Essential Role of the cVRG in the Generation of Both the Expiratory and Inspiratory Components of the Cough Reflex.

As stated by Korpás and Tomori (1979), cough is the most important airway protective reflex which provides airway defensive responses to nociceptive stimuli. They recognized that active expiratory efforts, due to the activation of caudal ventral respiratory group (cVRG) expiratory premotoneurons, are the prominent component of coughs. Here, we discuss data suggesting that neurons located in the cVRG have an essential role in the generation of both the inspiratory and expiratory components of the cough reflex. Some lines of evidence indicate that cVRG expiratory neurons, when strongly activated, may subserve the alternation of inspiratory and expiratory cough bursts, possibly owing to the presence of axon collaterals. Of note, experimental findings such as blockade or impairment of glutamatergic transmission to the cVRG neurons lead to the view that neurons located in the cVRG are crucial for the production of the complete cough motor pattern. The involvement of bulbospinal expiratory neurons seems unlikely since their activation affects differentially expiratory and inspiratory muscles, while their blockade does not affect baseline inspiratory activity. Thus, other types of cVRG neurons with their medullary projections should have a role and possibly contribute to the fine tuning of the intensity of inspiratory and expiratory efforts.

Comparison between the effects of lisinopril and losartan on the cougn reflex in anesthetized and awake rabbits.

The aim of the present study was to analyze differences in cough induction between losartan and lisinopril in both anaesthetized and awake rabbits, i.e., under conditions in which the influences of higher brain areas on the cough reflex are strongly reduced or abolished. Losartan (500 µg/kg), lisinopril (100 µg/kg) and NaCl 0.9% saline solution (vehicle) were administered by intravenous injections. Animals were randomly assigned to the different experimental treatments. The cough reflex was induced by chemical (citric acid) and/or mechanical stimulation of the tracheobronchial tree. In anaesthetized rabbits, losartan and lisinopril caused similar hypotensive effects. Lisinopril, but not losartan, increased the cough response induced by both mechanical and chemical stimulation due to increases in the cough number, i.e. the number of coughs induced by each stimulation challenge. In awake animals, only lisinopril significantly increased the cough number. The results support the notion that cough potentiation induced by losartan, and possibly other sartans, is lower than that induced by most angiotensin-converting enzyme inhibitors despite the reduction or complete absence of higher brain functions. In this connection, the comparison between present results and our previous findings on ramipril and zofenopril shows that losartan and zofenopril display similar cough-inducing potency, much lower than that of lisinopril and ramipril.

Role of neurokinin receptors and ionic mechanisms within the respiratory network of the lamprey.

We have suggested that in the lamprey, a medullary region called the paratrigeminal respiratory group (pTRG), is essential for respiratory rhythm generation and could correspond to the pre-Bötzinger complex (pre-BötC), the hypothesized kernel of the inspiratory rhythm-generating network in mammals. The present study was performed on in vitro brainstem preparations of adult lampreys to investigate whether some functional characteristics of the respiratory network are retained throughout evolution and to get further insights into the recent debated hypotheses on respiratory rhythmogenesis in mammals, such as for instance the "group-pacemaker" hypothesis. Thus, we tried to ascertain the presence and role of neurokinins (NKs) and burst-generating ion currents, such as the persistent Na(+) current (I(NaP)) and the Ca(2+)-activated non-specific cation current (I(CAN)), described in the pre-Bötzinger complex. Respiratory activity was monitored as vagal motor output. Substance P (SP) as well as NK1, NK2 and NK3 receptor agonists (400-800 nM) applied to the bath induced marked increases in respiratory frequency. Microinjections (0.5-1 nl) of SP as well as the other NK receptor agonists (1 microM) into the pTRG increased the frequency and amplitude of vagal bursts. Riluzole (RIL) and flufenamic acid (FFA) were used to block I(NaP) and I(CAN), respectively. Bath application of either RIL or FFA (20-50 microM) depressed, but did not suppress respiratory activity. Coapplication of RIL and FFA at 50 microM abolished the respiratory rhythm that, however, was restarted by SP microinjected into the pTRG. The results show that NKs may have a modulatory role in the lamprey respiratory network through an action on the pTRG and that I(NaP) and I(CAN) may contribute to vagal burst generation. We suggest that the "group-pacemaker" hypothesis is tenable for the lamprey respiratory rhythm generation since respiratory activity is abolished by blocking both I(NaP) and I(CAN), but is restored by enhancing network excitability.

