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Spontaneous contractions of the urinary bladder (SBCs) and experimental elevations of carotid sinus pressure (CSP) have been shown to result in respiratory inhibition with preferential reduction in hypoglossal (HG) nerve activity as compared with that of phrenic nerve discharge. We assessed the interaction between these respiratory inhibitory stimuli in decerebrate, vagotomized, paralyzed and artificially ventilated cats. We denervated the right carotid sinus and pressurized the isolated left carotid sinus region within the linear range of the baroreflex, while maintaining systemic arterial pressure at approximately 100 mmHg. We monitored the HG and phrenic nerve responses to SBCs, to elevations in CSP between SBCs, and to elevations in CSP during SBCs. Our results show that superimposing these stimuli results in respiratory inhibition, especially of HG activity, that exceeds that resultant from either stimulus alone. We speculate that the combined presence of SBCs and episodic hypertension may contribute to the development of periodic breathing or obstructive apnea, particularly during sleep.

Severe hypoxia or ischemia causes an alteration from eupnea to gasping. At body temperatures approximating 37 degrees C in vivo, the frequency of gasping is much less than that of eupnea. However in a perfused juvenile rat preparation, which is maintained at 30-31 degrees C, the frequency of eupnea and gasping is the same. We hypothesized that brainstem mechanisms responsible for the neurogenesis of eupnea and gasping might have different sensitivities to alterations in temperature. In both decerebrate adult rats in vivo and in a perfused juvenile rat preparation, eupnea and gasping had different frequencies at rectal or perfusate temperatures in excess of 34 degrees C, whereas, at lower temperatures, eupnea and gasping had identical frequencies in both preparations. These findings support the conclusion that different brainstem mechanisms underlie the neurogenesis of eupnea and gasping. In addition, these findings have implications for interpretation of results from in vitro mammalian preparations, which are examined at temperatures at which the frequency of eupnea and gasping are indistinguishable.

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.

As a first step towards elucidating the synaptic organization underlying segmental responses of abdominal muscles I recorded the responses of branches of the left cranial (L(1)L) and caudal (L(2)L) and right caudal (L(2)R) lumbar (iliohypogastric) nerves to electrical shocks of different intensities to the caudal branch of L(2)L in nine decerebrate paralyzed and ventilated cats. If such reflex responses subserve a respiratory function, then they should be bilaterally similar; if they do not, lateral asymmetry should be evident. At intensities activating only large diameter axons (i.e. spindle and tendon organ afferents), stimulation typically elicited in the rostral branch of L(2)L a brief (approximately 1.6 ms) short-latency (approximately 1.8 ms) excitation followed by a suppression of activity (approximately 8-26 ms). Responses increased in amplitude as stimulus intensity increased, the suppression of activity being interrupted by an excitation (latency approximately 5. 4 ms, duration approximately 3.6 ms) in four cats. L(1)L responses were similar. Contralateral responses in the same segment (L(2)R) in five cats consisted of a suppression of activity in four, a short-latency (approximately 3.3 ms) excitation being present in three; increases in stimulus intensity in two additional cats elicited these excitatory and inhibitory responses. I conclude: (1) the variable responses between cats reflect differences in nerve bundles and, therefore, target muscles, from which the recordings were made; and (2) because of the lateral asymmetry of responses, abdominal afferent activation elicited postural (rotational) rather than respiratory reflexes.

The ventilatory response to acute hypoxia in mammalian species is biphasic, an initial hyperventilatory response is followed by a reduction in ventilation within 2-3 min below the peak level (roll-off). Brain amino acid neurotransmitters also change during hypoxia. This study explores the role of neurotransmitters in anesthetized adult Sprague Dawley rats mechanically ventilated during 20 min of 10% O2 breathing. Phrenic nerve activity was recorded, and microdialysate concentrations of selected amino acids were determined at 3- to 5-min intervals in respiratory chemosensitive areas of the ventrolateral medulla (VMS) 1.25-2.00 mm below the surface. Phrenic nerve output was biphasic during hypoxia, concurrent with a rapid glutamate and gradual GABA increase. Taurine first decreased, then increased. In both intact and chemodenervated animals, time-dependent change in phrenic nerve activity during hypoxia was associated with corresponding changes in glutamate, GABA, and taurine concentrations, suggesting that cumulative effects of changes in the concentration of these three amino acids could account for response of the phrenic nerve to hypoxia.

Transcutaneous electrophrenic twitch stimulation is a potentially powerful way to assess diaphragm contractile function in response to interventions which may alter respiratory muscle strength and endurance. At present, the variability of the transdiaphragmatic twitch pressure (Pdi(T)) over a several hour period is not well described. The present study examines the reproducibility of Pdi(T) amplitude and the twitch occlusion technique of assessing maximum transdiaphragmatic pressure (Pdi(max)) in seven normal adults stimulated intermittently every hour for a total 4-h period. In one subject, data were obtained on two occasions separated by a 2-month interval. Among all subjects, the Pdi(T) amplitude expressed as a percentage of the Pdi(max) was highly reproducible over 4 h (coefficient of variation 5.3). Peak Pdi(T) was inversely related to graded voluntary Pdi (r = -0.0996) and the relationship was virtually identical over 4 h (r = - 0.999, P = 0.96). These data show that Pdi(T) at functional residual capacity and the twitch occlusion relationship are highly reproducible.

Experiments were performed in 18 paralysed, ventilated, decerebrate adult cats to characterise projections from the Kölliker-Fuse nucleus(KFN) to hypoglossal(HG) motoneurons. Efferent neural activity was recorded from the medial branch of both HG nerves, right recurrent laryngeal(RL) nerve, and C3 branch of the left phrenic nerve. Electrical stimulation(1 Hz, 1 msec pulse duration) of discrete areas within the KFN coordinates elicited a preferential, predominantly ipsilateral burst of HG action potentials with an average stimulus-response latency of 8 msec. Tonic stimulation(5-20 Hz) frequently produced considerable HG temporal summation and the appearance of phasic inspiratory HG activity. Injection of 40-100 nl kainic acid(6.37 mM) into the rostral pontine site with the lowest electrical threshold for HG activation elicited a prolonged tonic HG activation. Following kainate injection, the electrical stimulation threshold for HG excitation increased. Pressure injections of 5-100 nl of 2 mM N-methyl-D-aspartic acid (NMDA)and 2 mM(+/-)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid hydrobromide(AMPA) into the KFN were associated with activation and/or suppression of HG motor output. The results indicate that HG motoneurons innervating protrusor tongue muscles receive a selective projection from the KFN that can be activated by glutamate receptors on KF neurons.

