Stimulation of the hypothalamic paraventricular nucleus modulates cardiorespiratory responses via oxytocinergic innervation of neurons in pre-Botzinger complex.

Previously we reported that oxytocin (OT)-containing neurons of the hypothalamic paraventricular nucleus (PVN) project to the pre-Bötzinger complex (pre-BötC) region and phrenic motoneurons innervating the diaphragm (D). The aim of these studies was to determine pathways involved in PVN stimulation-induced changes in upper airway and chest wall pumping muscle activity. In addition, we determined the role of OT-containing neurons in the PVN in mediating increased respiratory output elicited by PVN stimulation. Neuroanatomical experiments, using pseudorabies virus (PRV) as a transneuronal tracer in C8 spinalectomized animals showed that PVN neurons project to hypoglossal motoneurons innervating the genioglossus (GG) muscle. Furthermore, microinjection of the PVN with bicuculline, a GABA(A) receptor antagonist, significantly increased (P < 0.05) peak electromyographic activity of GG (GG(EMG)) and of D(EMG), frequency discharge, and arterial blood pressure (BP) and heart rate. Prior injection of OT antagonist [d-(CH(2))(5),Tyr(Me)(2),Orn(8)]-vasotocin intracisternally or blockade of OT receptors in the pre-BötC region with OT antagonist l-368,899, diminished GG(EMG) and D(EMG) responses and blunted the increase in BP and heart rate to PVN stimulation. These data show that PVN stimulation affects central regulatory mechanisms via the pre-BötC region controlling both respiratory and cardiovascular functions. The parallel changes induced by PVN stimulation were mediated mainly through an OT-OT receptor signaling pathway.

Effect of I1-imidazoline receptor activation on responses of hypoglossal and phrenic nerve to chemical stimulation.

Sedation elicited by some centrally acting antihypertensive agents may interfere with respiratory control, and by selectively inhibiting upper airway dilating muscle activity it may facilitate obstructive sleep apnea. Autoradiographic studies with [125I]p-iodoclonidine in the presence of 10 microM epinephrine to block alpha 2-adrenergic sites or 100 nM moxonidine to mask I1-imidazoline sites show that both I1- as well as alpha 2-sites are localized in putative chemosensory areas of the rostral ventrolateral medulla in the cat. We sought to determine the effect of activating I1 and alpha 2-receptors on central chemosensitivity by using moxonidine as a selective I1 agonist, clonidine as a mixed I1/alpha 2 agonist, SK&F-86466 as a specific alpha 2-antagonist, and efaroxan as a mixed I1/alpha 2 antagonist. We recorded responses of phrenic, hypoglossal, and cervical sympathetic nerve activities to progressive hypercapnia after hyperventilation to apnea. Moxonidine (3-100 micrograms/kg i.v.) caused dose-dependent decreases in tonic cervical sympathetic nerve activity and blood pressure, but had no effect on the CO2 threshold (after 30 or 100 micrograms/kg moxonidine, phrenic nerve activity reappeared at 5.8 +/- 0.2% CO2 versus 5.6 +/- 0.3% CO2 in control). Following moxonidine, the slope of the steep portion of the CO2 response tended to increase (10.3 +/- 1.8 versus 7.3 +/- 0.9). Peak phrenic nerve activity was comparable to control at 7.5% CO2 (20 +/- 2 U in control) and at 9.5% CO2 (30 +/- 3 versus 27. +/- 2 U). Similarly, the response of hypoglossal and inspiratory phasic cervical sympathetic nerve activity to a progressive CO2 rise was not affected by moxonidine. By contrast, clonidine in the same doses decreased CO2 sensitivity, because the CO2 threshold was elevated from 5.3 +/- 0.5% to 6.7 +/- 0.4% (p < 0.001). The slope of the CO2 response was decreased from 9.7 +/- 1.9 to 7.4 +/- 1.3 (p = 0.05). Peak phrenic nerve activity was reduced at 7.5% CO2 (11 +/- 5 versus 25 +/- 2 U; p < 0.05) and at 9.5% CO2 (21 +/- 4 versus 33 +/- 2 U; p = 0.06). Clonidine selectively inhibited the response of hypoglossal nerve activity to CO2. The depressive effects of clonidine were reversed by alpha 2-blockade with SK&F-86466 (0.5 or 1 mg/kg). Inspiratory phasic cervical sympathetic nerve activity increased after SK&F-86466 in parallel with phrenic and hypoglossal nerve activity, but the tonic component of cervical sympathetic nerve activity and blood pressure increased only transiently.(ABSTRACT TRUNCATED AT 400 WORDS)