Opioid-induced depression in the lamprey respiratory network.

The role of opioid receptors in modulating respiratory activity was investigated in in vitro brainstem preparations of adult lampreys by bath application of agonists and antagonists. The vagal motor output was used to monitor respiratory activity. Neuronal recordings were also performed to characterize the rostrolateral trigeminal region that has been suggested to be critical for respiratory rhythmogenesis. Microinjections of the micro-opioid receptor agonist [d-Ala(2), N-Me-Phe(4), Gly(5)-ol]-enkephalin (DAMGO) were also made into this region and at different locations within the brainstem. Bath application of DAMGO (0.5-2 microM) caused marked decreases in respiratory frequency up to complete apnea. Bath application of the delta-opioid receptor agonist [d-Pen(2,5)]-enkephalin (DPDPE) at 10-40 microM induced less pronounced depressant respiratory effects, while no changes in respiratory activity were induced by the kappa-opioid receptor agonist trans-(1S,2S)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl] benzeneacetamide (U50488) at 10-40 microM. Bath application of the opioid receptor antagonists naloxone and naltrindole did not affect baseline respiratory activity, but prevented agonist-induced effects. DAMGO microinjections (1 mM; 0.5-1 nl) at sites rostrolateral to the trigeminal motor nucleus, where respiration-related neuronal activity was recorded, abolished the respiratory rhythm. The results show that opioids may have an important role in the lamprey respiratory network and that micro-opioid receptor activation is the most effective in causing respiratory depression. They also indicate that endogenous opioids are not required for the generation of baseline respiratory activity. Apneic responses induced by DAMGO microinjections support the hypothesis that a specific opioid-sensitive region rostrolateral to the trigeminal motor nucleus, that we have termed the paratrigeminal respiratory group (pTRG), likely has a pivotal role in respiratory rhythmogenesis. Since the lamprey diverged from the main vertebrate line around 450 million years ago, our results also imply that the inhibitory role of opioids on respiration is present at an early stage of vertebrate evolution.

Central nervous mechanisms in the generation of the pattern of breathing.

The role of the Bötzinger complex (BötC) and the pre-Bötzinger complex (pre-BötC) in the genesis of the breathing pattern was investigated in anesthetized, vagotomized, paralysed and artificially ventilated rabbits making use of bilateral microinjections of kainic acid (KA) and excitatory amino acid (EAA) receptor antagonists. KA microinjections into either the BötC or the pre-BötC transiently eliminated respiratory rhythmicity in the presence of tonic phrenic activity (tonic apnea). Rhythmic activity resumed as low-amplitude, high-frequency irregular oscillations, superimposed on tonic inspiratory activity and displayed a progressive, although incomplete recovery. Microinjections of kynurenic acid (KYN) and D(-)-2-amino-5-phosphonopentanoic acid (D-AP5) into the BötC caused a pattern of breathing characterized by low-amplitude, high-frequency irregular oscillations and subsequently tonic apnea. Responses to KYN and D-AP5 in the pre-BötC were similar, although less pronounced than those elicited by these drugs in the BötC and never characterized by tonic apnea. Microinjections of 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) into the BötC and the pre-BötC induced much less intense responses mainly consisting of increases in respiratory frequency. The results show that the investigated medullary regions play a prominent role in the genesis of the normal pattern of breathing through the endogenous activation of EAA receptors.

Fog-induced respiratory responses are attenuated by nedocromil sodium in humans.