The ventilatory responses to electrical stimulation of phrenic afferents were examined in spontaneously breathing dogs at different levels of sodium pentobarbital anesthesia. High intensity stimulation (activation of all the afferents, including thin fibers) increased ventilation (V(E)). The increase in V(E) was comparable to that of breathing 10% CO2 and was inversely related to anesthesia level. Under light anesthesia, V(E) increased to 282+/-36% of the control value when the phrenic nerve was stimulated at 130 times the twitch threshold (n = 15; P < 0.01). The increase in V(E) was due to increases in breathing rate (193+/-19%) and tidal volume (V(T)) (143+/-8%). On the other hand, inspiratory time (T(I)) decreased. Thus, average airflow rate (V(T)/T(I)) increased to 204+/-23%. After administration of 20 and 40% of the initial dose of pentobarbital, V(E) response was attenuated to 157+/-21 and 121+/-4%, respectively. We conclude that thin muscle afferents are capable of eliciting pronounced ventilatory stimulation. The small responses observed earlier were likely due to depth of anesthesia.

The effects of an intravenous nicotine challenge on the ventilation and activity of rib cage muscles were studied in 33 pentobarbitone-chloralose anaesthetized cats. Bolus injection of nicotine (200 microg) into the right femoral vein evoked in 19 of the intact animals prompt, short-lived apnoea, or prolongation of the first expiration after the drug, the occurrence of which was significantly reduced by midcervical vagotomy (P < 0.001). In breaths that followed the apnoea, peak activity of the parasternal intercostal muscles increased from a baseline of 3.1 +/- 0.8 to 9.2 +/- 1.8 arbitrary units (P < 0.001). Nicotine produced a similar increase in peak phrenic ENG (7.0 +/- 0.5 to 14.5 +/- 1.2 arbitrary units; P < 0.001). Peak triangularis sterni muscle EMG was reduced from 8.9 +/- 1.2 to 6 +/- 1.7 arbitrary units (P < 0.05) and the onset of response was delayed to 30 s after the challenge. The changes of respiratory effectors induced by nicotine were independent of vagal integrity. The results show that post-nicotine apnoea is to large extent vagally dependent though the response of the respiratory muscles is mediated by non-vagal influences.

In these studies, we determined the contribution of central mechanisms and the role of GABA(A)-receptor signal transduction pathways in mediating hypercapnia-induced slowing of breathing frequency. Experiments were performed in decerebrate, vagotomized, paralyzed and mechanically ventilated piglets of 3-5 days and 2-3 weeks of age (n=19). Repeated exposure to progressive hyperoxic hypercapnia induced a reproducible increase in phrenic nerve activity, accompanied by a CO2 concentration-dependent increase in expiratory duration. No differences were observed in piglets with intact or cut carotid sinus nerves. Intravenous administration of bicuculline (2 mg/kg: n=7), a gamma-aminobutyric acid (GABA(A)) receptor antagonist, significantly reduced the CO2-induced prolongation of TE. These data demonstrate for the first time that in early postnatal life, hypercapnia induced increase in phrenic activity is associated with centrally mediated prolongation of expiratory duration. Furthermore. the results suggest that brainstem GABAergic mechanisms play an important role in CO2-induced prolongation of expiratory time during early development.

Gradual distension of the urinary bladder evokes spontaneous bladder contractions (SBCs), which are associated with reduced inspiratory activity in the phrenic and other inspiratory motor nerves. We examined the influence of isovolumetric SBCs on the threshold for termination of phrenic inspiration by electrical stimulation of superior laryngeal and/or mid-thoracic intercostal nerves (ICN) in decerebrate, vagotomized, paralyzed, ventilated cats. Although SBCs reduced phrenic inspiratory activity, the threshold for inspiratory termination by nerve stimulation was increased. The results emphasize the complexity of the synaptic connections among brain stem neurons governing micturition and breathing.

Eupnea is generated by mechanisms within the pons and medulla. Following removal of pons or exposure to anoxia, gasping is elicited. Eupnea and gasping are markedly different ventilatory patterns. The genesis of gasping is dependent upon rostral medullary neuronal activities. To generate the gasp, these activities should commence before the phrenic burst. In decerebrate, vagotomized, paralyzed and ventilated cats, eupnea was altered to gasping in anoxia. Rostral medullary neuronal activities had inspiratory, expiratory and phase-spanning patterns in eupnea. During gasping, some inspiratory neuronal activities commenced before the phrenic gasp; these same neurons had commenced activities after the onset of the eupneic phrenic burst. Expiratory and phase-spanning neurons did not discharge. Neuronal activities which are consonant with a role in the neurogenesis of gasping had very different discharge patterns in eupnea. Results support the concept that medullary mechanisms for gasping are incorporated in the ponto-medullary circuit responsible for the neurogenesis and expression of eupnea.

The involvement of the medullary raphé in modulating cardiorespiratory activity was examined by microinjecting L-glutamate (L-Glu) into the raphé of rats. Animals were vagotomized, paralyzed, artificially ventilated, maintained at 37 degrees C, and instrumented to record arterial blood pressure (BP) and phrenic nerve activity (PNA). Mock cerebrospinal fluid (mCSF, 10 nl, pH 7.4; control) and L-Glu dissolved in mCSF (10, 100, 1000 mM; 10 nl; pH 7.4; experimental) were microinjected into the raphé. L-Glu affected both BP and PNA in a dose dependent manner. Blood pressure was reduced by 6.30 +/- 0.97 and 12.98 +/- 1.29% by 100 and 1000 mM L-Glu, respectively, without affecting heart rate. PNA increased by 23 and 38% with 100 and 1000 mM L-Glu, respectively. Mock CSF and 10 mM L-Glu had no effect. It is concluded that there are sites in the medullary raphé that affect blood pressure only and other sites which can affect both blood pressure and respiration.

Power spectra were derived from the diaphragm electromyogram (EMG) in anesthetized rabbits subjected to inspiratory resistive loading (IRL) with airway pressure swings of 40-60 cm H2O for 20 min to 2 h. Shifts in the centroid frequencies of the power spectra were found to be associated with the appearance of power spectral peaks in the range of 105-140 Hz, termed high-frequency oscillation, or HFO. Such peaks have been described before in phrenic nerve activity and in the diaphragm EMG. However, these peaks have not previously been connected with the shifts in centroid frequency seen during loaded breathing. Although such changes in frequency content have been taken to indicate fatigue in the diaphragm, we find that HFO can also cause a shift in centroid frequency during loaded breathing, an effect whose relation to fatigue has yet to be established.