Moxonidine acting centrally inhibits airway reflex responses.

We examined the role of I1-imidazoline (I1-IR) receptors in control of airway function, by testing the effects of systemic administration of the I1-IR agonist moxonidine on reflex responses of tracheal smooth muscle (TSM) tone to either lung deflation or mechanical stimulation of intrapulmonary rapidly adapting receptors. Experiments were performed in either alpha-chloralose anesthetized or decorticate, paralyzed, and mechanically ventilated beagle dogs. Moxonidine (10-100 micrograms/kg) administered via three different routes (femoral vein, muscular branch of superior thyroid artery, and vertebral artery) attenuated TSM responses to stimulation of airway sensory nerve fibers by two different ways and caused a decrease in arterial pressure and heart rate. These effects were dose dependent and were significantly reversed by efaroxan (an I1-IR and alpha 2-adrenergic blocker) administered via the vertebral artery. Intravertebral efaroxan abolished the hemodynamic effects of moxonidine. Intravenous moxonidine (10-100 micrograms/kg) did not alter airway smooth muscle responses to electrical stimulation of the peripheral vagus nerve. In addition, in vitro moxonidine (1-100 micrograms/ml) had no effect on contractile responses to increasing doses of acetylcholine. These findings indicate that moxonidine may act at a central site to suppress reflex airway constriction, even when given into the systemic circulation. Given the presence of I1-IR sites and alpha 2-adrenergic receptors in brain regions participating in airway reflexes, these receptor classes may be involved in brainstem control of the cholinergic outflow to the airways.

Chronic recordings of hypoglossal nerve activity in a dog model of upper airway obstruction.

The activity of the hypoglossal nerve was recorded during pharyngeal loading in sleeping dogs with chronically implanted cuff electrodes. Three self-coiling spiral-cuff electrodes were implanted in two beagles for durations of 17, 7, and 6 mo. During quiet wakefulness and sleep, phasic hypoglossal activity was either very small or not observable above the baseline noise. Applying a perpendicular force on the submental region by using a mechanical device to narrow the pharyngeal airway passage increased the phasic hypoglossal activity, the phasic esophageal pressure, and the inspiratory time in the next breath during non-rapid-eye-movement sleep. The phasic hypoglossal activity sustained at the elevated level while the force was present and increased with increasing amounts of loading. The hypoglossal nerve was very active in rapid-eye-movement sleep, especially when the submental force was present. The data demonstrate the feasibility of chronic recordings of the hypoglossal nerve with cuff electrodes and show that hypoglossal activity has a fast and sustained response to the internal loading of the pharynx induced by applying a submental force during non-rapid-eye-movement sleep.

Influence of ventrolateral surface of medulla on tracheal gland secretion.

