, we investigated whether repeated daily ozone exposure diminishes the general responsiveness of RARs. Guinea pigs (n = 30) were exposed to 0.5 parts/million ozone or filtered air (8 h/day for 7 days). The animals were then anesthetized, and RAR impulse activity, dynamic compliance (Cdyn), and lung resistance were recorded at baseline and in response to four stimuli: substance P, methacholine, hyperinflation, and removal of positive end-expiratory pressure. Repeated daily ozone exposure exaggerated RAR responses to substance P, methacholine, and hyperinflation without causing physiologically relevant effects on baseline or substance P- and methacholine-induced changes in Cdyn and lung resistance. Because agonist-evoked changes in RAR activity preceded Cdyn changes, the data suggest that repeated daily ozone exposure enhances RAR responsiveness via a mechanism other than changes in Cdyn.

Sidestream smoke exposure enhances rapidly adapting receptor responses to substance P in young guinea pigs.

We determined the effect of sidestream tobacco smoke (SS) exposure on responses of lung rapidly adapting receptors (RARs), peak tracheal pressure (Ptr), and arterial blood pressure (ABP) to substance P in young guinea pigs. Guinea pigs were exposed to SS or filtered air from day 8 to days 41-45 of life. They were then anesthetized and given three doses of intravenous substance P (1.56-4.94 nmol/kg). SS exposure augmented substance P-evoked increases in RAR activity (P = 0.029 by analysis of variance) but not substance P-evoked increases in peak Ptr or decreases in ABP. Neurokinin 1-receptor blockade (CP-96345, 400 nmol/kg) attenuated substance P-evoked increases in RAR activity (P = 0.001) and ABP (P = 0.009) but not in peak Ptr (P = 0.06). This chronic exposure to SS in young guinea pigs exaggerates RAR responsiveness to substance P. The findings may help explain the increased incidence of airway hyperresponsiveness and cough in children chronically exposed to environmental tobacco smoke.

Chronic exposure to sidestream tobacco smoke augments lung C-fiber responsiveness in young guinea pigs.

Children chronically exposed to environmental tobacco smoke (ETS) have more coughs, wheezes, and airway obstruction, which may result in part from stimulation of lung C fibers. We examined the effect of chronic exposure to sidestream tobacco smoke (SS, a surrogate for ETS) on lung C-fiber responsiveness in guinea pigs, in which dynamic compliance (Cdyn), lung resistance, tracheal pressure, arterial blood pressure, and heart rate were also monitored. Guinea pigs were exposed to SS (1 mg/mm(3) total suspended particulates) or filtered air 5 days/wk from 1 to 6 wk of age. They were then anesthetized, and lung C fibers (n = 55), identified by a conduction velocity of <2.0 m/s, were tested for responsiveness to chemical and mechanical stimuli. SS exposure doubled C-fiber responsiveness to left atrial capsaicin (P = 0.02) and lung hyperinflation (P = 0.03) but had no effect on responsiveness to inhaled capsaicin or bradykinin or on baseline activity. The data indicate that chronically exposing young guinea pigs to SS enhances C-fiber sensitivity to certain stimuli and may help explain respiratory symptoms in children exposed to ETS.

Exposing young guinea pigs to sidestream tobacco smoke decreases rapidly adapting receptor responsiveness.

We exposed 21 young guinea pigs to 5 wk of either sidestream tobacco smoke (SS) or filtered air (FA). The exposure started on day 8 of life and ended at 41-45 days of life. The animals were then anesthetized, and lung rapidly adapting receptor (RAR) and slowly adapting receptor (SAR) activities and peak tracheal pressure (TP) were examined in response to mainstream smoke. SS exposure did not alter baseline RAR activity. Low-nicotine smoke increased RAR activity in the FA but not in the SS group. High-nicotine smoke increased RAR activity in both groups but more so in the FA than in the SS group. Baseline TP was lower in the SS group. Both low- and high-nicotine smoke increased TP but more so in the FA than in the SS group. The increase in RAR activity preceded the increase in TP. SS exposure increased baseline SAR activity but did not affect the variable responses of SARs to low- and high-nicotine smoke. We suggest that exposing guinea pigs to SS during development diminishes the responsiveness of RARs to acute inhalation of mainstream smoke.

Pulmonary venous congestion augments respiratory motoneuronal responses to cigarette smoke in rabbit.