The present study was undertaken to investigate firing patterns, locations, and projections to the phrenic motor nucleus of respiratory neurons in medullary raphe nuclei of rat. Experiments were performed on spontaneously breathing rats anesthetized with sodium pentobarbital. Extracellular spikes of single respiratory neurons were explored in midline medullary tegmentum. A total of 107 respiratory neurons was recorded in the raphe magnus, obscurus and pallidus. They were classified into the following eight types based on the relation of their firing patterns to the phase of respiration: (1) Inspiratory (I) throughout (n = 42); (2) I-late (n = 9); (3) I-decrementing (n = 1); (4) Pre-I (n = 2); (5) I-frequency modulated (n = 13); (6) Post-I (n = 12); (7) Expiratory (E) (n = 23) and (8) E-frequency modulated neurons (n = 5). Twenty of the 45 respiratory neurons examined were antidromically activated from the phrenic motor nucleus at the C4 spinal level with thresholds of 2-58 microA and latencies of 0.4-2.4 ms. Among the 20 neurons, 11 neurons were I-throughout, five were I-frequency modulated and four were E neurons. These results suggest that there is a population of neurons in the medullary raphe nuclei that projects to the phrenic motor nucleus at the C4 spinal level. It is possible that this projection may, in part, mediate the control of the diaphragmatic muscle motor neurons located in the C4 segments.

We analyzed the changes induced by central chemoreceptor stimulation on the lung resistances and phrenic neurogram of anesthetized newborn (3-6 days, n = 9) and 9 week old lambs (n = 3). Starting from hypocapneic apnea, 5% CO2 inhalation evoked a reversible increase in total lung resistance in both newborn and 9 week old lambs (median = 112%). The resistance increase preceded phrenic breathing and was greater for the peripheral (233%) than for the central airways (57%), independent of age. Increases in lung and airway resistance caused by CO2 were reversed totally by atropine and only partially by apnea-producing doses of fentanyl. Our results demonstrate that parasympathetic outflow to the sheep airways is already driven by central chemoreceptor inputs during the newborn period. Even at this early age, bronchomotor responses to central chemoreceptor stimulation are more prominent in the peripheral than in the central airways and exhibit a lower threshold for activation and less sensitivity to opioid inhibition than phrenic responses.

We characterized the role of neurons within the midline of the medulla oblongata on phrenic and hypoglossal nerve responses to hypercapnia during early-development. Studies were performed on decorticate or anesthetized; vagotomized and mechanically ventilated 14-20 day old piglets. Reversible withdrawal of midline neuronal activity was induced by microinjections of lidocaine (2%, 300 nl; n = 10) and lesioning was caused by microinjections of the neurotoxic agent, ibotenic acid (n = 12), at the same sites. At any given end-tidal CO2, peak phrenic and hypoglossal activities after lidocaine were significantly lower than in the control period (P < 0.01). Similarly, 1-2 h after injections of ibotenic acid, both phrenic and hypoglossal nerve responses to CO2 were significantly lower than in the control period (P < 0.01). The results indicate for the first time that the medullary midline neurons are required for full expression of ventilatory responses to hypercapnia and raise the possibility that dysfunction of these nuclei may contribute to respiratory instability during early postnatal life.

The characteristics of GABAergic inhibitory modulation of respiratory bulbospinal neuronal activity and short-term potentiation (STP) of phrenic motoneuronal activity were studied. Extracellular unit recording and picoejection techniques in anesthetized dogs showed that both the spontaneous rhythmic and reflexly induced discharge patterns of inspiratory (I) and expiratory (E) premotor neurons were proportionately amplified by the localized application of picomole amounts of bicuculline (Bic), a competitive GABAA antagonist. Intracellular recording and paired-pulse stimulation techniques in anesthetized rats demonstrated an STP of phrenic motor output that appears to be mediated by NMDA receptors and is associated with facilitation of EPSPs and prolonged depolarization of individual phrenic motoneurons. We speculate that both GABAergic gain modulation of premotor neuronal activity and NMDA-mediated STP of phrenic activity may be neural substrates which are involved with the optimization of respiratory and non-respiratory behaviors, via adaptive and/or differential control of breathing.

Eighteen spontaneously breathing anesthetized rats were selected to belong to three groups: control (C), unilateral (U), and bilateral phrenicotomy (B). Eight days after surgery, the passive and active mechanical properties of the respiratory system, the shape of the occlusion pressure wave, the decay of inspiratory muscle activity during expiration and control of breathing were analysed. Passive and active elastances increased significantly from C to U and from U to B. Passive and active time constants decreased either in uni- or bilateral phrenicotomies. Passive and active resistances remained unaltered. The intensity of respiratory drive increased from C to U and B. In conclusion, uni- and bilateral phrenicotomies increase the elastic load of the respiratory system, because of both its passive and active components, which raised the respiratory neuromuscular drive of the remaining muscles. Consequently, minute ventilation remained unchanged. The higher frequency was allowed for, by a shorter time constant of the respiratory system and by a faster decay of post-inspiratory muscle activity.

The present study was undertaken to investigate whether, independent of changes in PaCO2, ventilatory assist influences not only the pattern but also the level of the respiratory drive. The experiments were performed on decerebrate and paralyzed cats ventilated by a phrenic-driven servo respirator at three different FICO2 levels (0, 0.30, 0.05). The level of ventilatory assist was altered within the range where PaCO2 did not exceed 80 Torr. A higher FICO2 accompanied a higher level of ventilatory assist. The relationship between the minute phrenic activity and log10 PaCO2 at a given FICO2 was linear. No significant difference was found in the regression lines at different levels of FICO2. We conclude that ventilatory assist has little effect on the respiratory drive at a constant level of chemical feedback during hypercapnia.

This study evaluates the delayed respiratory consequences of selective resection of one or several roots of the right phrenic nerve in rabbits. A total of 50 animals were operated on according to five modalities of root resection. A total of 11 animals served as control. The breathing pattern was analysed 8 weeks after surgery. Transdiaphragmatic pressure was measured during transjugular supramaximal stimulation of the phrenic nerve, unilaterally or bilaterally and during prolonged tracheal occlusion (PImax). No difference was observed between the esophageal pressure observed during bilateral phrenic nerve stimulation (BilPeso) in control animals when compared to animals with resection of the highest root of the right phrenic nerve (16.2 +/- 1.0 versus 14.5 +/- 1.0 cmH2O (mean +/- SE). Resection of the two highest or of the two lowest roots of the right phrenic nerve resulted in a similar BilPeso (11.3 +/- 0.8 versus 11.1 +/- 1.2 cmH2O). Preservation of only the accessory phrenic nerve (PN) resulted in a low value of BilPeso (9.8 +/- 1.0 cmH2O) similar to that obtained with complete denervation of the right hemidiaphragm. Ventilation and PImax were not different between the denervated or intact rabbits during quiet breathing. We conclude that in rabbits: (1) Diaphragmatic function is preserved after resection of the highest root of the phrenic nerve. (2) Diaphragmatic function is altered if only the APN is preserved.