Airway secretion can be modified reflexly as well as locally. Previous studies indicate that neurons in a circumscribed region near the ventral surface of the medulla (VMS) can substantially modify airway tone and reflex responses to vagal inputs. In the present studies we assessed the importance of these neurons on tracheal gland secretion. We examined the changes in the number of hillocks of secretion appearing from submucosal glands in an exposed field of tracheal epithelium (1.2 cm2) coated with tantalum dust before and after interventions on the VMS. Experiments were performed in alpha-chloralose-anesthetized dogs paralyzed and ventilated with 40% O2. Stimulation of nicotinergic receptors by application of a pledget containing nicotine in 11 dogs caused a significant elevation in tracheal gland secretion in the subsequent 60 s, compared with a control period in which buffered saline was applied. Prior application of lidocaine or hexamethonium bromide to the VMS blocked the effect of topically applied nicotine. The central effects of nicotine were diminished by atropine methylnitrate given intravenously. In addition, lidocaine application to the VMS or focal cooling of intermediate areas to between 20 and 15 degrees C significantly decreased secretion rates reflexly produced by capsaicin-induced stimulation of pulmonary C-fiber receptors and by mechanical stimulation of the carina and larynx. These findings suggest that the ventral medulla contains cells near its surface that influence tracheal fluid secretion and modulate reflex responses of airway submucosal glands, probably by altering the level of general excitation within the central respiratory integrating circuits.

Reflex responses of laryngeal and pharyngeal submucosal glands in dogs.

In dogs tracheal secretion is enhanced reflexly and by locally acting mediators such as substance P (SP). To evaluate the role of these mechanisms on submucosal gland secretion in the larynx (L) and pharynx (Ph), we compared the effects of mechanical stimulation of intrapulmonary irritant receptors and stimulation of pulmonary C-fiber receptors by capsaicin (20 micrograms/kg iv) with the response produced by intravenous SP. In six alpha-chloralose-anesthetized, paralyzed, and artificially ventilated dogs, submucosal gland secretion was monitored by analyzing the areas covered by hillocks of liquid and calculating the volume of secreted liquid (microliter) in the L and Ph. Mechanical stimulation of the carina increased both the number of hillocks and the volume of secreted liquid in the L. Excitation of pulmonary C-fiber receptors also increased the number of hillocks, and total volume of secreted liquid was elevated from 1.9 +/- 0.5 to 8.3 +/- 1.4 microliters (P less than 0.01). These responses were significantly reduced by prior cervical vagotomy and intravenous administration of atropine. Neither stimulation of irritant receptors nor stimulation of pulmonary C-fiber receptors caused discernible effects on Ph submucosal gland secretion. However, intravenous SP increased the number of Ph hillocks and elevated the volume of secreted Ph liquid from 1.0 +/- 0.6 to 10.2 +/- 1 microliters (P less than 0.01); similar responses to intravenous SP were observed in the L. Prior intravenous administration of atropine methylnitrate or bilateral vagotomy did not alter Ph or L secretory responses to intravenous SP.(ABSTRACT TRUNCATED AT 250 WORDS)

Relation between upper airway volume and hyoid muscle length.

Previous studies have suggested that the geniohyoid and sternohyoid muscles act to enlarge the upper airway. If correct, there should be an inverse relation between upper airway volume and the length of hyoid muscles. To test this, known volumes of air were injected into or removed from the isolated sealed upper airway of eight pentobarbital sodium-anesthetized cats, and the resultant changes in geniohyoid and sternohyoid length were measured using sonomicrometry. Increases in upper airway volume shortened the geniohyoid in all cats (P less than 0.001) and shortened the sternohyoid in seven of eight cats (P less than 0.01); mean geniohyoid shortening (as a % of resting length) exceeded that of the sternohyoid. Decreases in upper airway volume lengthened the geniohyoid in all cats (P less than 0.001) but caused variable changes in sternohyoid length. Extension of the neck increased the resting lengths of both the geniohyoid (P less than 0.001) and sternohyoid (P less than 0.002). Neck flexion shortened the resting length of both hyoid muscles (P less than 0.001 for both), with the geniohyoid shortening more (as a % of resting length) than the sternohyoid (P less than 0.005). Progressive flexion of the neck from 180 to 90 degrees caused progressive increases in the ratio of changes in muscle length to changes in upper airway volume during airway inflation but did not affect this relation during airway deflation.(ABSTRACT TRUNCATED AT 250 WORDS)

Mechanical function of hyoid muscles during spontaneous breathing in cats.