We examined the effects of cigarette smoke inhaled during subthreshold pulmonary venous congestion (sPVC) on phrenic nerve (PN) and unit activity in the ventral respiratory group in rabbits. sPVC was achieved by inflating a balloon in the left atrium. Inhalation of low-nicotine cigarette smoke produced initial prolonged bursts in 34 (19 bulbospinal) out of 43 inspiratory (I) cells and in PN. Smoke decreased the activity of 29 out of 36 expiratory (E) cells (27 of 32 early E and 2 of 4 late E). The prolonged PN bursts occasionally progressed to doublets superimposed over regularly occurring PN bursts. sPVC augmented the smoke effects: I cells displayed greater increases in spikes/burst (27 vs. 12%; P = 0.02) and burst duration (42 vs. 20%; P = 0.02) and greater decreases in interburst interval (34 vs. 10%; P < 0.02); PN displayed greater increases in I time (40 vs. 27%; P < 0.05), greater decreases in E time (18 vs. 26%; P < 0.05), and a greater incidence and duration of time of PN doublets (29 +/- 9 vs. 9 +/- 4 s; P < 0.03); E cells displayed greater decreases in spikes/burst (43 vs. 29%; P = 0.01) and burst durations (35 vs. 18%; P < 0.01). Smoke-induced respiratory changes may be exaggerated during sPVC.

The cardiovascular effects of centrally and peripherally administered indoramin in conscious rats.

Indoramin has centrally mediated hypotensive effects in anesthetized animals. In the present study, the cardiovascular effect of central and peripheral indoramin was determined in conscious, freely moving rats. Animals were instrumented with femoral arterial and venous catheters and miniaturized pulsed-Doppler flow probes were placed on the superior mesenteric and renal arteries and lower abdominal aorta. Injection of indoramin (25-100 micrograms) in the lateral cerebroventricle produced an immediate (1.5 min) increase in arterial pressure which was accompanied by vasoconstriction in all three vascular beds. By 10 min all values had returned to control except for heart rate which was decreased. Vehicle alone or intravenous indoramin (100 micrograms) had no effect. In baroreceptor-denervated rats smaller effects were seen. Intravenous indoramin (3.0-13.5 mg/kg) produced dose-related decreases in arterial pressure, heart rate, and hindquarter vascular resistance. The 13.5 mg/kg dose blocked to a similar degree the cardiovascular effect produced by intravenous norepinephrine or stimulation of the paraventricular nucleus. These data suggest that indoramin is an effective peripheral alpha-adrenergic receptor antagonist but does not appear to be centrally active as a hypotensive agent.

Hepatic resection for metastatic colorectal adenocarcinoma: a proposal of a prognostic scoring system.

BACKGROUND: Hepatic resection for metastatic colorectal cancer provides excellent longterm results in a substantial proportion of patients. Although various prognostic risk factors have been identified, there has been no dependable staging or prognostic scoring system for metastatic hepatic tumors. STUDY DESIGN: Various clinical and pathologic risk factors were examined in 305 consecutive patients who underwent primary hepatic resections for metastatic colorectal cancer. Survival rates were estimated by the Cox proportional hazards model using the equation: S(t) = [So(t)]exp(R-Ro), where So(t) is the survival rate of patients with none of the identified risk factors and Ro = 0. RESULTS: Preliminary multivariate analysis revealed that independently significant negative prognosticators were: (1) positive surgical margins, (2) extrahepatic tumor involvement including the lymph node(s), (3) tumor number of three or more, (4) bilobar tumors, and (5) time from treatment of the primary tumor to hepatic recurrence of 30 months or less. Because the survival rates of the 62 patients with positive margins or extrahepatic tumor were uniformly very poor, multivariate analysis was repeated in the remaining 243 patients who did not have these lethal risk factors. The reanalysis revealed that independently significant poor prognosticators were: (1) tumor number of three or more, (2) tumor size greater than 8 cm, (3) time to hepatic recurrence of 30 months or less, and (4) bilobar tumors. Risk scores (R) for tumor recurrence of the culled cohort (n = 243) were calculated by summation of coefficients from the multivariate analysis and were divided into five groups: grade 1, no risk factors (R = 0); grade 2, one risk factor (R = 0.3 to 0.7); grade 3, two risk factors (R = 0.7 to 1.1); grade 4, three risk factors (R= 1.2 to 1.6); and grade 5, four risk factors (R > 1.6). Grade 6 consisted of the 62 culled patients with positive margins or extrahepatic tumor. Kaplan-Meier and Cox proportional hazards estimated 5-year survival rates of grade 1 to 6 patients were 48.3% and 48.3%, 36.6% and 33.7%, 19.9% and 17.9%, 11.9% and 6.4%, 0% and 1.1%, and 0% and 0%, respectively (p < 0.0001). CONCLUSIONS: The proposed risk-score grading predicted the survival differences extremely well. Estimated survival as determined by the Cox proportional hazards model was similar to that determined by the Kaplan-Meier method. Verification and further improvements of the proposed system are awaited by other centers or international collaborative studies.