Partial unilateral diaphragmatic paralysis remains poorly understood. This study evaluates the residual innervation of the diaphragm after selective resection of one or several roots of the right phrenic nerve in rabbits. Forty-seven animals were operated on according to five root resection modalities. Seven animals served as control. Eight weeks after surgery, the different regions of each hemidiaphragm were analyzed. Electromyographic activity was measured during quiet inspiration and the following histomorphometric parameters were studied: mean fiber area, fiber area dispersion, and ratio large diameter over small diameter. The results obtained from the two measurements were similar. When the accessory phrenic nerve was spared, the crural diaphragmatic region was preserved; denervation was encountered in anterior and lateral parts of the hemidiaphragm. When the highest root of the right phrenic nerve was resected, denervation denervation was limited to the sternal region. When resection of the two highest roots was performed, partial denervation was observed in each region, with residual innervation in the posterior hemidiaphragm. When resection of both the lowest roots was performed, denervation was maximal in the costal region; sternal region remained intact. No contralateral innervation was observed. We conclude that in rabbits: 1) resection of a single root of the phrenic nerve preserves consistent residual innervation. 2) somatotopy of the diaphragm innvervation follows an anteroposterior distribution.

The purpose of this study was to test the hypothesis that carotid body-mediated, phrenic nerve responses to hypoxia are attenuated in adult rats that had been previously exposed to perinatal hyperoxia (one month of 60% O2; perinatal treated rats.) Integrated phrenic nerve responses to strictly controlled isocapnic hypoxia were measured in urethane-anesthetized, vagotomized, paralyzed and ventilated adult rats 2-5 months after perinatal hyperoxia, before and after bilateral carotid denervation. In untreated control rats, phrenic burst frequency, peak amplitude of integrated phrenic activity and minute phrenic activity increased 21 +/- 3 bursts/min (mean +/- SE), 158 +/- 20% and 279 +/- 34%, respectively, during hypoxia (50 Torr PaO2). In contrast, phrenic nerve activity increased to a significantly lesser degree in perinatal treated rats (frequency, 12 +/- 2 bursts/min; amplitude, 87 +/- 13%; minute activity, 150 +/- 19%; all P < 0.05). Hypoxic phrenic responses were abolished by carotid degeneration in both rat groups. In rats exposed to hyperoxia as adults, hypoxic phrenic responses were not attenuated versus untreated control rats. The data indicate that carotid body-mediated, isocapnic hypoxic chemoreflexes are impaired in perinatal treated rats, an effect unique to development. These effects cannot be accounted for by differences in blood gases (O2 or CO2) or pulmonary mechanics.

Spontaneous bladder contractions (SBCs) in decerebrate, vagotomized, paralyzed, ventilated cats have been shown to decrease phrenic and hypoglossal inspiratory nerve activities, as well as the activities of other respiratory motor nerves. To determine whether vagal afferents from the lung influence the respiratory inhibition associated with SBCs, we recorded phrenic and hypoglossal nerve activities in decerebrate, paralyzed, vagally intact cats. The animals were ventilated by a servo-respirator, which inflated the lungs in accordance with integrated phrenic nerve activity. Maintained increases in end-expiratory lung volume were produced by the application of 2-10 cm H2O positive end-expiratory pressure (PEEP). SBCs were accompanied by decreases in both phrenic and hypoglossal peak integrated nerve activities, as well as by marked decreases in respiratory frequency. The reduction of respiratory frequency was greater with higher levels of PEEP, a few animals becoming apneic during SBCs. After bilateral vagotomy, SBCs continued to decrease phrenic and hypoglossal peak integrated nerve activities as previously reported, but the reduction of respiratory frequency was much less striking than when the vagi were intact. These results indicate that activity of vagal afferents from the lung augments the respiratory influence of SBCs. Furthermore, SBCs in vagally intact animals can induce periodic breathing.

Medullary regions, termed 'pre-inspiratory' and 'pre-Bötzinger', are considered critical for the neurogenesis of rhythmic ventilatory activity of in vitro preparations of the neonatal rat. We examined the influence of destruction of neurons in these regions, by microinjections of kainic acid, upon eupnea and gasping in vivo. Decerebrate, vagotomized, paralyzed and ventilated rats of age 8-15 days were used; the phrenic nerve activity was recorded. Eupnea was not consistently altered following destruction of neurons in any region. However, in the majority of animals, anoxia-induced gasping was not observed following injections of kainic acid into the 'pre-inspiratory' region, 'pre-Bötzinger' complex or lateral tegmental field; the latter region is important for the neurogenesis of gasping in adults. Injections into other regions did not prevent the elicitation of gasping. These results do not support the possibility that neuronal activities which are responsible for respiratory rhythm generation in vitro underlie the neurogenesis of eupnea in vivo.

In decerebrate or anesthetized cats with moderately distended urinary bladders, spontaneous bladder contractions (SBCs) have been shown to decrease phrenic and hypoglossal nerve activities. To determine the involvement of both the pontine micturition center (PMC) and the pneumotaxic center in the respiratory response to SBCs, we recorded phrenic and hypoglossal nerve activities in decerebrate, paralyzed, vagotomized, artificially ventilated cats. Electrical stimulation of the PMC in cats with subthreshold bladder volumes below the threshold for SBCs elicited both increases in intravesical pressure (IVP) and attenuation of respiratory motor nerve activities. Respiration was not altered after PMC lesions, which abolished SBCs, contractions in response to PMC stimulation, and respiratory inhibition due to passive bladder distension. Electrical stimulation of the pneumotaxic center altered respiratory motor nerve activities and increased IVP in cats with subthreshold bladder volumes. Pneumotaxic center lesions caused apneusis, but did not abolish the SBCs, which continued to attenuate the apneustic respiratory motor nerve activity. These results indicate that the PMC is an important component of the reflex pathway from urinary bladder distension to respiratory inhibition, whereas the pneumotaxic center does not appear to be an essential part of this pathway.

5-Hydroxytryptamine (serotonin, 5-HT) affects upper airway and chest wall inspiratory muscle control. The purpose of this study was to investigate the relative interaction of serotonergic agents on these two muscle groups. We measured the responses of the hypoglossal and phrenic nerves to the systemic administration of serotonergic-active agents and determined the receptor types through which these agents act in anesthetized, vagotomized, paralyzed and artificially ventilated rats. The serotonin precursor, L-5-hydroxytryptophan (L-5-HTP) produced equivalent stimulation of phasic inspiratory activity of the hypoglossal and phrenic nerves. General serotonin antagonists produced significant and equivalent diminution of both motoneuron pools. Specific 5-HT1A stimulation and 5-HT1C/2 antagonism enhanced ventilatory activity. We conclude: (1) a baseline level of serotonergic input to hypoglossal and phrenic motoneuron pools was present, (2) different 5-HT receptors had different effects on ventilatory neural activity, and (3) hypoglossal and phrenic motoneuron pools responded similarly to the serotonergic agents given.