We assessed the mechanical behavior of the geniohyoid and sternohyoid muscles during spontaneous breathing using sonomicrometry in anesthetized cats. When the animals breathed O2, the hyoid muscles either became longer or did not change length (but never shortened) during inspiration. During progressive hyperoxic hypercapnia, transient increases in geniohyoid muscle inspiratory lengthening occurred in many animals; however, at high PCO2 the geniohyoid invariably shortened during inspiration (mean 4.9% of resting length at the end of CO2 rebreathing; P less than 0.001). The PCO2 at which geniohyoid inspiratory lengthening changed to inspiratory shortening was significantly higher than the CO2 threshold for the onset of geniohyoid electrical activity (P less than 0.01). For the sternohyoid muscle, hypercapnia caused inspiratory lengthening in 13 of 17 cats and inspiratory shortening in 4 of 17 cats; on average the sternohyoid lengthened by 1.6% of resting length at the end of CO2 rebreathing (P less than 0.01). Sternohyoid lengthening occurred in spite of this muscle being electrically active. These results suggest that the relationship between hyoid muscle electrical activity and respiratory changes in length is very complex, so that the presence of hyoid muscle electrical activity does not necessarily indicate muscle shortening, and among the geniohyoid and sternohyoid muscles, the geniohyoid has a primary role as a hypopharyngeal dilator in the spontaneously breathing cat, with the sternohyoid muscle acting in an accessory capacity.

Response of upper airway and chest wall muscles to selective brain stem hypoxia in the newborn.

In animals with intact peripheral chemosensory afferents, hypoxia differentially affects upper airway (UA) and chest wall muscles. To determine the contribution of brain stem (BS) hypoxia to the response of UA and chest wall muscles during early life, we perfused the BS through a vertebral artery intermittently with blood from an extracorporeal circuit in nine newborn piglets (age 1-5 days). BS perfusions were performed with hypoxemic blood (arterial PO2 32 +/- 6 to 38 +/- 8 Torr) with different levels of BS PCO2 (28 +/- 2, 37 +/- 4, and 56 +/- 5 Torr) while systemic normocapnic hyperoxia was maintained (arterial PCO2 36 +/- 3 to 40 +/- 6 Torr, arterial PO2 345 +/- 73 to 392 +/- 37 Torr). Electromyograms (EMGs) of alae nasi (AN), external intercostal (EI), and diaphragm (DIA) were recorded. Normocapnic hypoxia of the BS induced a sustained increase in AN EMG (P < 0.01, analysis of variance) and depression of EI and DIA EMGs without a transient increase. These contrasting responses were also observed during hypocapnic and hypercapnic hypoxia of the BS and were not affected by inputs from the peripheral chemoreceptors or rostral cerebral structures that were not exposed to hypoxia. We conclude that, despite eliciting the known central respiratory depression, BS hypoxia causes an increase in the respiratory drive to an UA airway muscle. Thus, BS hypoxia elicits a selective rather than a generalized respiratory muscle depression. The respiratory muscles with high energy expenditure (DIA and EI) are depressed while UA muscles are stimulated or disinhibited. This response is independent of the level of BS arterial PCO2.

Effects of tracheal airway occlusion on hyoid muscle length and upper airway volume.