Fog inhalation induces cough and bronchoconstriction in patients with asthma, but only cough in normal subjects; whether it also influences the pattern of breathing is unclear. Nedocromil sodium (NCS) inhibits the cough response to inhalation of several pharmacological agents but its effects on fog-induced cough and changes in the pattern of breathing are unknown. We evaluated the effects of no drug, placebo, and 4- and 8-mg NCS administration on the cough threshold and changes in the pattern of breathing during fog inhalation in 14 healthy subjects. Measurements of tidal volume (VT), duration of inspiratory and expiratory times (TI and TE, respectively), total duration of the respiratory cycle (TT), mean inspiratory flow (VT/TI), duty cycle (TI/TT), respiratory frequency (f, 60/TT), and inspiratory minute ventilation (V I) were obtained by inductive plethysmography. Median cough threshold values were unaffected by placebo, but were increased (p < 0.01) by both NCS doses. In no-drug and placebo trials, inhalation of the threshold fog concentration caused increases in both VT/TI and V I (p always < 0.05) due to selective increases (p < 0.01) in VT. These changes were markedly attenuated by both NCS doses administration. Thus, fog induces coughing and increases in VT, VT/ TI, and V I in healthy subjects; NCS possesses antitussive effects and attenuates fog-induced changes in the pattern of breathing, possibly through inhibition of rapidly adapting "irritant" receptors.

Respiratory neuronal activity during apnea and poststimulatory effects of laryngeal origin in the cat.

We investigated the behavior of medullary respiratory neurons in cats under pentobarbitone anesthesia, vagotomized, paralysed, and artificially ventilated to elucidate neural mechanisms underlying apnea and poststimulatory respiratory depression induced by superior laryngeal nerve (SLN) stimulation. Inspiratory neurons were completely inhibited during SLN stimulation and poststimulatory apnea. During recovery of inspiratory activity, augmenting inspiratory neurons were depressed, decrementing inspiratory neurons were excited, and late inspiratory neurons displayed unchanged bursts closely locked to the end of the inspiratory phase. Augmenting expiratory neurons were either silenced or displayed different levels of tonic activity during SLN stimulation; some of them were clearly activated. These expiratory neurons displayed activity during poststimulatory apnea, before the onset of the first recovery phrenic burst. Postinspiratory or decrementing expiratory neurons were activated during SLN stimulation; their discharge continued with a decreasing trend during poststimulatory apnea. The results support the three-phase theory of rhythm generation and the view that SLN stimulation provokes a postinspiratory apnea that could represent the inhibitory component of respiratory reflexes of laryngeal origin, such as swallowing. In addition, because a subpopulation of augmenting expiratory neurons displays activation during SLN stimulation, the hypothesis can be advanced that not only postinspiratory, or decrementing expiratory neurons, but also augmenting expiratory neurons may be involved in the genesis of apnea and poststimulatory phenomena. Finally, the increase in the activity of decrementing inspiratory neurons after the end of SLN stimulation may contribute to the generation of poststimulatory respiratory depression by providing an inhibitory input to bulbospinal augmenting inspiratory neurons.

Respiratory responses to thyrotropin-releasing hormone microinjected into the rabbit medulla oblongata.

We investigated the respiratory role of thyrotropin-releasing hormone (TRH) input to medullary structures involved in the control of breathing in anesthetized, vagotomized, paralyzed, and artificially ventilated rabbits. Microinjections (10-20 nl) of 1 or 10 mM TRH were performed in different regions of the ventral respiratory group (VRG), namely the rostral expiratory portion or Bötzinger complex (Böt. c.), the inspiratory portion, the transition zone between these two neuronal pools, and the caudal expiratory component. TRH microinjections were also performed in the dorsal respiratory group (DRG) and the area postrema (AP). Injection sites were localized by using stereotaxic coordinates and extracellular recordings of neuronal activity; their locations were confirmed by subsequent histological control. TRH microinjections in the Böt. c. and the directly caudally located region where a mix of inspiratory and expiratory neurons were encountered elicited depressant respiratory responses. TRH microinjections were completely ineffective at sites within the inspiratory and the caudal expiratory components of the VRG. TRH microinjections in either the DRG or the AP induced excitatory effects on inspiratory activity. The results show for the first time that TRH may exert inhibitory influences on respiration at medullary levels by acting on rostral expiratory neurons and that not only the DRG, as previously suggested, but also the AP may mediate TRH-induced excitatory effects on respiration.

Coughing in laryngectomized patients.

