Kazuo Takano

Inspiration-promoting vagal reflex under NMDA receptor blockade in anaesthetized rabbits.

1 This study describes a novel vagal respiratory reflex in anaesthetized rabbits. In contrast to the well‐known inspiratory (I) off‐switching by vagal afferent excitation, this vagal reflex initiates and maintains the central I activity of phrenic nerve discharges in rabbits pre‐treated with antagonists of N‐methyl‐D‐aspartate‐type excitatory amino acid receptors (NMDA‐Rs). 2 Under NMDA‐R blockade with either dizocilpine (0·025‐0·3 mg kg−1), D‐2‐amino‐5‐phosphonopentanoic acid (AP5, 0·5‐1 mg, i.c.v.) or ketamine (10 mg kg−1), vagal stimulation at low frequencies (5‐40 Hz) during the I phase prevented or markedly delayed the spontaneous I termination. In contrast, stimulation of the same vagal afferent at the same intensity but at a higher frequency (100‐160 Hz) during the I phase immediately terminated the I phase. 3 In non‐vagotomized rabbits, maintaining the tidal volume at end‐expiratory levels during the I phase prevented spontaneous I termination and maintained apneusis after NMDA‐R blockade with dizocilpine. 4 Brief stimulation of vagal afferents at low frequency (5‐40 Hz) during the expiratory (E) phase constantly initiated phrenic I discharge after NMDA‐R block. 5 We conclude that low‐frequency discharge of vagal pulmonary stretch receptor afferents, as when lung volume is near functional residual capacity, promotes central I activity under NMDA‐R blockade.

Inspiration‐Promoting Vagal Reflex in Anaesthetized Rabbits after Rostral Dorsolateral Pons Lesions

The centrally generated respiratory rhythm is under strong modulation by peripheral information, such as that from the slowly adapting pulmonary stretch receptors (SA‐PSRs) conveyed via the vagus nerve. We have already demonstrated that vagal afferent stimulation at a low frequency (5–40 Hz), or holding the lung volume at the end‐expiratory level (no‐inflation test) prevents spontaneous termination of the inspiratory (I) phase or initiates I activity in anaesthetized rabbits in which the NMDA receptors (NMDA‐Rs) are pharmacologically blocked. Here we show that this I‐promoting vagal reflex also becomes manifest in animals where the pontine respiratory groups are ablated. Following lesions of the rostral dorsolateral pons, including the nucleus parabrachialis medialis and Kölliker‐Fuse nucleus, with radio‐frequency current or local injection of kainic acid, low‐frequency stimulation of the vagus nerve and the no‐inflation test significantly prolonged the I phase in a manner highly similar to that observed in rabbits with NMDA‐R block. Brief stimuli at low frequency during the mid‐expiratory (E) phase evoked I discharge with a latency significantly smaller and less variable than that before the lesions. It is concluded that low‐frequency input from the SA‐PSR suppresses I‐to‐E phase transition and promotes central I activity when the medullary respiratory network is released from pontine influence, which involves NMDA‐R‐mediated signalling.

A dual-role played by extracellular ATP in frequency-filtering of the nucleus Tractus solitarii network.

ATP is now identified to be an important signaling molecule in the CNS1, 2, 3. However, there are only few brain regions in which the function of ATP-mediated signaling is demonstrated from the molecular to whole animal levels. The caudal part of the nucleus of the solitary tract (cNTS) is such a rare structure. In the cNTS, neuronal ATP release4,5, hypoxia-induced increase in purine concentration6, abundant expression of P2X and P2Y receptors7, 8, 9, 10, 11, 12, extracellular hydrolysis of ATP to adenosine4,13, and rich expression of adenosine transporters14 have been demonstrated. In addition, a microinjection of agonists for P2X and adenosine receptors into cNTS in anesthetized rats exerts profound cardiorespiratory effects15, 16, 17. Taken together, ATP, in tandem with its extracellular metabolite adenosine, is thought to be involved in the neuronal signaling in the cNTS, where various visceral signals including those from pulmonary stretch receptors and peripheral chemoreceptor converge.

Vagally induced inspiratory on-switch under NMDA-receptor blockade in rabbits

A lung volume holding (no-inflation test) at the functional residual capacity (FRC) in vagus-intact animals and a low frequency vagal afferent stimulation in vagotomized animals induce a sustained inspiratory phase after the pharmacological blockade of NMDA-receptors. This reflex may underlie the “deflation reflex” of Hering-Breuer (Takano and Kato, Neurosci. Res., 1997). In the present study it was attempted to clarify whether low frequency vagal afferent induces inspiratory on-switch. We stimulated vagal afferents (0.5 V, 0.1 ms, 20-40 Hz, 2-3 pulses) during the expiratory phase in rabbits under blockade of NMDA-receptors with dizocilpine (0.3 mg/kg, iv) or AP5 (0.5 mg/50 ~1, icv). A low frequency vagal stimulation caused an early expiratory termination and initiated inspiratory phrenic burst immediately. When stimulation frequency was higher (~100 Hz), this expiratory-to-inspiratory phase transition did not take place. We conclude that the inspiration-promoting reflex induced by low frequency vagal afferent plays a role not only in inspiratory sustaining but also in the reflexogenic on-switch of the inspiratory phase.

405 Low-frequency vagal input prevents central inspiratory off-switch under NMDA-receptor blockade

EIICHI JODO’, Gary Aston-Jones2 We examined the role of excitatory amino acids (EAAs) in activation of locus coeruleus (LC) neurons evoked by single pulse electrical stimulation of the medial prefrontal cortex (PFCm) in halothane anesthetized rats, by microinfusing antagonists of EAAs into LC while recording impulse activity of single LC neurons for PFCm stimulation: The results indicated that phasic activation of LC by PFCm stimulation is mediated by both NMDAand non-NMDA-type EAA channels.