Role of the vagal afferents in substance P-induced respiratory responses in anaesthetized rabbits

Since substance P (SP)-like immunoreactivity has been demonstrated in vagal sensory fibres of bronchopulmonary origin, it was considered of interest to (1) characterize the pattern of responses to SP injected into the pulmonary as well as the systemic arterial system, and (2) assess the types of vagal afferents that are affected by SP. Experiments were performed on 15 pentobarbital-anaesthetized, spontaneously breathing rabbits. Efferent phrenic nerve activity was monitored as an index of central respiratory neural output. Intra-atrial injections of SP into the pulmonary circulation (100 ng kg-1) increased the respiratory rate, and peak integrated phrenic amplitude by 47 +/- 8 and 40 +/- 4%, respectively, above the controls. In addition, SP elicited augmented breaths (ABs) within 2-3 s in 67% of the trials. In contrast to right atrial injections, no ABs and no significant changes in respiratory rate were observed in response to intra-aortic injections of SP (100 ng kg-1). Tidal phrenic activity rise after aortic injections of SP was significantly less as compared with right atrial administrations of SP. Since both routes of administration decreased the arterial blood pressure to the same extent, these respiratory responses were not likely secondary to cardiovascular changes. After administration of an SP antagonist (D-Arg-D-Trp7,9, Leu11, SP), respiratory responses to SP were significantly attenuated. Also, the rate of occurrence of ABs elicited by releasing the tracheal occlusions was reduced (control 95 vs. 14% SP antagonist). Bilateral vagotomy abolished the tachypnoeic response and reduced the magnitude of the phrenic nerve increments caused by right atrial injection of SP.(ABSTRACT TRUNCATED AT 250 WORDS)     

Role of sympathetics in the response to acute venous occlusion.

The effect of venous ligation and subsequent blockade of alpha receptors on hindlimb venous pressure, vascular resistance, oxygen extraction and carbon dioxide removal was evaluated in mongrel dogs with use of constant-flow perfusion of the extremity bed. Perfusion, metatarsal vein, femoral vein, and central vein pressures, and changes in paw and thigh circumference were recorded in mongrel dogs in which the hindlimb was perfused at a constant flow. Arterial, metatarsal venous, and femoral venous blood gases were drawn and analyzed for arteriovenous oxygen and carbon dioxide differences. Measurements were repeated following extensive ligation of veins and after subsequent alpha-receptor blockade with Dibenzyline. Findings indicated that ligation of extremity veins resulted in an active increase in total limb resistance upstream from the ligation, and an increase in volume of the limb. Following alpha-adrenergic blockade with Dibenzyline, limb volume increased and oxygen extraction decreased below control levels. The reflex constriction following ligation of veins protected against the detrimental effect of excessive accumulation of fluid in tissue spaces.     

Role of vagal afferents in vasodepressor effects of PGE2 in spontaneously hypertensive rats.

In anesthetized, spontaneously hypertensive rats (Okamoto-Aoki), injections of 0.75, 1.5, and 3.0 microgram/kg PGE2 into the jugular vein caused transient decreases (mean +/- SE) in arterial pressure of 21 +/- 2, 37 +/- 3, and 78 +/- 6 mmHg, respectively, before cervical vagotomy and of 1 +/- 1, 15 +/- 4, and 15 +/- 6 mmHg after cervical vagotomy. The vasodepressor effect of jugular vein injections of 3.0 microgram/kg PGE2, but not of lower doses, was depressed by vagotomy in normotensive Wistar-Kyoto and Sprague-Dawley rats. Vagotomy did not reduce the hypotensive response to intra-aortic injections of PGE2 in these hypertensive and normotensive rats. The depressor effect of PGE2 thus appears to have a significant reflex component mediated through cardiopulmonary receptors subserved by vagal afferents, with hypertensive rats exhibiting a lower threshold than normotensive rats. A vagally mediated reflex component to the depressor effect of PGE2 could not be demonstrated in normotensive rabbits or in rabbits and rats with chronic renovascular hypertension. Thus, a naturally occurring vasoactive substance can stimulate cardiopulmonary receptors subserved by vagal afferents in the rat, and spontaneously hypertensive rats appear to be especially sensitive to this effect.     

Cardiac receptors with non-medullated vagal afferents in the rat.