The electromyographic response of the diaphragm to (a) transcutaneous electrical stimulation (TCES) of the spinal cord at C5 and above, (b) transcranial magnetic stimulation (TMS) over the motor cortex and (c) transcutaneous electrical stimulation of the phrenic nerve in the neck (TPNS), was recorded in six normal subjects at the antero-lateral chest wall. The compound motor evoked potentials (cMEPs) recorded in response to both TMS and TCES were facilitated to a similar extent during volitional inspiration; this facilitation was greater than any change seen in response to TPNS with inspiration. The results show that facilitation of the response in the diaphragm to TMS during volitional inspiration is due to increased excitability at synapses associated with the spinal motoneurone pool, but they do not exclude a component due to increased higher centre excitability. We conclude that it is unsafe to assign a cortical contribution to 'automatic' inspiration on the sole basis of facilitation of the electromyographic response in the diaphragm to TMS.

The purpose of this study was to determine if the initial ventilatory and phrenic nerve responses to isometric contraction of the triceps surae muscle of anesthetized cats are influenced by the pattern of the contraction. To address this, three different types of muscle contraction were evoked: (1) a high tension, continuous tetanic (HT-CT) contraction; (2) a moderate tension, continuous tetanic (MT-CT) contraction; and (3) high tension, intermittent tetanic (HT-IT) contractions. The duration of each contraction period was 60 sec. The MT-CT and HT-IT contractions increased minute volume (VE; 19 +/- 4% and 15 +/- 5%, respectively) within the first 15 sec. These increases were the result of rises in breathing frequency and tidal volume. However, only the MT-CT contraction increased phrenic activity (pVE) in the first 15 sec. By contrast, ventilation and phrenic nerve activity failed to increase within the first 15 sec of the HT-CT contraction. If fact, 'tidal' phrenic activity (pVT; -14 +/- 5%) decreased during the first 5 sec, and there was a tendency for tidal volume (VT; -8 +/- 5%), VE (-8 +/- 6%), and pVE (-16 +/- 8%) to fall. These data suggest that stimulation of muscle afferent fibers by static contraction can initially inhibit phrenic nerve activity, provided the activation is sustained and of sufficient intensity.

Repeated isocapnic hypoxia evokes long-term facilitation (LTF) of phrenic nerve activity in rats. We wished to determine: (1) whether hypoxia-induced LTF is serotonin dependent; and (2) whether hypoxia-induced LTF is a property of upper airway motoneurons. Phrenic and hypoglossal nerve activities were recorded in urethane anesthetized, vagotomized, paralyzed and artificially ventilated rats (n = 7). Rats were exposed to three, 5-min hypoxic episodes (FIo2 = 0.10) separated by 5 min of hyperoxia (FIo2 = 0.50). One hour after the final hypoxic episode, integrated phrenic and hypoglossal amplitudes and burst frequency were increased above control values (63 +/- 17%, 78 +/- 26% and 9.6 +/- 2.1 bursts/min, respectively: p < 0.05). In rats pretreated with methysergide (n = 7; 4 mg/kg), no changes in phrenic or hypoglossal activity from pre-stimulus control values were observed at any time post-stimulation. The results indicate that hypoxia-induced LTF requires 5-HT receptors and is characteristic of both hypoglossal and phrenic motor output.

We developed a decerebrate, vagotomized, newborn rat preparation to investigate brainstem respiratory control mechanisms without the influence of anesthesia, supra-pontine structures, or vagally mediated feedback mechanisms. We measured the changes in phrenic nerve electrical activity in response to breathing 3% and 5% CO2 in unanesthetized, vagotomized, decerebrate newborn rats from 0 to 10 days of age and compared them with the changes in anesthetized, vagotomized, newborn rats and adult, vagotomized, decerebrate or anesthetized, animals. Phrenic nerve activity was irregular in the young newborn rats and became more regular between 7 and 10 days of age. T1 and T1/Ttot increased with age but increasing age had no influence on the response to CO2. The response to CO2 was dominated by increases in phrenic amplitude, minute activity, and inspiratory slope with no change in timing variables. These responses are similar to those that have been reported previously in vagally intact animals, suggesting that vagal feedback contributes little to the response to hypercapnia in the newborn rat. In summary, decerebrate newborn rats consistently respond to hypercapnia by increasing inspiratory drive similar to conscious animals.

The purpose of this study was to test the hypothesis that respiratory and apneas induced by alpha 2 agonists in anesthetized goats are associated with an increase of upper airway expiratory-related activity, rather than a general depression of breathing. Activities of phrenic (Phr) and recurrent laryngeal nerves (RLN) were recorded in response to the alpha 2 agonists clonidine (0.5-3.0 microgram.kg-1 i.v.) or guanabenz (7.0-20.0 micrograms.kg-1 i.v.) in ten chloralose-anesthetized goats. Injection of either alpha 2 agonist resulted in respiratory arrhythmias with a greater than seven-fold increase in TE and a 30% reduction in TI. During apneas RLN expiratory-related activity remained tonic until the next Phr burst, consistent with our hypothesis. Cessation of Phr activity during hypocapnia also resulted in a tonic increase of RLN expiratory activity; and injection of NaCN (50 micrograms.kg-1 i.v.) increased Phr and RLN inspiratory activities, while attenuating RLN expiratory-related activity. Inspiratory and expiratory-related activity of RLN motoneurons appear to be reciprocally modulated by alpha 2 agonists or changes in central or peripheral chemoreceptor drive. The results indicate that central apneas and respiratory arrhythmias may be associated with alpha 2-adrenoceptor modulation of laryngeal expiratory-related activity.

Previously we showed that prolonged exposure to severe hypoxia produces decreased peripheral chemoreceptor responsiveness to hypoxia and attenuates central nervous system (CNS) chemosensory translation, which together may contribute to the decreased hypoxic ventilatory response (HVR) in chronic hypoxia. In this study, we sought to determine whether the central or peripheral activity of endogenous dopamine modulates this decreased HVR. We examined the effects of peripheral and central dopamine receptor blockade on HVR and carotid sinus nerve (CNS) response to hypoxia in controls and in cats exposed to a simulated altitude of 5500 m for 3 weeks. Domperidone increased CSN response to hypoxia in hypoxic cats to levels similar to those observed in controls. HVR was also augmented by domperidone in hypoxic cats, but remained below that of controls. As a result, the CNS chemosensory translation remained reduced in hypoxic animals. We further treated animals with haloperidol. However, this combined treatment with domperidone and haloperidol led to no further increase in CSN or ventilatory responses to hypoxia, or in CNS chemosensory translation in hypoxic cats. Thus, decreased HVR in hypoxic cats is mediated both by depression of hypoxic sensitivity of the carotid body, which is largely dopaminergic, and by decreased CNS chemosensory translation which must involve non-dopaminergic mechanisms.

