Endogenous hydrogen sulfide maintains eupnea in an in situ arterially perfused preparation of rats.

Hydrogen sulfide (H2S) is constitutively generated in the human body and works as a gasotransmitter in synaptic transmission. In this study, we aimed to evaluate the roles of endogenous H2S in generating eupnea at the respiratory center. We employed an in situ arterially perfused preparation of decerebrated rats and recorded the central respiratory outputs. When the H2S-producing enzyme cystathionine ß-synthase (CBS) was inhibited, respiration switched from the 3-phase eupneic pattern, which consists of inspiration, postinspiration, and expiration, to gasping-like respiration, which consists of inspiration only. On the other hand, when H2S synthesis was inhibited via cystathionine γ-lyase (CSE) or when H2S synthesis was activated via CBS, eupnea remained unchanged. These results suggest that H2S produced by CBS has crucial roles in maintaining the neuronal network to generate eupnea. The mechanism of respiratory pattern generation might be switched from a network-based system to a pacemaker cell-based system in low H2S conditions.

Breath hold effect on cardiovascular brain pulsations - A multimodal magnetic resonance encephalography study.

Ultra-fast functional magnetic resonance encephalography (MREG) enables separate assessment of cardiovascular, respiratory, and vasomotor waves from brain pulsations without temporal aliasing. We examined effects of breath hold- (BH) related changes on cardiovascular brain pulsations using MREG to study the physiological nature of cerebrovascular reactivity. We used alternating 32 s BH and 88 s resting normoventilation (NV) to change brain pulsations during MREG combined with simultaneously measured respiration, continuous non-invasive blood pressure, and cortical near-infrared spectroscopy (NIRS) in healthy volunteers. Changes in classical resting-state network BOLD-like signal and cortical blood oxygenation were reproduced based on MREG and NIRS signals. Cardiovascular pulsation amplitudes of MREG signal from anterior cerebral artery, oxygenated hemoglobin concentration in frontal cortex, and blood pressure decreased after BH. MREG cardiovascular pulse amplitudes in cortical areas and sagittal sinus increased, while cerebrospinal fluid and white matter remained unchanged. Respiratory centers in the brainstem - hypothalamus - thalamus - amygdala network showed strongest increases in cardiovascular pulsation amplitude. The spatial propagation of averaged cardiovascular impulses altered as a function of successive BH runs. The spread of cardiovascular pulse cycles exhibited a decreasing spatial similarity over time. MREG portrayed spatiotemporally accurate respiratory network activity and cardiovascular pulsation dynamics related to BH challenges at an unpreceded high temporal resolution.

Relationship between the distribution of the paired-like homeobox gene (Phox2b) expressing cells and blood vessels in the parafacial region of the ventral medulla of neonatal rats.

It has been reported that central chemoreceptor cells in the medulla are distributed in close apposition to capillary blood vessels in the medulla. Phox2b-expressing neurons in the retrotrapezoid nucleus (RTN) respond to high CO(2)/H(+) stimulation and have been suggested to play an important role in central chemoreception. In newborn rats, the RTN overlaps at least partially with the parafacial respiratory group (pFRG), which consists predominantly of preinspiratory neurons. In the present study, we visualized the blood vessels in the ventral medulla of newborn rats using a neurobiotin method and examined the relationship between the blood vessels and the location of Phox2b-immunoreactive (-ir) neurons. We showed that Phox2b-ir neurons in the parafacial region of the rostral ventral medulla tended to assemble around capillary blood vessels. We also confirmed that pFRG/preinspiratory neurons that were sensitive to hypercapnic stimulation in the presence of tetrodotoxin were Phox2b-ir neurons and were tightly apposed to the blood vessels along the longitudinal axis. Our findings suggested that the location of Phox2b-ir neurons, including preinspiratory neurons of the pFRG, matched their role as sensors of blood CO(2) concentration.

Cerebrovascular reactivity among native-raised high altitude residents: an fMRI study.

BACKGROUND: The impact of long term residence on high altitude (HA) on human brain has raised concern among researchers in recent years. This study investigated the cerebrovascular reactivity among native-born high altitude (HA) residents as compared to native sea level (SL) residents. The two groups were matched on the ancestral line, ages, gender ratios, and education levels. A visual cue guided maximum inspiration task with brief breath holding was performed by all the subjects while Blood-Oxygenation-Level-Dependent (BOLD) functional Magnetic Resonance Imaging (fMRI) data were acquired from them. RESULTS: Compared to SL controls, the HA group showed generally decreased cerebrovascular reactivity and longer delay in hemodynamic response. Clusters showing significant differences in the former aspect were located at the bilateral primary motor cortex, the right somatosensory association cortex, the right thalamus and the right caudate, the bilateral precuneus, the right cingulate gyrus and the right posterior cingulate cortex, as well as the left fusiform gyrus and the right lingual cortex; clusters showing significant differences in the latter aspect were located at the precuneus, the insula, the superior frontal and temporal gyrus, the somatosensory cortex (the postcentral gyrus) and the cerebellar tonsil. Inspiratory reserve volume (IRV), which is an important aspect of pulmonary function, demonstrated significant correlation with the amount of BOLD signal change in multiple brain regions, particularly at the bilateral insula among the HA group. CONCLUSIONS: Native-born HA residents generally showed reduced cerebrovascular reactivity as demonstrated in the hemodynamic response during a visual cue guided maximum inspiration task conducted with BOLD-fMRI. This effect was particularly manifested among brain regions that are typically involved in cerebral modulation of respiration.

