Language：Japanese   Publishing type：Research paper (scientific journal)  

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DOI： 10.3892/or_00000409

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DOI： 10.3892/ijo_00000036

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DOI： 10.1016/j.lungcan.2007.06.009

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DOI： 10.1111/j.1440-1843.2007.01055.x

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DOI： 10.1007/0-387-31311-7_41

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

To determine if doxapram stimulates the carotid body through the same mechanism as hypoxia, we compared the effects of doxapram and hypoxia on isolated-perfused carotid bodies in rabbits. Doxapram stimulated the carotid body in a dose-dependent manner. In Ca2+-free solution, neither doxapram nor hypoxia stimulated the carotid body. Although, doxapram had an additive effect on the carotid body chemosensory response to hypercapnia, a synergistic effect was not observed. Also, we investigated the various K+ channel activators on the response to doxapram and hypoxia: pinacidil and levcromakalim as ATP-sensitive K+ channel activators; NS-1619 as a Ca2+-sensitive K+ channel activator; and halothane as a TASK-like background K+ channel activator. The hypoxic response was partially reduced by halothane only, while pinacidil, levcromakalim and NS-1619 had no effect. Interestingly, the effect of doxapram was partially inhibited by NS-1619. Neither pinacidil nor levcromakalim affected the stimulatory effect of doxapram. We conclude that doxapram stimulates the carotid body via a different mechanism than hypoxic chemotransduction. © 2005 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.resp.2005.01.005

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：KLUWER ACADEMIC/PLENUM PUBL  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：KLUWER ACADEMIC/PLENUM PUBL  

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A 65-yr-old female developed cough, fever and dyspnoea following repeated exposure to a home ultrasonic humidifier. High-resolution computed tomography showed ground-glass opacity in both lung fields. Arterial blood gas analysis gave an oxygen tension of 8.38 kPa (63 Torr). Pulmonary function testing revealed restrictive ventilatory impairment with a reduction in the diffusing capacity. The diagnosis of extrinsic allergic alveolitis (EAA) was confirmed by radiographic findings, pathological evidence of alveolitis and reproductive development by a provocation test to the humidifier water. The yeast Debaryomyces Hansenii was the only microorganism cultured from the water of the humidifier. The double diffusion precipitating test and lymphocyte proliferative response was positive for an extract of D. Hansenii, providing evidence to incriminate this fungus. This is the first described case of EAA caused by D. Hansenii.

DOI： 10.1183/09031936.02.00030402

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：MUNKSGAARD INT PUBL LTD  

In the present study; respiratory drives to chemical stimuli and peripheral chemosensitivity were evaluated in patients with obstructive sleep apnoea (OSAS), The effects of oral administration of domperidone, a selective dopamine D-2-receptor antagonist, were also examined, to study the respiratory effects of endogenous dopamine on peripheral chemoreceptors.
Sixteen patients with OSAS and nine normal control subjects were studied. Respiratory responses to hypercapnia and hypoxia were measured using the rebreathing method and isocapnic progressive hypoxia method, respectively. The hypoxic withdrawal test, which measures the decrease in ventilation caused by two breaths of 100% O-2 under mild hypercapnic hypoxic conditions (end-tidal oxygen and carbon dioxide tensions approximate to 8.0 kPa and 5.3-6.7 kPa, respectively), was used to evaluate peripheral chemosensitivity,
In the patients with OSAS, ventilatory responses to hypercapnia and hypoxia were significantly decreased compared with those of control subjects. Hypoxic withdrawal tests showed that peripheral chemosensitivity was significantly lower in patients with OSAS than in normal subjects. Hypercapnic ventilatory response and peripheral chemosensitivity were enhanced by administration of domperidone in the patients with OSAS, although no changes in either of these were observed in the control subjects. The hypoxic ventilatory response and peripheral chemosensitivity in the patients with OSAS were each significantly correlated with severity of hypoxia during sleep.
These findings suggest that peripheral chemosensitivity in patients with obstructive sleep apnoea syndrome may be decreased as a result of abnormality in dopaminergic mechanisms and that the reduced chemosensitivity observed in patients with obstructive sleep apnoea syndrome may affect the severity of hypoxia during sleep.