Complex relationships exist among electromyograms (EMGs) of the upper airway muscles, respective changes in muscle length, and upper airway volume. To test the effects of preventing lung inflation on these relationships, recordings were made of EMGs and length changes of the geniohyoid (GH) and sternohyoid (SH) muscles as well as of tidal changes in upper airway volume in eight anesthetized cats. During resting breathing, tracheal airway occlusion tended to increase the inspiratory lengthening of GH and SH. In response to progressive hypercapnia, the GH eventually shortened during inspiration in all animals; the extent of muscle shortening was minimally augmented by airway occlusion despite substantial increases in EMGs. SH lengthened during inspiration in six of eight animals under hypercapnic conditions, and in these cats lengthening was greater during airway occlusion even though EMGs increased. Despite the above effects on SH and GH length, upper airway tidal volume was increased significantly by tracheal occlusion under hypercapnic conditions. These data suggest that the thoracic and upper airway muscle reflex effects of preventing lung inflation during inspiration act antagonistically on hyoid muscle length, but, because of the mechanical arrangement of the hyoid muscles relative to the airway and thorax, they act agonistically to augment tidal changes in upper airway volume. The augmentation of upper airway tidal volume may occur in part as a result of the effects of thoracic movements being passively transmitted through the hyoid muscles.

Spiral nerve cuff electrode for recordings of respiratory output.

The feasibility of using the spiral nerve cuff electrode design for recordings of respiratory output from the hypoglossal (HG) and phrenic nerves is demonstrated in anesthetized, paralyzed, and artificially ventilated cats. Raw neural discharges of the HG nerve were analyzed in terms of signal-to-noise ratios and frequency spectra. The rectified and integrated moving average activity of the HG nerve had a peak value of 1.74 +/- 0.21 microV and a baseline value of 0.72 +/- 0.11 microV at elevated respiratory drive induced by increases in CO2 or oxygen deprivation when recorded with 10-mm-long cuffs. The frequency content of the HG electroneurogram extended from several hundred hertz to 6 kHz. Spiral nerve cuff recordings without desheathing of the nerve provided large enough signal-to-noise ratios that allowed them to be used as a measure of respiratory output and had much wider frequency bandwidths than the hook electrode preparations. A major advantage of the cuff electrode over the hook electrode was its mechanical stability, which significantly improved the reproducibility of the recordings both in terms of signal amplitudes and frequency contents.

Role of costal and crural diaphragm and parasternal intercostals during coughing in cats.

The inspiratory phase of coughs often consists of large inspired volumes and increased motor discharge to the costal diaphragm. Furthermore, diaphragm electrical activity may persist into the early expiratory portion of coughs. To examine the role of other inspiratory muscles during coughing, electromyograms (EMG) recorded from the crural diaphragm (Dcr) and parasternal intercostal (PSIC) muscles were compared to EMG of the costal diaphragm (Dco) in anesthetized cats. Tracheal or laryngeal stimulation typically produced a series of coughs, with variable increases in peak inspiratory EMGs of all three muscles. On average, peak inspiratory EMG of Dco increased to 346 +/- 60% of control (P less than 0.001), Dcr to 514 +/- 82% of control (P less than 0.0002), and PSIC to 574 +/- 61% of control (P less than 0.0005). Augmentations of Dcr and PSIC EMG were both significantly greater than of Dco EMG (P less than 0.05 and P less than 0.002, respectively). In most animals, EMG of Dco correlated significantly with EMG of Dcr and of PSIC during different size coughs. Electrical activity of all three muscles persisted into the expiratory portions of many (but not all) coughs. The duration of expiratory activity lasted on average 0.17 +/- 0.03 s for Dco, 0.25 +/- 0.06 s for Dcr, and 0.31 +/- 0.09 s for PSIC. These results suggest that multiple respiratory muscles are recruited during inspiration of coughs, and that the persistence of electrical activity into expiration of coughs is not unique to the costal diaphragm.

Influence of respiratory drive on airway responses to excitation of lung C-fibers.