Neurons in the preBötzinger complex and VRG are located in proximity to arterioles in newborn mice.

The constant cyclic respiratory activity in the brainstem requires an un-interrupted blood flow providing glucose and O(2) to neurons generating respiratory rhythm. Here we used a combination of classical vascular visualization techniques, and calcium imaging, to compare the microvascular structure and localization of active respiratory neurons in the brainstem of newborn mice at the level of the preBötzinger complex (PBC) and ventral respiratory group. The brainstem is supplied with perforating arteries, which enter primarily in the midline and in a circumscribed region mid-laterally in the medulla. Presumed arterioles then pass dorso-medially with a high density immediately lateral to the midline, and mid-laterally at approximately 60% of the midline-to-lateral edge distance. Calcium imaging, using Fluo-8, AM, showed that active PBC/VRG neurons are located in the same region where a high density of arterioles is found. We conclude that the striking co-localization of medullary arterioles and the PBC/VRG could imply that respiratory neurons may derive part of their glucose and oxygen consumption directly from arterioles, and that humoral factors affecting ventilation may reach respiratory neurons by precapillary transport mechanisms.

A role for KATP+-channels in mediating the elevations of cerebral blood flow and arterial pressure by hypoxic stimulation of oxygen-sensitive neurons of rostral ventrolateral medulla.

Reticulospinal sympathoexcitatory neurons of rostral ventrolateral medulla (RVL) are selectively excited by hypoxia to elevate arterial pressure (AP) and cerebral blood flow (rCBF), that are elements of the oxygen-conserving (diving) reflex. We investigated whether KATP+-channels participate in this. Tolbutamide and glibenclamide, KATP+-channel blockers, microinjected into RVL in anesthetized rats, dose-dependently and site-specifically elevated AP and rCBF and potentiated responses to hypoxemia. KATP+-channels may mediate hypoxic excitation of oxygen-sensing RVL neurons.

Isolated capillary proliferation in Leigh's syndrome.

An infant with hypotonia and recurrent apneic spells died with a diagnosis of pyruvate dehydrogenase deficiency and showed typical pathological changes of Leigh's syndrome at postmortem. Despite the prominence of symptoms suggesting dysfunction of brainstem respiratory centers during life, lesions were not found in the upper medulla. However, quantitative morphometric analysis demonstrated abnormal capillary hyperplasia in the region including and between the nucleus ambiguus and nucleus tractus solitarius. There was an average area of 8.0 +/- 2.5 x 10(6) mm2 occupied by capillaries per 0.75 mm2 field in the patient's brainstem, compared with 4.6 +/- 1.6 x 10(6) mm2 and 5.5 +/- 1.4 x 10(6) mm2 in two age-matched controls (p < 0.01). We speculate that capillary hyperplasia is a pathological marker of chronically impaired oxidative metabolism in the central nervous system in metabolic disease.

Inspiratory response to occlusion of arteries in the ventral surface of the medulla in anesthetized cats.

By the occlusion of arteries in the ventral surface of the medulla, the blood supply to the central chemoreceptor for respiration was examined in anesthetized, paralyzed and peripheral chemodenervated cats. Phrenic nerve activities (P.N.A.), as an index of the respiratory center output, increased with an injection (3 ml/min, 10 sec) of hypercapnic blood (PCO2 = 104.5 mmHg) into the vertebral artery (VA injection response). The VA injection responses during occlusion of arteries in the ventral surface of the medulla were classified into three groups: 1) The response disappeared by the bilateral occlusion of the anterior inferior cerebellar arteries (AICA) in 8 out of 29 cats. 2) The response disappeared by the occlusion of both AICA and the posterior inferior cerebellar arteries (PICA) in 9 cats. 3) The response did not disappear in spite of the additional occlusion of several branches from the basilar artery in 11 cats, although the response had diminished. These different results may be due to the complexity of the central chemosensitive structure or of the central vascular system. However, among arteries the AICA blood flow seemed to be most preferentially related to the VA injection response. Thus, at least a part of the central chemosensitive structure may be located in the area perfused by the AICA.