Substance P (SP) has been proposed as an excitatory neuromodulator of the carotid body (CB) response to hypoxia based on data from the cat and rat. The role of SP as a CB neuromodulator in the goat is unknown. Awake (n = 14) and chloralose anesthetized goats (n = 6) were used to investigate the effects of intracarotid (IC) SP infusions (1-6 micrograms.kg-1.min-1) and bolus injections (6 micrograms kg-1) to the CB intact and denervated (CBX) sides (control) on mean ventilation (VE) and mean blood pressure (MBP). In awake goats VE was decreased by infusion or bolus SP injection at a dose of 6 micrograms.kg-1 (P < 0.05) and occurred with infusions to the intact or CBX sides. MBP was elevated with SP infusion to either the CB intact or CBX sides at all SP doses. The SP antagonist CP-96,345 (0.1 mg.kg-1, IV) blocked the decrease in VE induced by SP in normoxia and significantly increased the hypoxic ventilatory response (PaO2 = 40 torr). In anesthetized goats, IC injections of SP (1 to 6 micrograms.kg-1) reduced phrenic activity and MBP before and after CBX. In only one of five goats airway pressure was increased suggesting that bronchoconstriction was not a cause for the reduced ventilatory and phrenic activity induced by SP. Immunohistochemistry provided evidence of SP in CB nerve fibers and terminals, carotid sinus nerve axons and petrosal ganglion cells, but not in type I glomus cells. Our results do not support the view that SP is an excitatory neuromodulator of CB chemotransduction in the goat.

We have used the isolated brainstem-spinal cord preparation of the neonatal rat to study the effects of theophylline on the ventilatory response to hypoxia. The brainstem-spinal cord was isolated from neonatal rats (0-4 days) and superfused with mock cerebrospinal fluid (CSF), equilibrated with a gas mixture (FO2, 0.90; FCO2, 0.02; FN2, 0.08; control CSF) at 27 degrees C. We recorded phrenic nerve discharge from C4 roots, using suction electrodes, and measured respiratory frequency (fR) and the amplitude of the integrated phrenic neurogram (integral of phr). We examined how theophylline and the specific adenosine antagonist, 8-p-sulfophenyltheophylline (SPT), modify the ventilatory response to hypoxia. The response during superfusion with hypoxic CSF (FO2, 0.06) consisted of a marked decrease in fR (to 60% of control) and a slight decline in integral of phr (to 85% of control). By contrast, in the presence of theophylline (30 mg/L = 165 microM) and SPT (5 mg/L = 15 microM) in the superfusate hypoxia reduced fR only moderately (to 87% of control) and exerted virtually no effect on integral of phr (105% of control). Theophylline and SPT attenuated the rate of decrease in fR and completely blocked the decrease in integral of phr. There was no difference between the effects of theophylline and those of SPT. The results suggest that theophylline attenuates hypoxic respiratory depression, and that this effect is mediated by the blockade of adenosine.

To determine whether decreases in neural activation and/or neuromuscular transmission to the diaphragm contribute to ventilatory failure observed during inspiratory resistive loaded breathing, peak integrated activity of the intact phrenic nerve (ENGdi) and costal diaphragm (EMGdi), transdiaphragmatic pressure swings (Pdi) and evoked diaphragm compound action potentials (M-wave) were measured in anesthetized rabbits subjected to inspiratory resistive loads of varying intensities and duration breathing supplemental oxygen. Sustainable loads were studied for 4 h. Severe loads were applied in increments and studied for 50 min each. Loading resulted in parallel increases in ENGdi, EMGdi and Pdi that stabilized within 20 min. With severe loading, peak inspiratory pressure (Pao = -55 +/- 4 cm H2O) was maintained for 30 min after which there was a significant drop in inspiratory pressure (task failure). Despite hypoventilation and profound changes in blood gases, both activation (ENGdi) and neuromuscular transmission (ENGdi/EMGdi ratio or M-wave) were maintained throughout all loads even at task failure when a critical level of PaO2 (27 +/- 1 mm Hg) was reached. We conclude that neural activation and neuromuscular transmission to the diaphragm do not fail during inspiratory resistive breathing and discuss our findings in terms of current concepts of diaphragm fatigue and control of breathing in this model.

Mechanisms of respiratory muscle dysfunction leading to respiratory failure during incremental inspiratory threshold loading were studied in unbound spontaneously breathing rabbits during light and deeper anesthesia. Low or high frequency contractile fatigue was not found at the point of respiratory failure in any of the animals. On the other hand, alterations in central drive to the diaphragm played a dominant role in the observed respiratory failure. In animals receiving light anesthesia the intensity of central drive increased with loading, but then fell as respiratory failure approached. In all animals the intensity of central drive at peak activation and at the point of respiratory failure was submaximal, in spite of the diaphragm's ability to generate additional forces. In addition, the time tension index of the diaphragm rose in response to increasing loads to a level reported to produce contractile fatigue, at which time the index peaked and then fell in spite of increasing load demands. The fall in the time tension index as respiratory failure approached was due primarily to a fall in inspiratory time and duty cycle. Ultimately, there was an abrupt cessation in central drive resulting in apnea. These findings suggest that alterations in central drive play a major role in respiratory muscle dysfunction and respiratory failure associated with inspiratory loading in unbound spontaneously breathing rabbits.

To map the superficial locations which are involved in the control of respiration and tracheal smooth muscle tone in ventrolateral medulla, we examined the effects of local anesthesia on phrenic activity and tracheal tone in twelve anesthetized, paralyzed, and artificially ventilated dogs. 0.5 microliter of 5% procaine was injected 0.3 to 0.5 mm below the surface unilaterally to the ventral superficial layer (from the rostral part of the trapezoid body to the caudal hypoglossal rootlets and lateral from the pyramids to 5.5 mm from the midline), which included rostral, intermediate and caudal areas, and the area lateral to the hypoglossal rootlets. The peak amplitude of the integrated phrenic neurogram was decreased by procaine injection to the intermediate area and the area lateral to the hypoglossal rootlets. Tracheal tone decreased only by procaine injection to the intermediate area. In the intermediate area, some injections decreased either phrenic output alone or tracheal tone alone. These results suggest that the two ventral medullary areas, i.e. the intermediate and caudolateral parts, contain neural structures which are involved in the shaping of phrenic output, but only the intermediate area is involved in the regulation of tracheal tone. It is also suggested that, in the intermediate area, the structures responsible for the maintenance of respiration and tracheal tone are, at least in part, separable.