To determine whether the responses of tracheal smooth muscle and the nasal vasculature to stimulation of lung C-fiber receptors depend on the level of respiratory drive, the effects of right atrial injection of capsaicin and phenyldiguanide were studied in chloralose-anesthetized, paralyzed, artificially ventilated cats. Studies were performed while the animals were hyperventilated to apnea and, in addition, when breathing was stimulated by inhalation of 7% CO2 or by N-methyl-D-aspartic acid (NMDA) applied to the ventral surface of the medulla. When the cats were hyperventilated to apnea with O2, injection of capsaicin into the right atrium increased tracheal tone and slightly raised nasal resistance. However, when the animals were ventilated with 7% CO2 in O2 or respiratory activity was stimulated by the application of NMDA, administration of capsaicin eliminated spontaneous phrenic nerve activity and caused an abrupt decrease in tracheal tone but still increased nasal resistance. Similar responses were also obtained with right atrial injection of phenyldiguanide. These results showed for the first time that in the cat the direction of the reflex effects on tracheal tone but not nasal resistance depends on the preexisting level of respiratory drive and on cholinergic activity to airway smooth muscle.

Central action of tachykinins on activity of expiratory pumping muscles.

The central effects of tachykinins (substance P, neurokinin A, and neurokinin B) on the distribution of the motor activity to rib cage and abdominal expiratory muscles were studied in anesthetized tracheotomized spontaneously breathing dogs and cats. Intracisternal application of substance P (11 dogs) in doses of 10(-5) to 10(-4) M caused diaphragm electrical activity to change insignificantly from 19.3 +/- 1.9 to 24.8 +/- 3.2 units (P greater than 0.05), produced a moderate increase of triangularis sterni activity from 12.6 +/- 2.2 to 19.2 +/- 2.2 units (P less than 0.05), and stimulated a large increase of transversus abdominis activity from 9.4 +/- 2.7 to 28.5 +/- 2.6 units (P less than 0.01). Comparable effects were seen with similar doses of neurokinin A (8 dogs) and neurokinin B (3 dogs) administered intracisternally. Local application of substance P to the ventral medullary surface (5 dogs and 4 cats) also caused expiratory muscle activity to increase more than diaphragm activity, and in addition transversus abdominis activity increased to a larger extent than triangularis sterni activity. Furthermore, administration of the substance P antagonist [D-Pro2,D-Trp7,9]-SP to the ventral medullary surface decreased respiratory motor output, with expiratory muscles activity being attenuated to a greater extent than diaphragm activity. Application of neurotensin and N-methyl-D-asparate to the ventral surface of the medulla produced responses similar to those observed as a result of central administration of tachykinin peptides. The results suggest that 1) mammalian tachykinins are involved in the regulation of thoracic and abdominal expiratory muscle activity, 2) these muscles manifest substantial differences in their electrical responses to excitatory neuropeptides acting centrally, and 3) inputs from modulatory neurons located in this vicinity of the ventral medullary surface seem to be distributed unevenly to different expiratory premotor and/or motoneurons.

Respiratory changes in nasal muscle length.

Respiratory changes in alae nasi muscle length were recorded using sonomicrometry in pentobarbital sodium-anesthetized tracheostomized dogs spontaneously breathing 100% O2. Piezoelectric crystals were inserted via small incisions into the alae nasi of 11 animals, and bipolar fine-wire electrodes were inserted contralaterally in nine of the same animals. The alae nasi shortened during inspiration in all animals. The mean amount of shortening was 1.33 +/- 0.22% of resting length (LR), and the mean velocity of shortening during the first 200 ms was 4.60 +/- 0.69% LR/S. The onset of alae nasi shortening preceded inspiratory flow by 77 +/- 18 ms (P less than 0.002), at which time both alae nasi shortening and the moving average of electromyographic (EMG) activity had reached approximately one-third of their peak values. In contrast, there was a relative delay in alae nasi relaxation relative to the decay of alae nasi EMG at the end of expiration. Single-breath airway occlusions at end expiration changed the normally rounded pattern of alae nasi shortening and moving average EMG to a late-inspiratory peaking pattern; both total shortening and EMG were increased by similar amounts. The onset of vagally mediated volume-related inhibition of alae nasi shortening occurred synchronously with the onset of inhibition of alae nasi EMG; both occurred at lung volumes substantially below tidal volume. These results indicate that the pattern of inspiratory shortening of this nasal dilating muscle is reflected closely in the pattern of EMG activity and that vagal afferents cause substantial inhibition of alae nasi inspiratory shortening.