DOI： 10.1183/09031936.99.13241899

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER PHYSIOLOGICAL SOC  

It is hypothesized that carotid body chemosensory activity is coupled to neurosecretion. The purpose of this study was to examine whether there was a correspondence between carotid body tissue dopamine (DA) levels and neuronal discharge (ND) measured from the carotid sinus nerve of perfused cat carotid bodies and to characterize interaction between CO(2) and O(2) in these responses. ND and tissue DA were measured after changing from normoxic, normocapnic control bicarbonate buffer (PO(2) >120 Torr, PCO(2) 25-30 Torr, pH similar to 7.4) to normoxic hypercapnia (PCO(2) 55-57 Torr, pH 7.1-7.2) or to hypoxic solutions (PO(2) 30-35 Torr) with normocapnia (PCO(2) 25-30 Torr, pH similar to 7.4) or hypocapnia (PCO(2) 10-15 Torr, pH 7.6-7.8). Similar temporal changes for ND and tissue DA were found for all of the stimuli, although there was a much different proportional relationship for normoxic hypercapnia. Both ND and DA increased above baseline values during flow interruption and normocapnic hypoxia, and both decreased below baseline values during hypoxic hypocapnia. In contrast, normoxic hypercapnia caused an initial increase in ND, from a baseline of 175 +/- 12 (SE) to a peak of 593 +/- 20 impulses/s within 4.6 +/- 0.9 s, followed by adaptation, whereas ND declined to 423 +/- 20 impulses/s after 1 min. Tissue DA initially increased from a baseline of 17.9 +/- 1.2 mu M to a peak of 23.2 +/- 1.2 mu M within 3.0 +/- 0.7 s, then declined to 2.6 +/- 1.0 mu M. The substantial decrease in tissue DA during normoxic hypercapnia was not consistent with the parallel changes in DA with ND that were observed for hypoxic stimuli.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

We measured the effect of high P-CO (500-550 Torr) on the pH(i) and [Ca2+](i) in cultured glomus cells of adult rat carotid body (CB) as a test of the two models currently proposed for the mechanism of CB chemoreception. The metabolic model postulates that the rise in glomus cell [Ca2+](i), the initiating reaction in the signalling pathway lending to chemosensory neural discharge, is due to [Ca2+] release from intracellular Ca2+ stores. The membrane potential model postulates that the rise in [Ca2+](i) comes from influx of extracellular Ca2+ through voltage-dependent Ca2+ channels (VDCC) of the L-type. High P-CO did not change pH(i) at PO2 of 120-135 Torr, showing that CO-induced changes in [Ca2+](i) are not due to changes in pH(i). High P-CO caused a highly significant rise in [Ca2+](i) from 90 +/- 12 nM to 675 +/- 65 nM, both in the absence and in the presence of 200 mu M CdCl2, a potent blocker of L-type VDCCs. This result is fully consistent with release of Ca2+ from glomus cell intracellular stores according to metabolic model, but inconsistent with influx of extracellular Ca2+ through VDCCs according to the membrane potential model. (C) 1998 Elsevier Science B.V. All rights reserved.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

Studies of dopamine (DA) release were conducted with 10 perfused/superfused cat carotid bodies using shallow recessed Nafion polymer-coated microsensors (tips similar to 5 mu m). Simultaneous measurements of tissue DA and neuronal discharge (ND) from the sinus nerve were made after switching from normoxic, normocapnic control perfusate (20% O-2, 5% CO2, balance N-2) to a normoxic, normocapnic perfusate equilibrated with a high tension (> 550 Torr) of carbon monoxide (CO). When high P-CO perfusate was delivered in the dark, ND increased from a baseline of 89 +/- 24 (SE) impulses/s, to a peak excitation of 374 +/- 44 impulses/s within 15-30 s. Excitation then diminished to a plateau of 281 +/- 36 impulses/s within 1-2 min. Both peak and plateau ND were significantly above baseline (P < 0.05). Average tissue DA values increased above basal levels by + 7.2 +/- 1.0 and + 5.6 +/- 0.6 mu M, respectively during the peak and plateau Nn phases (P < 0.05). Bright light restored the chemosensory activity to baseline, but had no effect on DA. Both chemosensory excitation and tissue DA responses to high CO in the dark were diminished in 3 carotid bodies perfused with Ca2+-free solutions. Responses were reduced even further with Ca2+ chelator (EGTA) in the perfusate. The results suggest that the effect of high P-CO on DA release and chemosensory excitation are dependent on Ca2+ in the media, but the two events are not coupled. (C) 1997 Elsevier Science B.V.