Studies on the mechanism of the central antihypertensive effect of guanabenz and clonidine.

Mean arterial pressure and heart rate responses were measured following intracerebroventricular (i.c.v.) injections of guanabenz and clonidine in conscious intact, sinoaortic baroreceptor denervated (SAD) animals, and in SAD animals with anteroventral third ventricle (AV3V) or sham-AV3V lesions. These results suggest that in the conscious unrestrained rat: (1) the centrally-mediated depressor effect of guanabenz and clonidine is masked by intact baroreceptors; (2) the centrally mediated bradycardia is independent of baroreceptor function and (3) the integrity of the AV3V region is not required for expression of these central effects.

Neurotransmitters in the CNS control of breathing.

This review summarises our current understanding of the neurotransmitters involved in the generation, transmission and modulation of respiratory rhythm. The principal neurotransmitters involved in generating and transmitting respiratory rhythm include glutamate, GABA, and glycine. Glutamate acts primarily at non-NMDA receptors within the networks to generate respiratory rhythm in neonatal in vitro preparations, but it may also engage NMDA receptors in mature intact animals. Glutamate may likewise act as presynaptic AP-4 metabotropic receptors to fine tune its own release in the transmission of respiratory rhythm to the phrenic motoneurones. The role of other metabotropic receptors in rhythmogenesis is not known. GABA (primarily by acting at GABAA receptors), as well as glycine, transmit phasic waves of inhibition within the primary respiratory network. Neuroactive agents synthesized outside the primary network may shape the final expression of the basic rhythm. The most studied inputs originate in the pons and from the slowly adapting pulmonary stretch receptors (SAR). Both of these inputs contribute to the transition from inspiration to expiration. Pontine mechanisms rely on excitatory amino acid activation of NMDA receptors, while SAR pathways utilize non-NMDA receptors. Serotonin has also been implicated in regulating respiratory rhythm, possibly via serotonergic projections originating in the raphe nuclei. The amine has diverse effects on respiratory neuronal activity; the most consistent effect appears to be an augmentation of phrenic motoneuronal at the level of the spinal cord. Substance P regulates respiratory activity by acting in the CNS and on peripheral sensory receptors. Centrally, substance P largely augments respiration, by increasing respiratory rhythm in neonatal in vitro preparations and also by increasing tidal volume in the intact animal. Substance P is also released by carotid chemoreceptor afferents during hypoxia. Opioids are well known to decrease respiration; the central mechanism involves the suppression of baseline inspiratory neuronal activity and possibly the blunting of glutamate-evoked increases in inspiration drive.

Neurones in commissural nucleus tractus solitarii required for full expression of the pulmonary C fibre reflex in rat.