Differential cardiorespiratory control elicited by activation of ventral medullary sites in mice.

We studied the respiratory and blood pressure responses to chemical stimulation of two regions of the ventral brainstem in mice: the rostral and caudal ventrolateral medulla (RVLM and CVLM, respectively). Stimulation of the RVLM by microinjections of the excitatory amino acid L-glutamate induced increases in diaphragm activity and breathing frequency, elevation of blood pressure (BP), and a slight increase in heart rate (HR). However, activation of the CVLM induced a decrease in breathing frequency, mainly due to prolongation of expiratory time (TE), and hypotension associated with a slight slowing of HR. Because adrenergic mechanisms are known to participate in the control of respiratory timing, we examined the role of alpha(2)-adrenergic receptors in the RVLM region in mediating these inhibitory effects. The findings demonstrated that blockade of the alpha(2)-adrenergic receptors within the RVLM by prior microinjection of SKF-86466 (an alpha(2)-adrenergic receptor blocker) significantly reduced changes in TE induced by CVLM stimulation but had little effect on BP responses. These results indicate that, in mice, activation of the RVLM increases respiratory drive associated with an elevation of BP, but stimulation of CVLM induces prolongation of TE via an alpha(2)-adrenergic signal transduction pathway.

Central and spinal effects of sodium cyanide on respiratory activity.

The pharmacological actions of cyanide on respiratory activity have been known for some time and are attributed mainly to effects on peripheral chemoreceptors. In the studies reported here, we have examined the acute central effects of cyanide when applied topically to the ventral surface of the medulla (VMS) and when administered into the spinal intrathecal space at the C5-T3 level on activities of the phrenic nerve, diaphragm, parasternal intercostal, triangularis sterni, and transversus abdominis muscles. Topical application of 10-100 micrograms (10 microliters of 1-10 mg/ml) cyanide to the intermediate area of the VMS decreased respiratory activity by > 50%, and expiratory muscles were more sensitive to inhibition than inspiratory muscles. The onset of depression of phrenic nerve or respiratory muscle activity occurred within 20 s of administration, and the effects reversed after washout. In contrast, intrathecal administration of cyanide in doses of 10-100 micrograms (100 microliters of 0.1-1 mg/ml) increased electrical activity of the respiratory muscles. Diaphragm activity changed from 17 +/- 2 to 42 +/- 8 (SE) units (P < 0.01), parasternal intercostal activity increased from 18 +/- 3 to 46 +/- 9 units (P < 0.01), and expiratory activity of the chest wall and abdominal muscles increased from 9 +/- 2 to 39 +/- 10 units (P < 0.05). Both topical application on the VMS and intrathecal administration of cyanide caused an increase in arterial blood pressure and a slight insignificant acceleration of heart rate. These data suggest that cyanide acting on the VMS causes respiratory depression and enhancement of sympathetic outflow.(ABSTRACT TRUNCATED AT 250 WORDS)

Pathways and mechanisms involved in neural control of laryngeal submucosal gland secretion.

