Mitsuko Kanamaru

Autoregulation of histamine release in medulla oblongata via H3-receptors in rabbits.

The release of histamine (HA) from the rostral ventrolateral medulla (RVL), the raphe nuclei (nR), and the solitary nucleus (nTS) was investigated in anesthetized rabbits using microdialysis and high-performance liquid chromatography. HA release upon electrical stimulation of the posterior hypothalamus (PH), where histaminergic cell bodies are located, was increased to 168% of the baseline level in the RVL (n = 6), 139% of the baseline level in the nR (n = 5), and 166% of the baseline level in the nTS (n = 4). Upon perfusion of thioperamide, an H3-receptor antagonist, via a microdialysis probe, HA release from the RVL, nR and nTS increased. The increase in HA release from the RVL, nR and nTS following thioperamide perfusion was suppressed by co-perfusion of thioperamide and an H3-receptor agonist, imetit. We found that HA is released from the RVL, nR and nTS, that the HA release from all three areas is increased upon stimulation of the PH, and that the HA release is locally influenced in opposite directions by thioperamide and imetit. These results suggest that HA release in the medulla oblongata is controlled by the PH and that H3-receptors participate in the autoregulation of HA release by providing negative feedback locally. Autoregulation of HA release via H3-receptors may be important for maintaining tonic output to the sympathetic nervous system.

Impaired ventilation and metabolism response to hypoxia in histamine H1 receptor-knockout mice.

The role of central histamine in the hypoxic ventilatory response was examined in conscious wild-type (WT) and histamine type1 receptor-knockout (H1RKO) mice. Hypoxic gas (7% O(2) and 3% CO(2) in N(2)) exposure initially increased and then decreased ventilation, referred to as hypoxic ventilatory decline (HVD). The initial increase in ventilation did not differ between genotypes. However, H1RKO mice showed a blunted HVD, in which mean inspiratory flow was greater than that in WT mice. O(2) consumption (V(O2)) and CO(2) excretion were reduced 10min after hypoxic gas exposure in both genotypes, but (V(O2)) was greater in H1RKO mice than in WT mice. The ratio of minute ventilation to (V(O2)) during HVD did not differ between genotypes, indicating that ventilation is adequately controlled according to metabolic demand in both mice. Peripheral chemoreceptor sensitivity did not differ between genotypes. We conclude that central histamine contributes via the H1 receptor to changes in metabolic rate during hypoxia to increase HVD in conscious mice.

Dorsomedial medullary 5-HT2 receptors mediate immediate onset of initial hyperventilation, airway dilation and ventilatory decline during hypoxia in mice

The dorsomedial medulla oblongata (DMM) includes the solitary tract nucleus and the hypoglossal nucleus, to which 5-HT neurons project. Effects of 5-HT in the DMM on ventilatory augmentation and airway dilation are mediated via 5-HT2 receptors, which interact with the CO(2) drive. The interaction may elicit cycles between hyperventilation with airway dilation and hypoventilation with airway narrowing. In the present study, effects of 5-HT2 receptors in the DMM on hypoxic ventilatory and airway responses were investigated, while 5-HT release in the DMM was monitored. Adult male mice were anesthetized, and then a microdialysis probe was inserted into the DMM. The mice were placed in a double-chamber plethysmograph. After recovery from anesthesia, the mice were exposed to hypoxic gas (7% O(2) in N(2)) for 5 min with or without a 5-HT2 receptor antagonist (LY-53857) perfused in the DMM. 5-HT release in the DMM was increased by hypoxia regardless of the presence of LY-53857. Immediate onset and the peak of initial hypoxic hyperventilatory responses were delayed. Subsequent ventilatory decline and airway dilation during initial hypoxic hyperventilation were suppressed with LY-53857. These results suggest that 5-HT release increased by hypoxia acts on 5-HT2 receptors in the DMM, which contributes to the immediate onset of initial hypoxic hyperventilation, airway dilation, and subsequent ventilatory decline. Hypoxic ventilatory and airway responses mediated via 5-HT2 receptors in the DMM may play roles in immediate rescue and defensive adaptation for hypoxia and may be included in periodic breathing and the pathogenesis of obstructive sleep apnea.