Ablation of the larynx implies withdrawal of afferent information from receptors involved both in the control of expiratory flow and in the genesis of protective airway reflexes including coughing. To investigate the effects of laryngectomy on the sensory and motor component of coughing, maximal voluntary cough (MVC) efforts as well as the reflex cough (RC) responses at threshold (T) and suprathreshold (1.8 x T, ST) levels induced by inhalation of progressively increasing concentrations of ultrasonically nebulized distilled water (fog) were analyzed in 10 laryngectomized patients and 10 control subjects. Cough intensity was indexed in terms of both the peak amplitude of the integrated electromyographic activity of abdominal muscles (IEMGP) and the ratio of IEMGP to the duration of the expiratory ramp (TEC), i.e., the rate of rise of IEMG activity (IEMGP/TEC). Cough peak flow was also recorded. Cough threshold was similar in patients and controls, as were IEMGP, TEC, and IEMGP/ TEC recorded during MVC and RCST. In contrast, during RCT, patients' IEMGP was significantly reduced (p < 0.05), thus leading to a significant decrease in IEMGP/TEC (p < 0.05) even in the absence of significant differences in TEC. Cough flow closely correlated with IEMG-related variables. Cough volume acceleration, i. e., the ratio of cough peak flow to the corresponding time to cough peak flow was also significantly reduced in the patients, especially during RCT (p < 0.01). The results suggest that the lack of signals arising from the larynx may result in a reduction of cough volume acceleration as well as in the intensity of abdominal muscle contractions during RCT. These factors may contribute to facilitate the onset and/or the persistence of chest infections in laryngectomized patients.

Repeatability of cough-related variables during fog challenges at threshold and suprathreshold stimulus intensity in humans.

Cough-related variables such as cough frequency, time to onset (i.e. the time until the first cough occurs) and the cough index (i.e. the ratio between the cough frequency and the time to onset) may be important when interpreting results of cough challenges for therapeutic interventions or for comparative research purposes. Nevertheless, repeatability (or reproducibility) for these widely used variables has been poorly studied. In thirty normal subjects, coughing was induced by inhalation of threshold (T) and suprathreshold (1.6 x T) concentrations of ultrasonically nebulized distilled water (fog). Cough threshold was taken as the lowest fog concentration that evoked at least one cough effort during two challenges separated by a 30-min interval. During challenges performed at both threshold and suprathreshold stimulus intensity, cough frequency, time to onset, and the cough index were assessed; within-subject repeatability for these variables was subsequently evaluated. Median +/- interquartile range cough threshold value was 0.9+/-0.5 mL x min(-1). During the two challenges performed to assess cough threshold, the mean +/-SD values of cough frequency, time to onset, and cough index were similar (5.0+/-2.7 and 5.3+/-3.1 coughs x min(-1), 32.4+/-13.3 and 32.9+/-13.6 s, and 0.2+/-0.2 and 0.2+/-0.2, respectively). However, none of these cough-related variables proved to be sufficiently repeatable. During the two challenges performed at suprathreshold stimulus intensity, mean values of cough frequency, time to onset, and cough index were also similar (20.0+/-9.0 and 18.2+/-10.2 coughs x min(-1), 13.5+/-5.8 and 12.0+/-4.62 s, and 1.7+/-1.0 and 1.8+/-1.2); furthermore, all considered variable of suprathreshold challenge turned out to be reproducible. In conclusion, during fog challenges at threshold stimulus intensity, cough frequency, time to onset and cough index cannot reliably be used for evaluating cough responses. However, these cough-related variables may represent useful and reliable research tools in the evaluation of suprathreshold cough responses.

Respiratory responses to chemical stimulation of the parabrachial nuclear complex in the rabbit.

The respiratory role of the parabrachial nuclear complex (PNC) was investigated in alpha-chloralose-urethane anesthetized, vagotomized, paralysed and artificially ventilated rabbits by means of unilateral microinjections (10-20 nl) of 20 mM dl-homocysteic acid. Chemical stimulation elicited three main types of site-specific respiratory effects: excitatory, apneustic and inhibitory responses. The results suggest that the PNC plays a complex role in the control of breathing.