The purpose of this study was to define the pathways and mechanisms involved in the neural regulation of laryngeal mucosal gland functions. In anesthetized, paralyzed, and artificially ventilated dogs, the responses of laryngeal submucosal glands to stimulation of laryngeal mechanoreceptors and peripheral chemoreceptors were examined by measuring the number of hillocks and volume of secreted fluid before and after activation of sensory nerve endings. Compared with a control period, the number of hillocks and volume of secreted fluid significantly increased (P < 0.05) with mechanical stimulation of the vocal folds (n = 13) and with chemical activation of peripheral chemoreceptors by systemic administration of sodium cyanide (100 micrograms/kg; n = 11). The reflex responses induced by vocal fold stimulation and activation of peripheral chemoreceptors were slightly decreased by interrupting transmission in the recurrent laryngeal nerves (P > 0.05) and were abolished by subsequent sectioning of superior laryngeal nerves or prior intravenous administration of atropine methylnitrate (P < 0.05). In denervated animals, topical application of nicotine on laryngeal epithelium caused significant activation of submucosal glands (P < 0.05). We conclude that laryngeal secretion can be significantly altered reflexly by stimulation of laryngeal sensory nerve endings and peripheral chemoreceptors, that both superior and recurrent laryngeal nerves convey cholinergic outflow to laryngeal submucosal glands, and that nicotine acting locally activates laryngeal submucosal glands.

Respiratory changes in thoracic muscle length during bronchoconstriction.

The purpose of the present study was to assess the effects of bronchoconstriction on respiratory changes in length of the costal diaphragm and the parasternal intercostal muscles. Ten dogs were anesthetized with pentobarbital sodium and tracheostomized. Respiratory changes in muscle length were measured using sonomicrometry, and electromyograms were recorded with bipolar fine-wire electrodes. Administration of histamine aerosols increased pulmonary resistance from 6.4 to 14.5 cmH2O X l-1 X s, caused reductions in inspiratory and expiratory times, and decreased tidal volume. The peak and rate of rise of respiratory muscle electromyogram (EMG) activity increased significantly after histamine administration. Despite these increases, bronchoconstriction reduced diaphragm inspiratory shortening in 9 of 10 dogs and reduced intercostal muscle inspiratory shortening in 7 of 10 animals. The decreases in respiratory muscle tidal shortening were less than the reductions in tidal volume. The mean velocity of diaphragm and intercostal muscle inspiratory shortening increased after histamine administration but to a smaller extent than the rate of rise of EMG activity. This resulted in significant reductions in the ratio of respiratory muscle velocity of shortening to the rate of rise of EMG activity after bronchoconstriction for both the costal diaphragm and the parasternal intercostal muscles. Bronchoconstriction changed muscle end-expiratory length in most animals, but for the group of animals this was statistically significant only for the diaphragm. These results suggest that impairments of diaphragm and parasternal intercostal inspiratory shortening occur after bronchoconstriction; the mechanisms involved include an increased load, a shortening of inspiratory time, and for the diaphragm possibly a reduction in resting length.

Role of triangularis sterni during coughing and sneezing in dogs.

Studies in mammals have found that during breathing the triangularis sterni (TS) muscle regulates expiratory airflow and the end-expiratory position of the rib cage and furthermore that the respiratory activity of this muscle is influenced by a variety of chemical and mechanical stimuli. To assess the role of the TS during coughing and sneezing, electromyograms (EMGs) recorded from the TS were compared with EMGs of the transversus abdominis (TA) in eight pentobarbital-anesthetized dogs. During coughing induced by mechanically stimulating the trachea or larynx (n = 7 dogs), peak EMGs increased from 23 +/- 2 to 74 +/- 5 U (P less than 0.00002) for the TS and from 21 +/- 6 to 66 +/- 4 U (P less than 0.0002) for the TA. During sneezing induced by mechanically stimulating the nasal mucosa (n = 3 dogs), peak EMG of the TS increased from 10 +/- 3 to 66 +/- 7 U (P less than 0.005) and peak EMG of the TA increased from 10 +/- 2 to 73 +/- 7 U (P less than 0.02). For both muscles the shape of the EMG changed to an early peaking form during coughs and sneezes. Peak expiratory airflow during coughs of different intensity correlated more closely with peak TS EMG in three dogs and with peak TA EMG in four dogs; peak expiratory airflow during sneezes of different intensity correlated more closely with peak TS than TA EMG in all three animals. These results suggest that the TS is actively recruited during coughing and sneezing and that different neuromuscular strategies may be utilized to augment expiratory airflow.