Nociceptive pulmonary-cardiac reflexes are altered in the spontaneously hypertensive rat.

KEY POINTS: We investigated the cardiovascular and respiratory responses of the normotensive Wistar-Kyoto (WKY) rat and the spontaneously hypertensive (SH) rat to inhalation and intravenous injection of the noxious stimuli allyl isothiocyanate (AITC). AITC inhalation evoked atropine-sensitive bradycardia in conscious WKY rats, and evoked atropine-sensitive bradycardia and atenolol-sensitive tachycardia with premature ventricular contractions (PVCs) in conscious SH rats. Intravenous injection of AITC evoked bradycardia but no tachycardia/PVCs in conscious SHs, while inhalation and injection of AITC caused similar bradypnoea in conscious SH and WKY rats. Anaesthesia (inhaled isoflurane) inhibited the cardiac reflexes evoked by inhaled AITC but not injected AITC. Data indicate the presence of a de novo nociceptive pulmonary-cardiac reflex triggering sympathoexcitation in SH rats, and this reflex is dependent on vagal afferents but is not due to steady state blood pressure or due to remodelling of vagal efferent function. ABSTRACT: Inhalation of noxious irritants/pollutants activates airway nociceptive afferents resulting in reflex bradycardia in healthy animals. Nevertheless, noxious pollutants evoke sympathoexcitation (tachycardia, hypertension) in cardiovascular disease patients. We hypothesize that cardiovascular disease alters nociceptive pulmonary-cardiac reflexes. Here, we studied reflex responses to irritants in normotensive Wistar-Kyoto (WKY) rats and spontaneously hypertensive (SH) rats. Inhaled allyl isothiocyanate (AITC) evoked atropine-sensitive bradycardia with atrial-ventricular (AV) block in conscious WKY rats, thus indicating a parasympathetic reflex. Conversely, inhaled AITC in conscious SH rats evoked complex brady-tachycardia with both AV block and premature ventricular contractions (PVCs). Atropine abolished the bradycardia and AV block, but the atropine-insensitive tachycardia and PVCs were abolished by the ß1 -adrenoceptor antagonist atenolol. The aberrant AITC-evoked reflex in SH rats was not reduced by acute blood pressure reduction by captopril. Surprisingly, intravenous AITC only evoked bradycardia in conscious SH and WKY rats. Furthermore, anaesthesia reduced the cardiac reflexes evoked by inhaled but not injected AITC. Nevertheless, anaesthesia had little effect on AITC-evoked respiratory reflexes. Such data suggest distinct differences in nociceptive reflex pathways dependent on cardiovascular disease, administration route and downstream effector. AITC-evoked tachycardia in decerebrate SH rats was abolished by vagotomy. Finally, there was no difference in the cardiac responses of WKY and SH rats to vagal efferent electrical stimulation. Our data suggest that AITC inhalation in SH rats evokes de novo adrenergic reflexes following vagal afferent activation. This aberrant reflex is independent of steady state hypertension and is not evoked by intravenous AITC. We conclude that pre-existing hypertension aberrantly shifts nociceptive pulmonary-cardiac reflexes towards sympathoexcitation.

Central Respiration and Mechanical Ventilation in the Gating of Swallow With Breathing.

Swallow-breathing coordination safeguards the lower airways from tracheal aspiration of bolus material as it moves through the pharynx into the esophagus. Impaired movements of the shared muscles or structures of the aerodigestive tract, or disruptions in the interaction of brainstem swallow and respiratory central pattern generators (CPGs) result in dysphagia. To maximize lower airway protection these CPGs integrate respiratory rhythm generation signals and vagal afferent feedback to synchronize swallow with breathing. Despite extensive study, the roles of central respiratory activity and vagal feedback from the lungs as key elements for effective swallow-breathing coordination remain unclear. The effect of altered timing of bronchopulmonary vagal afferent input on swallows triggered during electrical stimulation of the superior laryngeal nerves or by injection of water into the pharyngeal cavity was studied in decerebrate, paralyzed, and artificially ventilated cats. We observed two types of single swallows that produced distinct effects on central respiratory-rhythm across all conditions: post-inspiratory type swallows disrupted central-inspiratory activity without affecting expiration, whereas expiratory type swallows prolonged expiration without affecting central-inspiratory activity. Repetitive swallows observed during apnea reset the E2 phase of central respiration and produced facilitation of swallow motor output nerve burst durations. Moreover, swallow initiation was negatively modulated by vagal feedback and was reset by lung inflation. Collectively, these findings support a novel model of reciprocal inhibition between the swallow CPG and inspiratory or expiratory cells of the respiratory CPG where lung distension and phases of central respiratory activity represent a dual peripheral and central gating mechanism of swallow-breathing coordination.

Carotid chemoreceptors tune breathing via multipath routing: reticular chain and loop operations supported by parallel spike train correlations.

We tested the hypothesis that carotid chemoreceptors tune breathing through parallel circuit paths that target distinct elements of an inspiratory neuron chain in the ventral respiratory column (VRC). Microelectrode arrays were used to monitor neuronal spike trains simultaneously in the VRC, peri-nucleus tractus solitarius (p-NTS)-medial medulla, the dorsal parafacial region of the lateral tegmental field (FTL-pF), and medullary raphe nuclei together with phrenic nerve activity during selective stimulation of carotid chemoreceptors or transient hypoxia in 19 decerebrate, neuromuscularly blocked, and artificially ventilated cats. Of 994 neurons tested, 56% had a significant change in firing rate. A total of 33,422 cell pairs were evaluated for signs of functional interaction; 63% of chemoresponsive neurons were elements of at least one pair with correlational signatures indicative of paucisynaptic relationships. We detected evidence for postinspiratory neuron inhibition of rostral VRC I-Driver (pre-Bötzinger) neurons, an interaction predicted to modulate breathing frequency, and for reciprocal excitation between chemoresponsive p-NTS neurons and more downstream VRC inspiratory neurons for control of breathing depth. Chemoresponsive pericolumnar tonic expiratory neurons, proposed to amplify inspiratory drive by disinhibition, were correlationally linked to afferent and efferent "chains" of chemoresponsive neurons extending to all monitored regions. The chains included coordinated clusters of chemoresponsive FTL-pF neurons with functional links to widespread medullary sites involved in the control of breathing. The results support long-standing concepts on brain stem network architecture and a circuit model for peripheral chemoreceptor modulation of breathing with multiple circuit loops and chains tuned by tegmental field neurons with quasi-periodic discharge patterns. NEW & NOTEWORTHY We tested the long-standing hypothesis that carotid chemoreceptors tune the frequency and depth of breathing through parallel circuit operations targeting the ventral respiratory column. Responses to stimulation of the chemoreceptors and identified functional connectivity support differential tuning of inspiratory neuron burst duration and firing rate and a model of brain stem network architecture incorporating tonic expiratory "hub" neurons regulated by convergent neuronal chains and loops through rostral lateral tegmental field neurons with quasi-periodic discharge patterns.