The purpose was to identify and characterize the discharge patterns of pontile neurons which are responsible for the termination of inspiratory activity. Phrenic discharge is prolonged following destruction of neurons at the junction of mesencephalon and pons by neurotoxins. Neuronal activities were recorded in this region in decerebrate, vagotomized, paralyzed and ventilated cats. At normocapnia, neurons had tonic discharge patterns, most of which were linked to phasic periods of phrenic activity. Peak activities occurred in late neural inspiration or early expiration. In hypercapnia, neuronal discharge frequencies did not increase, rather activity became more concentrated during one portion of the respiratory cycle. In severe hypoxia, neuronal activities diminished in parallel with the prolongation of phrenic discharge and establishment of apneusis. During recovery, some neurons transiently acquired phasic, respiratory-modulated discharge patterns. Neuronal activities from neighboring regions did not exhibit comparable changes in hypercapnia or hypoxia. We conclude that rostral pontile neuronal activities are a primary determinant of the reversible and irreversible terminations of eupneic inspiratory activity.

This study examined the cardiovascular, ventilatory, and phrenic nerve responses to graded activation of mechanically sensitive muscle afferents. Using eight alpha-chloralose anesthetized cats, the left and right triceps surae muscles were stretched individually and simultaneously at progressive increments (0.5, 1.0, 1.5, 1.75 cm). Muscle stretch elicited sustained increases in mean arterial blood pressure (MAP) and heart rate (HR). These changes were related to the degree of stretch, as stretching one muscle 0.5 cm increased MAP 15 +/- 2 mmHg and HR 7 +/- 2 beats/min, while stretching both legs (1.75 cm) increases these variables 40 +/- 11 mmHg and 11 +/- 3 beats/min. By contrast, muscle stretch initially decreased ventilation and phrenic nerve activity. After the initial fall, ventilation, but not tidal phrenic activity, increased above baseline. These results show that a divergence exists between the initial cardiovascular and ventilatory responses to activation of mechanically sensitive muscle afferents. Further, the hyperpnea elicited by muscle stretch in spontaneously breathing anesthetized cats appears to be the result of excitation of non-diaphragmatic muscles of ventilation.

In anesthetized (n = 26) or decerebrate (n = 15) rats, vagotomized, paralyzed and artificially ventilated, we recorded efferent respiratory-related discharges of nerves supplying the pharyngeal muscles, i.e. the glossopharyngeal nerve (IX; n = 30) and the pharyngeal ramus of the vagus nerve (PH.X; n = 33). In both types of preparation, all IX nerves fired during inspiration (I); most PH.X fired either during I (n = 11), expiration (E, n = 12), or both phases (n = 4); some of them were continuously active, without any respiratory modulation (n = 6). We also examined the timing of inspiratory pharyngeal bursts in relation to the phrenic (inspiratory) bursts. We found that the burst onset occurred significantly earlier in pharyngeal nerves than in phrenic ones (pharyngeal-to-phrenic delay). In anesthetized animals, this pharyngeal-to-phrenic delay was long enough to reveal that inspiratory activity appeared first on IX, then on PH.X, and then on phrenic nerves. Since hypoxia did not significantly alter the pharyngeal-to-phrenic delay, we conclude that a reliable organization of the inspiratory drive on pharyngeal and diaphragmatic muscles should exist, in the rat.

In chloralose-urethane anesthetized, paralyzed, and ventilated rats, we measured the effects of unilateral lesions in the region ventral and ventromedial to the facial nucleus, the retrotrapezoid nucleus (RTN), on eucapnic phrenic activity and the response to increased end-tidal CO2. Chemical (kainic acid injections; 4.7 mM; 10-100 nl) and electrolytic (5-15 mA; 5-15 sec) lesions, anatomically demonstrated to be in the RTN, resulted in a progressive decrease in the amplitude of the integrated phrenic nerve activity from baseline levels of 49-59% of maximum to values of 21-32% of maximum over 30 to 120 min. There were no consistent effects on frequency or on blood pressure. The initial slope of the response to hypercapnia was decreased by 86-92%. Bilateral carotid body ablation did not alter the general pattern of the responses. As in the cat, unilateral RTN lesions decrease baseline phrenic amplitude and virtually abolish the response to hypercapnia. We hypothesize that the RTN region provides; (1) a source of tonic activity which maintains eucapnic ventilatory output, and (2) allows expression of the response to hypercapnia.

Neonatal apnea is characterized by decreased neural output to the ventilatory muscles, and frequently associated with upper airway obstruction. We sought to characterize: (1) the role of central chemosensitive structures at the ventral medullary surface (VMS) in modulating hypoglossal and phrenic neural output, and (2) the recovery of hypoglossal and phrenic neural output during simulated central apnea. We studied 14 anesthetized, paralyzed, ventilated piglets aged 14-21 days and performed VMS cooling to inhibit central neural pathways mediating CO2 sensitivity. Phrenic and hypoglossal ENGs and end-tidal CO2 were continuously recorded. During CO2 rebreathing, hypoglossal activity was always more sensitive than phrenic activity to the inhibitory effects of VMS cooling. When phrenic apnea was induced by VMS cooling, and followed by discontinuation of ventilation for 60 sec in order to induce simultaneous hypercapnia and hypoxia, reappearance of hypoglossal ENG was delayed and recovery was significantly suppressed when compared to phrenic ENG. Therefore, attenuated central chemosensitivity during early postnatal life appears to preferentially inhibit neural output responsible for upper airway patency, and may predispose to upper airway obstruction during recovery from neonatal apnea.

Activation of thin-fiber (groups III and IV) afferents from the diaphragm using capsaicin or ischemia increases the respiratory muscle activity. To assess whether bradykinin causes similar effects, we injected boluses of bradykinin into the phrenic artery of in situ, isolated and innervated left hemi-diaphragm preparations in 8 alpha-chloralose anesthetized, vagotomized, mechanically ventilated dogs. Inspiratory motor drive during spontaneous breathing attempts was assessed from the integrated EMG activity of several inspiratory muscles. Fifty micrograms of bradykinin increased peak integrated EMG activities of alae nasi to 110%, genioglossus to 189%, left diaphragm to 115% (P < 0.05) and parasternal to 109% (P < 0.01) of baseline activity 60 sec after the injection. Inspiratory time decreased by 10% (P < 0.01). The mean arterial blood pressure increased by about 10 mmHg. Responses were similar with 10, 25 and 100 micrograms of bradykinin. After left phrenicotomy, bradykinin did not affect inspiratory muscle EMG or respiratory timing. In conclusion, thin-fiber phrenic afferent activation by bradykinin exerts an excitatory but disproportionate influence on the inspiratory motor drive.