Defective motor control of coughing in Parkinson's disease.

The high incidence of serious chest infections in patients with Parkinson's disease is unexplained, but an impairment in cough reflex may have a role. Maximal voluntary cough (MVC) and reflex cough (RC) to inhalation of ultrasonically nebulized distilled water were analyzed in patients with Parkinson's disease and age-matched control subjects by monitoring the integrated electromyographic activity (IEMG) of abdominal muscles. The peak amplitude of IEMG activity (IEMGP) was expressed as a fraction of the highest IEMGP value observed during MVC corrected to account for possible losses in abdominal muscle force due to reduced central muscle activation. Cough intensity was indexed in terms of both the IEMGP and the ratio of IEMGP to the duration of the expiratory ramp (TEC), i.e., the rate of rise of IEMG activity. Cough threshold was slightly higher in patients than in control subjects, but the difference failed to reach statistical significance. Compared with control subjects, patients displayed a lower IEMGP during maximal expiratory pressure maneuvers (PEmax), MVC, and RC (p always < 0.01); TEC during RC was longer (p < 0.01) than in controls. Consequently, the rate of rise of IEMG activity during cough was always lower in patients (p < 0. 01), especially during RC. Finally, PEmax, and both the peak and rate of rise of IEMG activity during RC were inversely related to the level of clinical disability (Spearman rank correlation coefficient, rs = -0.88, -0.86, and -0.85, respectively, p always < 0.01). The results indicate that the central neural mechanisms subserving the recruitment of motor units and/or the increase in their frequency of discharge during voluntary and, even more markedly, RC are impaired in patients with Parkinson's disease.

Area postrema glutamate receptors mediate respiratory and gastric responses in the rabbit.

The role of NMDA and non-NMDA receptors of the area postrema (AP) in the control of respiration and gastric motility was investigated in anaesthetized rabbits using microinjections (10-20 nl) of specific agonists or antagonists. NMDA (20 mM) or AMPA (10 mM) caused excitatory effects on respiration and gastric relaxation. Selective blockade of NMDA or non-NMDA receptors, respectively with D(-)-2-amino-5-phosphonopentanoic acid (D-AP5; 10 mM) and 6-nitro-7-sulphamoylbenzo(f)quinoxaline-2,3-dione (NBQX; 5 mM), decreased respiratory frequency and increased gastric tone. Both these effects were more marked following non-NMDA receptor blockade and were prevented by vagotomy. These findings show that NMDA and non-NMDA receptors are present on AP neurones and have a role in the tonic control of respiration and gastric motility.

Discharge patterns of Bötzinger complex neurons during cough in the cat.

This study was carried out on pentobarbital sodium-anesthetized, spontaneously breathing cats to address the hypothesis that Bötzinger complex (BötC) neurons are involved in the production of the cough motor pattern induced by mechanical stimulation of the tracheobronchial tree. Phrenic nerve and abdominal muscle activities as well as intratracheal pressure were monitored; single-unit extracellular recordings from BötC neurons (n = 87) were performed. The majority of augmenting expiratory (E-Aug) neurons encountered (n = 47) displayed excitatory responses during the expulsive phases of coughing in parallel with the main components of the abdominal bursts and the corresponding increases in tracheal pressure. We also encountered E-Aug neurons markedly depressed up to complete inhibition during coughing (n = 14) as well as E-Aug neurons assuming a decremental pattern without any increase or even with some reduction in their peak activity (n = 15). During the expiratory thrusts, most decrementing expiratory neurons (n = 7) presented excitatory responses, whereas others were depressed (n = 3) or completely inhibited (n = 1). The results are consistent with the view that these neurons are involved in the generation of the cough motor pattern and, in particular, that some BötC E-Aug neurons convey excitatory drive to caudal expiratory neurons and, hence, to expiratory motoneurons.

A noninvasive electromyographic study on threshold and intensity of cough in humans.