Central histaminergic neurons regulate rabbit tracheal tension through the cervical sympathetic nerve.

We previously showed that stimulation of the posterior hypothalamus decreases tracheal tension and involves central histaminergic neurons. In the present study, we reveal that central histaminergic neurons project to the rostral ventrolateral medulla and affect cervical sympathetic nervous activity in rabbits. Administration of histamine into the fourth ventricle increased cervical sympathetic nervous activity and decreased tracheal tension. These effects were inhibited by administration of a histamine H receptor antagonist, pyrilamine, into the fourth ventricle. Unilateral injection of DL-homocysteic acid into the tuberomammillary nucleus increased cervical sympathetic nervous activity, an effect was antagonized by bilateral injection of pyrilamine into the rostral ventrolateral medulla. The pulse correlogram between the stimulation pulse applied to the tuberomammillary nucleus and the cervical sympathetic nerve activity showed a mode at 150 to 200 ms, which was reduced by pyrilamine administration into the fourth ventricle. Fibers anterogradely labeled by Phaseolus vulgaris leucoagglutinin (PHA-L) injected into the tuberomammillary nucleus were distributed in the A1, A2, C1, and C2 areas which are determined by tyrosine hydroxylase-immunohistochemistry. PHA-L positive neurons were in close contact with tyrosine hydroxylase-immunoreactive neurons in these four areas. Cell bodies in the tuberomammillary nucleus retrogradely labeled with fluorogold from the rostral ventrolateral medulla were immunoreactive with histamine. These results suggest that an excitatory efferent pathway projects from the tuberomammillary nucleus to the cervical sympathetic nerve and that the histaminergic neurons of this pathway influence tracheal tension through the rostral ventrolateral medulla.

Central mediation of tracheal pressure through H1 and H2 receptors after histamine administration to the fourth ventricle of anesthetized rabbit

Administration of 1.5, 5.0 and 15 nmol histamine (HA) into the fourth ventricle (IVth) decreased tracheal pressure (PT) dose-dependently in anesthetized rabbits. Maximum decrease of PT occurred 0.9 +/- 0.1 min (mean +/- S.E.M., n = 9) after administration of 15 nmol, and recovery occurred at 4.5 +/- 1.0 min (n = 9). The decrease of PT was blocked by the H1 receptor antagonist, pyrilamine administration into the IVth, or intravenous injection of the alpha-adrenoceptor antagonist, phentolamine. Recovery from the PT decrease was delayed by the H2 receptor antagonist, cimetidine. The results suggest that HA centrally decreases PT through H1 receptors, which action is mediated by the sympathetic nervous system, and this decrease may be modulated through H2 receptors.

Involvement of central histaminergic neurons in polypnea induced by hyperthermia in rabbits

A role of central histamine in the preoptic area/anterior hypothalamus (POA/AH) for the regulation of hyperthermia-induced polypnea was examined in anesthetized, paralyzed, vagotomized and artificially ventilated rabbits. Phrenic nerve activities were recorded to monitor respiratory neuronal output. Hyperthermia increased respiratory frequency by reductions of inspiratory time (T(I)) and expiratory time (T(E)). Pyrilamine, an H1 receptor antagonist, which was applied to the POA/AH reduced polypnea under hyperthermia. The effect of S+alpha-fluoromethylhistidine, a specific inhibitor of histidine decarboxylase, applied in a lateral ventricle was comparable to the effect of pyrilamine on polypnea. Moreover, histamine dihydrochloride applied into the POA/AH at a normal body temperature produced polypnea by reductions of T(I) and T(E). The results suggest that central histamine in the POA/AH contributes to the generation of polypnea in hyperthermia through H1 receptors.

Breathing is affected by dopamine D2-like receptors in the basolateral amygdala.