Electrical stimulations of the pneumotaxic center can result in a phase-switch from neural inspiration to expiration or the reverse. Terminations of inspiration are also obtained from many loci ventral to the pneumotaxic center. We hypothesized that responses to some stimulations reflect an activation of fibers rather than neurons. Studies were conducted in decerebrate, vagotomized, paralyzed and ventilated cats. Activities of the phrenic and triangularis sterni nerves were recorded. A multibarreled pipette was inserted into the rostral pons. Electrical stimulation was delivered through two barrels; another contained kainic acid to destroy neurons. The threshold current for producing inspiratory termination was not altered in most regions following the injections of kainic acid. However, stimulation of neurons did appear to underlie the premature onset of phrenic activity. In addition, neurons in medial pontile regions regulate triangularis sterni activity. We conclude that some functions ascribed to the pneumotaxic center are, in fact, subserved by neurons in other regions of the central nervous system.

Multiple functions have been ascribed to the pontile pneumotaxic center. We hypothesized that these functions might be separable among neurons in different regions. In decerebrate, vagotomized, paralyzed and ventilated cats, activities of the phrenic and triangularis sterni nerves were recorded. Microinjections of kainic acid were used to destroy neurons. Neurons in the rostrolateral tegmentum at the ponto-mesencephalic border controlled the duration of neural inspiration. Expiratory duration was controlled by neurons in the more caudal nucleus parabrachialis medialis and Kolliker-Fuse nucleus. Ventilatory responses to hypercapnia were depressed following injections of kainic acid into regions controlling either inspiratory or expiratory durations. The phases of expiration were regulated by two groups of neurons, located medial and lateral in the rostral pons. We conclude that rostral pontile and mesencephalic mechanisms control multiple aspects of the eupneic ventilatory cycle. There mechanisms are served by neurons in separable anatomical regions.

In decerebrate, vagotomized cats, introduction of CO2 into the isolated laryngeal airway while systemic PCO2 is held constant evokes dose-related reflex changes in ventilatory activity. Because systemic hypoxia is known to exaggerate ventilatory responses to other types of laryngeal chemostimulation in neonates, we have compared the responses of phrenic and hypoglossal nerve activities to ventilation of the larynx with 10% CO2 during systemic hyperoxia (FIO2 = 1.00) to those during hypoxia (FIO2 = 0.12). Compared with the hyperoxic baseline condition, hypoxia stimulated phrenic activity but attenuated the reduction in phrenic activity evoked by intralaryngeal CO2. Hypoglossal activity was increased by intralaryngeal CO2 and this response appeared to be reduced by hypoxia, but neither of these findings was statistically significant. The response of phrenic activity to intralaryngeal CO2 during systemic hypercapnia was similar to that during hypoxia. The increase of phrenic activity in response to hypoxia was prevented by carotid body resection. Similarly, the hypoxic attenuation of the phrenic response to intralaryngeal CO2 appeared to be absent after carotid body resection, although this finding was not established statistically. These results differ from previous reports of exaggerated laryngeal chemoreflex responses during hypoxia. The difference may reflect differences in the receptors and synaptic mechanisms of the reflexes, the severity and time course of hypoxia or the presence or depth of general anesthesia or sleep.

The effects of digoxin on diaphragmatic contraction were studied in 12 sheep, within 6 days after a right thoracotomy, during the period of intense diaphragmatic inhibition. Diaphragmatic function was assessed by implanting sonomicrometry crystals and electromyographic (EMG) electrodes in both the costal and crural diaphragmatic regions. Awake sheep were studied before and after intravenous digoxin (0.04 mg/kg) during both quiet breathing (QB) and during CO2 rebreathing, until the fractional concentration of expired CO2 (FETCO2) reached 0.10. After digoxin infusion, during both QB and at FETCO2 of 0.10, esophageal and transdiaphragmatic pressures increased (P < 0.05). After digoxin infusion no changes were measured for end-expiratory resting length, shortening fraction, shortening velocity or EMG activity of either diaphragmatic segment or for respiratory frequency, ventilation, tidal volume and FETCO2. We conclude that intravenous digoxin given to awake sheep after a thoracotomy increases Pdi, but does not alter diaphragmatic shortening nor alter the level of diaphragmatic activation either during QB or at FETCO2 of 0.10.

The pulmonary chemoreflex components such as reactions of phrenic sympathetic neuron (PhSN) activity, phrenic nerve activity, heart rate and blood pressure were tested in chloralose-anesthetized, paralyzed cats. 10 micrograms to 160 micrograms phenylbiguanide (PBG) in 0.9% NaCl was injected into the pulmonary circulation. PBG injected into the right atrium (in 11 of 19 experiments) and into the pulmonary artery (in 5 of 8 experiments), evoked short-latency (1-1.4 sec) dose-dependent increase in PhSN activity accompanied by increase in blood pressure, and followed by decrease in these two variables. In all experiments, activity of the phrenic nerve was depressed, and bradycardia occurred after PBG injection. All responses to PBG injections into the pulmonary artery were abolished following bilateral vagotomy. In the same procedure related to the right atrium after vagotomy, the increases in PhSN activity and blood pressure were also abolished, although a decrease in heart rate, PhSN activity and in the amplitude of phrenic nerve discharges together with an increase in their frequency persisted. Our results suggest that short-latency increase in PhSN activity is a component of pulmonary chemoreflex.

Protriptyline (PRT) has been shown to preferentially stimulate upper airway inspiratory motorneurons relative to phrenic activity in hyperoxic hypercapnia in the decerebrate cat via a carotid body-independent mechanism. Since previous studies indicated that carotid body stimulation results in preferential activation of upper airway respiratory muscles during both hypercapnia and hypoxemia, we hypothesized that if PRT preferentially stimulated upper airway motorneurons, the mechanism of action might involve the carotid body. We investigated the effect of PRT on carotid body function by comparing the electrical activity of the hypoglossal (HYP) with that of the phrenic (PHR) nerve in carotid sinus nerve intact (CSNI) and CSN-sectioned (CSNX) anesthetized rats, before and after PRT (0.5 mg/kg i.v.), during 100% O2, 15% O2 (N2 balance), and 4% CO2 (O2 balance) administration. The moving time average (MTA) peak inspiratory electroneurogram activities of both the HYP and PHR nerves increased an equivalent amount after PRT injection during hyperoxia, in both CSNI and CSNX rats. During hypoxia, the HYP activity increased significantly more than the PHR activity only in CSNI rats after PRT injection. During hyperoxic hypercapnia, HYP MTAs increased a similar amount in the CSNI and CSNX rats. We conclude that the HYP and PHR respiratory motorneuron pool responses to PRT depend on the blood gas status at the time of drug administration.