The assessment of cough threshold and intensity is important in respiratory medicine. We have developed a method for objectively and noninvasively assessing cough threshold and intensity of expiratory muscle efforts in response to inhalation of ultrasonically nebulized distilled water (UNDW). Thirty (83%) out of 36 volunteers studied coughed in response to UNDW inhalation. Cough threshold was taken as the lowest nebulizer output (mL x min(-1)) that induced cough in two challenges performed at a 30 min interval. At threshold level, repeatability of peak and slope of the integrated electromyographic (IEMG) activity of abdominal muscles was evaluated. Short- and long-term repeatability of cough threshold were evaluated in 15 subjects following a 3 h and a 6-9 month interval, respectively. Dose-response relationships between nebulizer outputs and IEMG-related variables were also investigated, as were the correlations between the latter and expiratory flow during voluntary coughing. The median (1st and 3rd quartile) cough threshold value was 0.89 (0.40 and 1.54) mL x min(-1). At threshold level, peak and slope of IEMG activity were highly reproducible. Cough threshold displayed a high degree of short- and long-term repeatability. Peak and slope of IEMG activity displayed a clear trend to increase (p<0.01) following inhalation of progressively higher UNDW outputs. Maximum flow during voluntary coughs of varying intensity correlated with the peak (p<0.05) and, more closely, with the slope (p<0.01) of abdominal IEMG activity. The assessment of cough threshold as well as the evaluation of the intensity of cough efforts by abdominal integrated electromyographic recordings may represent useful and reliable tools for cough research in humans.

Depressant effects on inspiratory and expiratory activity produced by chemical activation of Bötzinger complex neurons in the rabbit.

The respiratory role of the Bötzinger complex (Böt. c.) was investigated in alpha-chloralose-urethane or pentobarbitone anesthetized rabbits by means of microinjections of DL-homocysteic acid (DLH). The animals were either spontaneously breathing or vagotomized, paralysed and artificially ventilated. Both phrenic and abdominal activities were monitored; extracellular recordings from medullary respiration-related neurons were performed. Unilateral microinjections (5-30 nl) of DLH (160 mM) into the Böt. c., at sites where intense expiratory activity with an augmenting discharge pattern was encountered, provoked mild or moderate depressant effects on inspiratory activity characterized by decreases in frequency as well as in peak amplitude and rate of rise of phrenic nerve discharge. Stronger depressant effects up to complete apnea were consistently obtained in response to bilateral microinjections. Concomitant depressant effects on the activity of both expiratory motoneurons and expiration-related (ER) neurons of the caudal ventral respiratory group (cVRG) were observed. At variance with previous findings in the cat, the results indicate that chemical activation of Böt. c. augmenting ER neurons may exert inhibitory influences not only on inspiratory activity, but also on cVRG ER neurons and, hence, on expiratory motoneurons. The functional role of the Böt. c. in the control of respiration deserves further investigations; present findings suggest that the rabbit may profitably be used for such a purpose.

Effects of central chemical drive on poststimulatory respiratory depression of laryngeal origin in the adult cat.

We investigated the influences of central CO2-related chemosensory drive on poststimulatory respiratory phenomena induced by superior laryngeal nerve (SLN) stimulation in pentobarbitone-anesthetized, vagotomized, carotid sinus-denervated, paralyzed, and artificially ventilated adult cats. Respiratory output was monitored as integrated phrenic nerve activity. Under eucapnic conditions, apnea-producing SLN stimulations of both short (10 s) and long (30 s) duration were followed by persistent apnea and depression in phrenic motor output; the latter showed a gradual recovery that followed an exponential time course. Hypocapnia increased the duration of poststimulatory apnea and the intensity of poststimulatory depression in phrenic minute output owing to changes in peak phrenic activity. Hypercapnia did not affect the duration of poststimulatory apnea, but markedly attenuated poststimulatory depression in respiratory activity, mainly due to changes in respiratory frequency. The rate of respiratory recovery was similar under eucapnic and hypocapnic conditions, but it was slower during hypercapnia. The results provide evidence that central chemosensitivity plays a prominent role in counteracting poststimulatory depressant effects on respiration induced by SLN stimulation.

[Highlights in the subject of low frequency-high intensity TENS (review)]. / Attualità in tema di TENS a bassa frequenza-alta intensità (rassegna sull'argomento).