The precise mechanisms underlying how emotions change breathing patterns remain unclear, but dopamine is a candidate neurotransmitter in the process of emotion-associated breathing. We investigated whether basal dopamine release occurs in the basolateral amygdala (BLA), where sensory-related inputs are received and lead to fear or anxiety responses, and whether D1- and D2-like receptor antagonists affect breathing patterns and dopamine release in the BLA. Adult male mice (C57BL/6N) were perfused with artificial cerebrospinal fluid, a D1-like receptor antagonist (SCH 23390), or a D2-like receptor antagonist ((S)-(-)-sulpiride) through a microdialysis probe in the BLA. Respiratory variables were measured using a double-chamber plethysmograph. Dopamine release was measured by an HPLC. Perfusion of (S)-(-)-sulpiride in the BLA, not SCH 23390, specifically decreased respiratory rate without changes in local release of dopamine. These results suggest that basal dopamine release in the BLA, at least partially, increases respiratory rates only through post-synaptic D2-like receptors, not autoreceptors, which might be associated with emotional responses.

Effects of CO2 inhalation on 5-HT release in the dorsomedial medulla oblongata in infant rats

5-HT release in the dorsomedial medulla oblongata (DMM), especially in the hypoglossal nucleus, affects genioglossus muscle activity, which may be related to obstructive sleep apnea. We previously showed that 5-HT release in the DMM in adult mice is increased by CO2 inhalation. Prematurity in medullary 5-HT neurons has been reported in sudden infant death syndrome. In the present study, 5-HT release in the DMM and the responses to CO2 inhalation were investigated in infant rats. Infant rats were anesthetized with pentobarbital sodium i.p. for insertion of a microdialysis probe in the DMM. They were then placed in a double chamber plethysmograph to record respiratory variables. After recovery from anesthesia, extracellular fluid was collected at 1.2 L/minute every 5 min. The 5-HT was analyzed with an ECD-HPLC. Infant rats were exposed to 0, 5, 7 and 9% CO2 in O2. 5-HT release in the DMM in infant rats was not dose-dependently increased by CO2 inhalation. The result suggests that 5-HT release in the DMM does not play a dominant role in mediation of CO2/pH sensitivity in infant rats.

Chemical Control of Airway and Ventilatory Responses Mediated Via Dorsomedial Medullary 5-HT2 Receptors

The airway and ventilatory responses in mice elicited by the inhalation of hypercapnic or hypoxic gas mixtures were investigated by a microdialysis technique, 5-HT release analysis and double-chamber plethysmography with or without 5-HT2 receptor activity in the dorsomedial medulla oblongata (DMM). Hypercapnia elicited compensatory airway dilation and additive ventilatory augmentation to 5-HT2 receptor activity in the DMM. Hypoxia mediated immediate onset of hypoxic hyperventilation and airway dilation, and subsequent hypoxic ventilatory decline. Chemical control of the airway and ventilatory responses mediated via 5-HT2 receptors in the DMM are reviewed.

Serotonin release acts on 5-HT2 receptors in the dorsomedial medulla oblongata to elicit airway dilation in mice

Serotonin (5-hydroxytryptamine; 5-HT) excites neurons in the hypoglossal and solitary tract nuclei through 5-hydroxytryptamine 2 (5-HT2) receptors, and contributes to genioglossal muscle activation, hypotension and bradycardia. This study investigated the influence of 5-HT2 receptor-mediated 5-HT action in the hypoglossal and solitary tract nuclei on respiratory variables, particularly airway resistance. Adult male mice were subjected to microdialysis and placed in a double-chamber plethysmograph. 5-HT release and respiratory variables were assessed in response to fluoxetine perfusion or fluoxetine plus LY-53857 coperfusion of the dorsomedial medulla oblongata (DMM), which includes the hypoglossal and solitary tract nuclei. 5-HT release in the DMM was increased but respiratory rate was not affected by fluoxetine perfusion with or without LY-53857. Specific airway resistance was significantly larger with fluoxetine plus LY-53857 coperfusion than at baseline or during perfusion with fluoxetine. Conversely, tidal volume was significantly lower with fluoxetine plus LY-53857-coperfusion than at baseline. These results suggest that 5-HT release in the DMM is regulated by a suppressive effect of local 5-HT transporter activity, which elicits airway dilation and increases tidal volume through local 5-HT2 receptors without affecting respiratory rate.