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This study was done using high P-CO (> 500 Torr at P-O2 of 120 Torr) in the carotid body perfusate in vitro, and recording simultaneously the activity of the whole carotid sinus nerve (CSN) and (V) over dot (O2) of the carotid body. In the cascade of excitation of CSN by high P-CO in the dark [light eliminated the excitation; S. Lahiri, News Physiol. Sci. 9 (1992) 161-165], Ca2+ effects occur at the level of neurosecretion after the level of oxygen consumption, according to the following scheme: CO-hypoxia --> (V) over dot decrease --> K+ conductance decrease --> cell depolarization --> cytosolic Ca2+ rise --> neurosecretion --> neural discharge. Thus, a part of the hypothesis was that [Ca2+] decrease, being a downstream event, may not affect (V) over dot (O2) Of the carotid body. Also, to determine to what extent the intracellular calcium stores contribute to cystolic [Ca2+] and chemosensory discharge with high P-CO, we tested the effect of interruption of perfusate flow with medium nominally free of [Ca2+] on CSN excitation and (V) over dot (O2) of the carotid body with and without high P-CO. High P-CO in the dark decreased carotid body (V) over dot (O2), independent of [Ca2+](o). CSN excitation was always enhanced by high P-CO, and its sensitivity to perfusate flow interruption. Also; nominally Ca2+-free solution increased the latency and decreased the rate of rise and peak activity of CSN during interruption of perfusate flow, but CO augmented the responses. This reversal effect by CO suggests that Ca2+ is released from intracellular stores, because CO has no other way to excite the chemoreceptors than by acting on the intracellular stores. (C) Elsevier Science B.V.

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To test the hypothesis whether CO2-HCO3- buffer is essential for the expression of chemoreception and to distinguish between pH(i) and pH(0) interaction with pCO in the carotid chemosensory response, we superfused-perfused in vitro cat carotid bodies using HEPES-Tyrode's solution with and without CO2-HCO3-, and compared the responses at the same pH(0) in the absence and presence of light. In the absence of light, pCO (>138 Torr) stimulated the carotid body chemoreceptors in CO2-HCO3- buffer at pH(0) of 7.40, whereas pCO (69-550 Torr) did not stimulate the neural discharge in HEPES buffer at the pH(0) of 7.4-7.1 but did so below pH(0) 7.1. In the presence of light, all the responses were diminished proportionately. (C) 1997 Elsevier Science B.V.

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The hypothesis that H2O2 plays a critical role in hypoxic chemoreception in the cat carotid body (CB) was tested using a perfused-superfused preparation in vitro, measuring chemosensory discharge and CB tissue P-O2 (P-tiO2). According to the hypothesis NADPH mediated, P-O2 dependant increase in H2O2 production would hyperpolarize the glomus cell, decreasing the chemosensory discharge. Thus, lactate and aminotriazole which would increase H2O2 concentration, would decrease the chemosensory discharge during hypoxia. However, 2.5-5.0 mM lactate and 25 mM aminotriazole did not diminish the hypoxic response. But, 2.5 mM lactate decreased the chemosensory discharge during normoxia which can be explained by an increase of CB P-tiO2. Diethyldithiocarbamic acid (5 mM), which blocks the conversion of superoxide to H2O2, also diminished the chemosensory discharge, presumably due to an increased CB P-tiO2. Menadione (increasing H2O2) and t-butyl hydroperoxide irreversibly decreased the chemosensory discharge, and the data are not useful. H2O2 increased the P-O2 Of the perfusate, and therefore could not be tested against P-O2 Thus, perturbation of endogenous or exogenous H2O2 did not provide any evidence for its critical role in O-2 chemoreception.

DOI： 10.1016/S0165-1838(96)00129-4

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Language：English   Publisher：FEDERATION AMER SOC EXP BIOL  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

Charybdotoxin (ChTX), a venom protein, suppresses Ca2+-activated K+ (K-Ca(+)) currents in the glomus cell of neonatal rat carotid body. If it works similarly for cat carotid body chemoreceptors, charybdotoxin is expected to stimulate the chemosensory discharge during normoxia, and particularly hypoxia and hypercapnia. We studied the effects of charybdotoxin (20-40 nM) in vitro (perfused/superfused) on the cat carotid chemosensory discharge, and simultaneously tissue PO2 (PtiO(2)), as a measure of positive control. ChTX (20 nM) only increased PtiO(2) and decreased carotid chemosensory discharge during hypoxia, indicating vasodilation. We conclude that K-Ca(+) channels do not appear to play a significant role in chemotransduction in the cat carotid body.