1. The pulmonary C fibre reflex, triggered by activating pulmonary C fibre endings in the lung, consists of rapid shallow breathing (which may be preceded by apnoea), bradycardia, and hypotension. The purpose of this work was to identify proximal synapses in this reflex. From pilot data, we hypothesized that neurones in a discrete region of the commissural nucleus in the nucleus tractus solitarii (NTS) are required for full expression of the pulmonary C fibre reflex. Studies were carried out in urethane-anaesthetized, unilaterally vagotomized, spontaneously breathing rats, in which diaphragm electromyogram, arterial pressure, and blood gases were measured. Phenyldiguanide (PDG) was injected in the right atrium to elicit the pulmonary C fibre reflex. Unilateral NTS injections were made through multibarrelled pipettes containing DL-homocysteic acid (DLH) to mimic the reflex, cobalt chloride to reversibly impair the reflex, and/or dye to mark the injection sites. 2. PDG (5-16 micrograms kg-1) injected in the right atrium of twenty-six rats produced the classic pulmonary C fibre reflex: a vagally mediated, rapid onset of rapid shallow breathing, bradycardia and hypotension. 3. Injection of DLH (3-12 nl of 20 mM for a total of 60-240 pmol) in the dorsomedial aspect of the commissural nucleus of the NTS in thirty rats mimicked the pulmonary C fibre reflex, producing rapid shallow breathing, hypotension, and a slight bradycardia. 4. Interruption of neuronal transmission by injecting cobalt chloride (15-30 nl of 100 mM) in the site where DLH produced rapid shallow breathing, reversibly impaired the rapid shallow breathing and bradycardia produced by right atrial injections of PDG in fifteen rats. The commissural region where DLH produced rapid shallow breathing and cobalt impaired the pulmonary C fibre reflex extended from 720-1100 microns caudal to the obex, 30-200 microns lateral to mid-line, and 200-600 microns ventral to the dorsal surface of the brain stem within the NTS. 5. Taken together, the results suggest that neurones within a discrete region in the dorsomedial commissural nucleus in caudal NTS are required for full expression of the pulmonary C fibre reflex.

Neurones in a discrete region of the nucleus tractus solitarius are required for the Breuer-Hering reflex in rat.

1. The Breuer-Hering reflex consists of a shortening of inspiration and lengthening of expiration in response to afferent input from slowly adapting pulmonary stretch receptors (SAR). We hypothesized that neurones in a discrete region of the nucleus tractus solitarius (NTS) are required for producing the reflex. Accordingly, the present studies were undertaken to: (1) identify sites in the NTS in which chemical excitation of neurones inhibited phrenic nerve discharge in a manner consistent with SAR activation, (2) determine whether localized interruption of synaptic transmission prevented the Breuer-Hering reflex, and (3) determine whether these regions contained pump cells and SAR terminal afferents. Studies were carried out in urethane-anaesthetized rats. 2. Injection of picomoles of an excitatory amino acid, DL-homocysteic acid (DLH), in the NTS, at the rostrocaudal level of the area postrema and immediately medial to the tractus solitarius, silenced phrenic nerve activity similarly to that expected from SAR activation. These apnoeas lasted from 3 to 43 s and were produced with little or no change in arterial pressure or heart rate. 3. The Breuer-Hering reflex, physiologically activated by maintaining lung inflation, was transiently impaired by interruption of synaptic transmission following injections of cobalt chloride in the DLH-responsive region. 4. Pump cell (SAR interneurone) and SAR afferent activity were recorded at the site in which DLH produced apnoea. 5. Taken together, the results of chemical excitation, interruption of synaptic transmission and extracellular recording, suggest that cells within a discrete region of the NTS, probably pump cells, are necessary for the production of the Breuer-Hering reflex.

Cardiorespiratory effects of DL-homocysteic acid in caudal ventrolateral medulla.

We carried out experiments in urethan-anesthetized rats to determine 1) whether increasing the activity of small groups of neurons in the caudal ventrolateral medulla (CVLM) by injecting picomoles of an excitatory amino acid altered cardiovascular and/or respiratory homeostasis and 2) whether the depressor responses after chemical excitation in the CVLM were elicited only from the immunohistochemically identified catecholamine-containing cell group. In discrete sites in the CVLM, unilateral injections of 1-12 nl (20-240 pmol) of DL-homocysteic acid (DLH; 20 mM, pH 7.4) selectively or concomitantly inhibited arterial pressure, heart rate, and diaphragm electromyogram (EMG) activity. In the region in which chemical excitation slowed breathing, units were recorded extracellularly that discharged with respiratory periodicity. Sites where the smallest volumes of DLH decreased arterial pressure were located outside the immunohistochemically identified DBH-positive cell bodies. These data suggest that either the same or neighboring neurons in the CVLM are involved in the central neural circuitry for both cardiovascular and respiratory control and that cells other than the catecholaminergic cell group are important in medullary depressor responses.

Area postrema excites and inhibits sympathetic-related neurons in rostral ventrolateral medulla in rabbit.