Transcutaneous electrical neural stimulation (l.f.-h.i. TENS), employed in dentistry, allows masticatory muscles relaxation, temporary clearance of muscular and periodontal proprioceptive input and even oro-facial pain relief. The mechanisms involved in this type of stimulation are not entirely clarified. According to the most recent neurophysiological researches, the authors describe several l.f.-h.i. TENS. action modalities. Some of them are well known such as the gate control theory, the endogenous antinociceptive system activation, the metabolic recovery of the muscular tissue and the unloading reflex. Other mechanisms, instead, are less known such as hypnosis and stress analgesia, exteroceptive suppression and counterirritation (DNIC). Some hypothetical mechanisms are also considered such as endogenous inhibition and sympathetic activity reduction.

Naloxone attenuates poststimulatory respiratory depression of laryngeal origin in the adult cat.

Poststimulatory depression in respiratory activity induced by superior laryngeal nerve (SLN) stimulation was quantitatively investigated in 20 adult cats. The role played in this phenomenon by endogenous opioids was studied using the opiate antagonist naloxone. The effects of hypercapnia on the same phenomenon were also investigated for comparison. Experiments were performed on cats anesthetized with pentobarbitone or alpha-chloralose, vagotomized, paralyzed, and artificially ventilated with 100% O2. Some animals were also carotid sinus denervated. Respiratory output was monitored as integrated phrenic nerve activity. SLN stimulation produced apnea, which outlasted the stimulation period; when respiration resumed, it was markedly depressed as revealed mainly by a decrease in phrenic minute output, respiratory frequency, and rate of rise of inspiratory activity. Phrenic output recovered gradually to control levels following an exponential time course. These effects varied as a function of the duration of SLN stimulation. Naloxone administration (0.8 mg/kg iv) significantly reduced the duration of poststimulatory apnea and attenuated the depression of phrenic minute output of the first recovery breath as a result of changes in peak phrenic activity; it also accelerated the time course of recovery. Hypercapnia did not affect the duration of poststimulatory apnea, but attenuated the initial poststimulatory depression because of changes in respiratory frequency; the rate of recovery was reduced. The results provide characterization of poststimulatory respiratory depression of laryngeal origin in the adult cat and suggest a role of endogenous opioids in its genesis or modulation.

Prostaglandin synthesis blockade by ketoprofen attenuates respiratory and cardiovascular responses to static handgrip.

We investigated the effects of prostaglandin synthesis blockade on the changes in breathing pattern, mean blood pressure (MBP), and heart rate (HR) elicited by 3 min of static handgrip at 30% of the maximum voluntary contraction in 12 healthy volunteers. Before each handgrip trial, subjects were treated with intravenous administration of either saline placebo (control) or 1 mg/kg of ketoprofen. Muscle tension and integrated electromyographic activity of exercising muscles remained fairly constant during each trial. In agreement with our earlier findings, during control handgrip minute ventilation progressively increased (P < 0.01) due to a rise in tidal volume and, to a lesser extent, in respiratory frequency. Mean inspiratory flow, MBP, and HR also increased (P < 0.01). End-tidal PCO2 decreased (P < 0.05) during the late phases of control handgrip bouts. Ketoprofen administration reduced serum thromboxane B2 levels (from 57.5 +/- 7.0 to 1.6 +/- 0.4 pg/ml; P < 0.01) and significantly attenuated mean increases in minute ventilation (40.25 +/- 0.60%), tidal volume (37.78 +/- 7.48%), respiratory frequency (55.94 +/- 17.92%), inspiratory flow (42.66 +/- 5.11%), MBP (22.33 +/- 6.82%), and HR (11.04 +/- 2.75%) during the 3rd min of handgrip. End-tidal PCO2 remained close to normocapnic levels. In agreement with previous animal investigations, the present results show that arachidonic acid metabolites are involved in the regulation of the cardiovascular responses to static efforts in humans, possibly through a stimulatory action on muscle receptors. Furthermore, they provide the first experimental evidence that products of the cyclooxygenase metabolic pathway play a role in the mediation of the respiratory adjustments elicited by this form of exercise.