The characteristics of 22 atrial receptors in 15 normotensive adult male Wistar rats were investigated. All the receptor afferents were included in the C-fibre group with conduction velocities from 0.4 to 1.2 m/sec. No atrial medullated receptors or ventricular C-fibre endings were found. Two receptors were located in right atrium and 2 receptors throughout left atrium. Upon elevation of the left atrial pressure the receptor discharge was markedly elevated with thresholds from 2.5 to 9 mmHg in mean left atrial pressure. Ten of the atrial receptors displayed a clear cardiac rhythmicity upon activation and the discharge correlated with the v-wave, indicating distension as the cause of receptor activation. The maximal firing rate in most receptors was very high (up to 70 Hz), but 8 receptors had maximal firing rates below 25 Hz. These low frequency receptors had higher threshold and showed a more irregular firing. Thus, there is a substantial population of atrial receptors with vagal non-medullated afferents in the rat heart and the thresholds for many of these receptors are so low that they are likely to be active during normal conditions.     

When tonic cardiac vagal tone predicts changes in phasic vagal tone: The role of fear and perceptual load

We examined the relationship between tonic—a correlate of self‐regulatory functioning—and phasic cardiac vagal activity (indexed by heart rate variability; HRV) during a selective attentional task with varying levels of load. Participants detected a target letter among letter strings superimposed on either fearful or neutral face distractors. Letter strings consisted of six target letters under low load and one target letter and five nontarget letters under high load. With fearful distractors, lower tonic HRV was associated with phasic HRV suppression, suggesting an autonomic stress response under both low and high load. In contrast, higher tonic HRV was associated with phasic HRV enhancement, suggesting greater self‐regulatory effort under low load and an absence of phasic HRV suppression under high load. The current research suggests that tonic cardiac vagal tone is associated with the ability to flexibly adapt autonomic responses.     

Sensing pulmonary oxidative stress by lung vagal afferents

Oxidative stress in the bronchopulmonary airways can occur through a variety of inflammatory mechanisms and also following the inhalation of environmental pollutants. Oxidative stress causes cellular dysfunction and thus mammals (including humans) have developed mechanisms for detecting oxidative stress, such that defensive behavior and defensive biological mechanisms can be induced to lessen its potential damage. Vagal sensory nerves innervating the airways play a critical role in the detection of the microenvironment in the airways. Oxidative stress and associated compounds activate unmyelinated bronchopulmonary C-fibers, initiating action potentials in these nerves that conduct centrally to evoke unpleasant sensations (e.g. urge to cough, dyspnea, chest-tightness) and to stimulate/modulate reflexes (e.g. cough, bronchoconstriction, respiratory rate, inspiratory drive). This review will summarize the published evidence regarding the mechanisms by which oxidative stress, reactive oxygen species, environmental pollutants and lipid products of peroxidation activate bronchopulmonary C-fibers. Evidence suggests a key role for transient receptor potential ankyrin 1 (TRPA1), although transient receptor potential vanilloid 1 (TRPV1) and purinergic P2X channels may also play a role. Knowledge of these pathways greatly aids our understanding of the role of oxidative stress in health and disease and represents novel therapeutic targets for diseases of the airways.     

Modulation of gastro-oesophageal vagal afferents by galanin in mouse and ferret

The neuropeptide galanin is found in the central and peripheral nervous systems. It may have excitatory or inhibitory actions via three subtypes of G-protein-coupled receptor, and it modulates the mechanosensitivity of somatic sensory fibres. We aimed to determine if galanin also modulates vagal afferent mechanosensitivity, and to localize endogenous sources. The responses of ferret and mouse gastro-oesophageal vagal afferents to graded mechanical stimuli were investigated in vitro. The effects of galanin and/or the galanin receptor antagonist galantide on these responses were quantified. Immunohistochemistry for galanin was performed in ferret and mouse proximal stomach and nodose ganglion. In ferrets, retrograde labelling of gastric afferents to the nodose ganglion was combined with immunohistochemistry. When exposed to galanin (1–10 n m ), 18/31 ferret and 12/15 mouse gastro-oesophageal afferents (tension, mucosal and tension/mucosal receptors) showed inhibition of mechanosensitivity. Four of 31 ferret afferents showed potentiation of mechanosensitivity, and 9/31 were unaffected (2/15 and 1/15 in mouse, respectively). Galanin effects were reversed after washout or by galantide (10–30 n m ). Galantide given alone increased mechanosensitivity. Galanin immunoreactivity was found in nodose neurones, including those innervating the stomach in ferret. Enteric neurones were also galanin immunoreactive, as were endings associated with myenteric ganglia and smooth muscle. We conclude that galanin potently modulates mechanosensitivity of gastro-oesophageal vagal afferents with either facilitatory or inhibitory actions on individual afferent fibres. Both intrinsic and extrinsic (vagal) neurones contain galanin and are therefore potential sources of endogenous galanin.     