This study investigated the effects of area postrema stimulation on the activity of cardiovascular-related neurons in the rostral ventrolateral medulla and determined whether the effects were mediated by cell bodies. Results are based on recordings of extracellular spikes from 113 neurons in 37 alpha-chloralose- or pentobarbital sodium-anesthetized rabbits. Single sequential stimuli evoked an excitation (onset, 22 +/- 8 ms; duration, 20 +/- 14 ms) followed by an inhibition (onset, 53 +/- 21 ms; duration, 127 +/- 82 ms) in 1) 58 neurons with discharge patterns that were correlated with sympathetic nerve activity (determined by spike-triggered averaging) and with the cardiac cycle (determined by post-R wave-triggered histograms) and that were inhibited by increasing arterial pressure and 2) 27 neurons that exhibited a cardiac rhythm but not a sympathetic rhythm. Area postrema-evoked excitation and inhibition were markedly attenuated by kainic acid injections in area postrema, suggesting that both inputs were derived from cell bodies. The results suggest that area postrema neurons may modulate the activity of medullary neurons in the baroreflex-sympathetic arc as well as neurons in other networks that share baroreceptor input but may not be related to sympathetic nerve activity.

Effect of cardiopulmonary C fibre activation on the firing activity of ventral respiratory group neurones in the rat.

1. Cardiopulmonary C fibre receptor stimulation elicits apnoea and rapid shallow breathing, but the effects on the firing activity of central respiratory neurones are not well understood. This study examined the responses of ventral respiratory group neurones: decrementing expiratory (Edec), augmenting expiratory (Eaug), and inspiratory (I) neurones during cardiopulmonary C fibre receptor-evoked apnoea and rapid shallow breathing. 2. Extracellular neuronal activity, phrenic nerve activity and arterial pressure were recorded in urethane-anaesthetized rats. Cardiopulmonary C fibre receptors were stimulated by right atrial injections of phenylbiguanide. Neurones were tested for antidromic activation from the contra- and ipsilateral ventral respiratory group (VRG), spinal cord and cervical vagus nerve. 3. Edec neurones discharged tonically during cardiopulmonary C fibre-evoked apnoea and rapid shallow breathing, displaying increased burst durations, number of impulses per burst, and mean impulse frequencies. Edec neurones recovered either with the phrenic nerve activity (25 s) or much later (3 min). 4. By contrast, the firing activity of Eaug and most I neurones was decreased, featuring decreased burst durations and number of impulses per burst and increased interburst intervals. Eaug activity recovered in approximately 3 min and inspiratory activity in approximately 1 min. 5. The results indicate that cardiopulmonary C fibre receptor stimulation causes tonic firing of Edec neurones and decreases in Eaug and I neuronal activity coincident with apnoea or rapid shallow breathing.

Lung congestion augments the responses of cells in the rapidly adapting receptor pathway to cigarette smoke in rabbit.

1. We examined the effects of cigarette smoke, inhaled alone and during mild pulmonary venous congestion, on the activity of fifty-three neurones in the nucleus tractus solitarii (NTS) that were excited by input from pulmonary rapidly adapting receptors (RAR). Ten neurones excited by slowly adapting stretch receptors (SAR) were also studied. 2. Extracellular recordings of RAR-activated neurones were recorded in alpha-chloralose anaesthetized rabbits. Smoke from low- and high-nicotine cigarettes was delivered through a ventilator. Mild pulmonary venous congestion was produced by inflating a balloon in the left atrium. 3. Inhalation of three breaths of smoke from low-nicotine cigarettes increased the activity of fifty-one out of fifty-three RAR-activated neurones from 5.9 +/- 1.0 to 14.4 +/- 2.1 spikes breath-1 (P < 0.05). 4. The responses of fifteen neurones were compared with smoke inhaled alone or during mild pulmonary venous congestion. Smoke alone increased unit activity from 6.8 +/- 2.3 to 12.6 +/- 3.7 spikes breath-1 (P < 0.05). Small increases in left atrial pressure (2.0 +/- 0.5 mmHg) had no effect on baseline unit activity (7.6 +/- 2.11 vs. 7.7 +/- 2.3 spikes breath-1; P > 0.05), but enhanced the responses to smoke, increasing the activity from 7.6 +/- 2.1 to 17.1 +/- 4.8 spikes breath-1 (P < 0.05). The response was greater than to smoke alone (P < 0.05). 5. Of ten SAR-activated neurones, seven failed to respond to inhaled cigarette smoke, two were excited and one was inhibited. Pulmonary venous congestion had no effect on the unit activity before and after smoke (n = 4 neurones). 6. We conclude that smoke-evoked excitation of RAR lower-order neurones is augmented by pulmonary venous congestion.