DOI： 10.1016/S0006-8993(96)01313-3

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Language：English   Publisher：FEDERATION AMER SOC EXP BIOL  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PLENUM PRESS DIV PLENUM PUBLISHING CORP  

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Language：Japanese   Publishing type：Research paper (scientific journal)  

We studied the effect of intravenous administration of a dopamine (DA) agonist and antagonist on the hypoxic response of phrenic nerve activity in anesthetized, vagotomized and mechanically ventilated rabbits. The experiments were performed in both intact and carotid sinus denervated animals. In the intact animals, hypoxic challenge (FIO2=0.10) increased the amplitude of integrated phrenic nerve activity (iPNA) without any alteration in respiratory frequency. In the carotid sinus denervated animals, the hypoxia progressively depressed iPNA. Neither the DA antagonist, haloperidol (0.5mg/kg i.v.), nor the DA agonist, apomorphine (0.3mg/kg, i.v.) changed the iPNA during normoxia in either the intact or denervated group. Administration of haloperidol enhanced iPNA response to hypoxia in the intact group. Apomorphine decreased the hypoxic response to iPNA. Although apomorphine did not change the control hypoxic response to iPNA in the denervated group, haloperidol augmented hypoxic respiratory depression in the carotid sinus denervated group. Therefore, we concluded that the effect of DA on peripheral chemoreceptors inhibits the hypoxic ventilatory response, but stimulates the hypoxic ventilatory response in the central nervous system.

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Language：English   Publisher：FEDERATION AMER SOC EXP BIOL  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

Since high P-CO in the dark works Like hypoxia in the carotid body chemoreceptors and since hypoxia shows a stimulus interaction with CO2, it is hypothesized that high P-CO will show a similar interaction with P-CO2 in the chemosensory excitation in the dark. We tested the hypothesis using cat carotid body perfused and superfused in vitro with P-o2 of about 100 Torr. In one series, the chemosensory discharges were tested at three levels of P-CO2 at high P-CO of 500 Torr in the absence and presence of light. In the dark, normocapnia (P-CO2 approximate to 30 Torr) with high P-CO promptly stimulated the sensory discharges to a peak, subsiding to a lower level. In hypocapnia (P-CO2 approximate to 18 Torr) with high P-CO, all phases of activities were significantly lower than those of normocapnia, showing stimulus interaction. Hypercapnia saturated the activity with high P-CO and seems to preclude a clear demonstration of stimulus interaction. In another series, an intermediate level of P-CO (approximate to 150 Torr), which showed a half-maximal activity in normoxia, showed a clear interaction with hypercapnia in the dark. With high P-CO, bright light promptly reduced the activity to baseline at all P-CO2 levels. This then increased somewhat to a steady-state. Withdrawal of the light was followed by a sharp rise in the activity to a peak which then fell to a somewhat lower level of steady-state. The peak discharge rate in the presence of light did not differ significantly from those of P-CO2 alone.

DOI： 10.1016/0006-8993(95)01400-4

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Language：English   Publisher：FEDERATION AMER SOC EXP BIOL  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

To test the hypothesis that Ca2+ is released from intracellular store in the carotid body glomus cells during hypoxia, we stimultaneously measured chemosensory discharge and tissue PO2 of perfused-superfused cat carotid body before and during flow interruption in the presence and absence of extracellular [Ca2+] with and without thapsigargin (1-10 mu M). Ca2+-free solution increased the latency of sensory response, and decreased the rate of rise and peak activity but thapsigargin significantly influenced these responses, without affecting oxygen consumption. Since thapsigargin depletes the intracellular Ca2+ store, and since Ca2+ is needed for the sensory discharge, these results suggest that intracellular release and influx of Ca2+ occur during hypoxia.