Cardiac receptors with non-medullated vagal afferents in the rat

The characteristics of 22 atrial receptors in 15 normotensive adult male Wistar rats were investigated. AH the receptor afferents were included in the C-fibre group with conduction velocities from 0.4 to 1.2 m/sec. No atrial medullated receptors or ventricular C-fibre endings were found. Two receptors were located in right atrium and 2 receptors throughout left atrium. Upon elevation of the left atrial pressure the receptor discharge was markedly elevated with thresholds from 2.5 to 9 mmHg in mean left atrial pressure. Ten of the atrial receptors displayed a clear cardiac rhythmicity upon activation and the discharge correlated with the v-wave, indicating distension as the cause of receptor activation. The maximal firing rate in most receptors was very high (up to 70 Hz), but 8 receptors had maximal firing rates below 25 Hz. These low frequency receptors had higher threshold and showed a more irregular firing. Thus, there is a substantial population of atrial receptors with vagal non-medullated afferents in the rat heart and the thresholds for many of these receptors are so low that they are likely to be active during normal conditions.     

Augmentation of muscle nociceptive respiratory reflex facilitation by vagal afferents

Vagal influence on the facilitation of phrenic neural activity during respiratory phase-locked, gastrocnemius muscle nerve nociceptive electrical stimulation was examined in anesthetized, glomectomized, paralyzed, and artificially ventilated cats. (1) In the vagi-intact state, respiratory reflex facilitation was characterized by a sharp rise in peak amplitude, maximum rate of rise or slope, and mean rate of rise of integrated phrenic nerve activity. This was greater during inspiratory phase-locked (T1-locked) muscle nerve electrical stimulation than during expiratory phase-locked (TE-locked) muscle nerve electrical stimulation. "Evoked post-inspiratory phrenic activity" during the early expiratory phase was also observed during TE-locked muscle nerve electrical stimulation. (2) Bilateral vagotomy significantly attenuated the respiratory facilitation during both T1- and TE-locked muscle nerve electrical stimulation. In particular, the "evoked post-inspiratory phrenic activity" during TE-locked muscle nerve electrical stimulation was also attenuated or almost completely abolished. (3) Conditioning electrical stimulation of the vagus nerve revealed facilitatory reflexes which co-exist with inspiratory inhibitory reflexes. (4) The "evoked post-inspiratory phrenic activity" during TE-locked muscle nerve electrical stimulation, which was attenuated or abolished after vagotomy, was restored after vagal T1-locked conditioning stimuli combined with TE-locked muscle nerve electrical stimulation. The results suggest that vagal facilitatory reflexes augment the respiratory reflex facilitation during muscle nociceptive stimulation.     

Multiple projection of vagal non-myelinated afferents to the anterior insular cortex in rats.

Projection of the vagal C-afferent to the insular cortex was examined in rats. Electrical activation of the C-afferent resulted in two cortical field potentials in the anterior insula. They were independent of each other and neither of them was attributed to the specific thalamic projection. These results imply that vagal information is conveyed to the cerebral cortex by more than one pathways.     

Gastric atropine-sensitive excitation by peripheral vagal stimulation after hexamethonium. Antidromic activation of afferents?

Experiments were performed in chloralosed cats with ligated adrenals with redording of arterial blood pressure, heart rate and gastric volume, the latter with a balloon method. Electric activation of the peripheral cut vagus at low and high intensity induced gastric excitatory and relaxatory responses, respectively. Hexamethonium blocked the stimulation-bound bradycardia but now high intensities induced excitatory gastric responses, resistant to a- and fi-adrenergic blocking agents and naloxone but sensitive to atropine. Heating of the intact vagus, to selectively activate thin afferents, resulted in gastric inhibition, due to vago-vagal reflex activation. When the nerve had been proximally cut, local nerve heating induced excitatory gastric responses, with the same pharmacological chnracteristics as those caused by electric nerve stimulation. The observations suggest that the hexamethonium-resistant gastric excitatory responses to peripheral vagal stimulation are due to antidromic activation of thin afferents which are proposed to function in axon reflexes affecting gastric motility.