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High carbon monoxide (CO) gas tensions (> 500 Torr) at normoxic PO2 (125-140 Torr) stimulates carotid chemosensory discharge in the perfused carotid body (CB) in the absence but not in the presence of light. According to a metabolic hypothesis of O-2 chemoreception, the increased chemosensory discharge should correspond to a photoreversible decrease of O-2 consumption, unlike a non-respiratory hypothesis. We tested the respiratory vs. non-respiratory hypotheses of O-2 chemoreception in the cat CB by measuring the effect of high CO2 Experiments were conducted using CBs perfused and superfused in vitro with high CO in normoxic, normocapnic cell-free CO2-HCO3- buffer solution at 37 degrees C. Simultaneous measurements of the rate of O-2 disappearance with recessed PO2 microelectrodes and chemosensory discharge were made after flow interruption with and without CO in the perfusate. The control O-2 disappearance rate without CO was -3.66 +/- 0.43 (S.E.) Torr/s (100 measurements in 12 cat CBs). In the dark, high CO reduced the O-2 disappearance rate to -2.35 +/- 0.33 Torr/s, or 64.2 +/- 9.0% of control (P < 0.005, 34 measurements). High CO was excitatory in the dark, with an increase in baseline neural discharge from 129.2 +/- 47.0 to 399.3 +/- 49.1 impulses per s (P < 0.0001), and maximum discharge rate of 659 +/- 76 impulses/s (N.S. compared to control) during now interruption. During perfusion with high CO in the light, there were no significant differences in baseline neural discharge or in the maximum neural discharge after now interruption, and little effect on O-2 metabolism (88.8 +/- 11.5% of control, N.S., 29 measurements). Thus the photoreversible decrease of O-2 consumption and chemosensory excitation in the CO-treated CB is consistent with the metabolic theory of O-2 chemoreception.

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Language：English   Publisher：FEDERATION AMER SOC EXP BIOL  

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Language：English   Publisher：FEDERATION AMER SOC EXP BIOL  

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Language：English   Publisher：FEDERATION AMER SOC EXP BIOL  

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Language：Japanese   Publishing type：Research paper (scientific journal)  

Pulmonary hypertension caused by acute pulmonary embolism has been attributed to mechanical obstruction of the pulmonary arteries and also to vasoconstriction. We examined the role of nitric oxide in the vasoreactivity associated with pulmonary microembolism. Two kinds of microemboli of similar size were used
thorny microemboli (lycopodium spores, LP) and smooth microemboli (latex microspheres, MS). In isolated rat lungs perfused with blood, five injections of LP or MS into the pulmonary artery each caused a rapid increase in mean perfusion pressure, followed by a slow fall to a new, higher base line. Vasoconstriction was significantly greater after embolization with LP than after embolization with MS. Preadministration of L- NMMA, a nitric oxide synthase inhibitor, enhanced the increase in mean perfusion pressure caused by embolization with LP, but not the increase caused by embolization with MS. Before embolization, acetylcholine caused slight vasodilation. After embolization with MS, acetylcholine caused vasodilation
but after embolization with LP, acetylcholine caused vasoconstriction. Thus, we conclude that repeated embolization with LP may cause endothelial injury, and that nitric oxide may protect against pulmonary hypertension induced by LP emboli.

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Language：English   Publisher：AMER LUNG ASSOC  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：CENTER ACADEMIC PUBL JAPAN  

We investigated the ventilatory responses to hypoxia and hypercapnia in patients with essential hypertension (HT) as compared with healthy subjects (NV). Further, to evaluate the contribution of the peripheral chemoreceptors to ventilatory response, we used a withdrawal test. Hypoxic ventilatory drive (HVR) was measured as the parameter A denoting the shape of VI (inspiratory minute ventilation)-PET(O2) (end-tidal P(O2)) curve which was calculated by the empirical equation: VI = V0 + A/(PET(O2)-32). Hypercapnic ventilatory drive (HCVR) was measured as the parameter S denoting the shape of the VI-PET(CO2) (end-tidal P(CO2)) relation which was calculated by the empirical equation: VI = S(PET(CO2)-B). There were no significant differences in the parameters of HVR and HCVR between NV and HT. A positive correlation between A/BSA and S/BSA was found to be significant in NV (r = 0.873, p < 0.05). Conversely, there was no significant correlation between A/BSA and S/BSA (r = 0.547) in HT. On the other hand, the withdrawal responses (DELTA-VI/BSA and % DELTA-VI:DELTA-VI/VI X 100%) were obtained from the magnitude of depression in ventilation caused by two breaths Of 02 in hypoxic hypercapnia. In the withdrawal responses, DELTA-VI/BSA and % DELTA-VI in HT were significantly higher than those in NV. A/BSA significantly correlated with DELTA-VI/BSA (NV, r = 0.684, p < 0.05; HT, r = 0.648, p < 0.05) in both NV and HT. However, DELTA-VI/BSA in HT tended to be higher than that in NV, under the same value of A/BSA. These results suggested that the peripheral chemoreceptor activity was augmented in HT.

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