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Biomedical subjects

A Dahan

Publications and source records attributed to A Dahan.

At least 73 records · Page 4Linked to original sources
PubMed1996

Ventilatory response to hypoxia in humans. Influences of subanesthetic desflurane.

BACKGROUND: At low dose, the halogenated anesthetic agents halothane, isoflurane, and enflurane depress the ventilatory response to isocapnic hypoxia in humans. In the current study, the influence of subanesthetic desflurane (0.1 minimum alveolar concentration [MAC]) on the isocapnic hypoxic ventilatory response was assessed in healthy volunteers during normocapnia and hypercapnia. METHODS: A single hypoxic ventilatory response was obtained at each of 4 target end-tidal partial pressure of oxygen concentrations: 75, 53, 44, and 38 mmHg, before and during 0.1 MAC desflurane administration. Fourteen subjects were tested at a normal end-tidal partial pressure of carbon dioxide (43 mmHg), with 9 subjects tested at an end-tidal carbon dioxide concentration of 49 mmHg (hypercapnia). The hypoxic sensitivity (S) was computed as the slope of the linear regression of inspired minute ventilation (V1) on (100-SPO2). Values are mean +/- SE. RESULTS: Sensitivity was unaffected by desflurane during normocapnia (control: S = 0.45 +/- 0.07 l.min-1.%-1 vs. 0.1 MAC desflurane: S = 0.43 +/- 0.09 l.min-1.%-1). With hypercapnia S decreased by 30% during desflurane inhalation (control: S = 0.74 +/- 0.09 l.min-1.%-1 vs. 0.1 MAC desflurane: S = 0.53 +/- 0.06 l.min-1.%-1; P < 0.05). CONCLUSIONS: On the basis of the data, subanesthetic desflurane has no detectable effect on the normocapnic hypoxic ventilatory response sensitivity. However, the carbon dioxideinduced augmentation of the hypoxic response was reduced. This indicates that subanesthetic desflurane effects the chemoreceptors at the carotid bodies.

Adult↗
PubMed1996

Acute pain and central nervous system arousal do not restore impaired hypoxic ventilatory response during sevoflurane sedation.

BACKGROUND: To quantify the effects of acute pain on ventilatory control in the awake and sedated human volunteer, the acute hypoxic ventilatory response was studied in the absence and presence of noxious stimulation before and during 0.1 minimum alveolar concentration sevoflurane inhalation. METHODS: Step decreases in end-tidal partial pressure of oxygen from normoxia into hypoxia (approximately 50 mmHg) were performed in 11 healthy volunteers. Four acute hypoxic ventilatory responses were obtained per subject: one in the absence of pain and sevoflurane (C), one in the absence of sevoflurane with noxious stimulation in the form of a 1-Hz electrical current applied to the skin over the tibial bone (C + P), one in the absence of pain during the inhalation of 0.1 minimum alveolar concentration sevoflurane (S), and one during 0.1 minimum alveolar concentration sevoflurane with noxious stimulation (S + P). The end-tidal partial pressure of carbon dioxide was held constant at a value slightly greater than baseline (44 mmHg). To assess the central nervous system arousal state, the bispectral index of the electroencephalogram was monitored. Values are mean +/- SE. RESULTS: Pain caused an increase in prehypoxic baseline ventilation before and during sevoflurane inhalation: C = 13.7 +/- 0.9 l.min-1, C + P = 16.0 +/- 1.0 l.min-1 (P < 0.05 vs. C and S), S = 12.7 +/- 1.2 l.min-1, and S + P = 15.9 +/- 1.1 l.min-1 (P < 0.05 vs. C and S). Sevoflurane decreased the acute hypoxic ventilatory response in the absence and presence of noxious stimulation: C = 0.69 +/- 0.20 l.min-1 (% change in arterial hemoglobin-oxygen saturation derived from pulse oximetry [SpO2])-1, C + P = 0.64 +/- 0.13 l.min-1.%SpO2(-1), S = 0.48 +/- 0.15 l.min-1.%SpO2(-1) (P < 0.05 vs. C and C + P) and S + P = 0.46 +/- 0.21 l.min-1.%SpO2(-1) (P < 0.05 vs. C and C + P). The bispectral indexes were C = 96.2 +/ 0.7, C + P = 97.1 +/- 0.4, S = 86.3 +/- 1.3 (P < 0.05), and S + P = 95.0 +/- 1.0. CONCLUSIONS: The observation that acute pain caused an increase in baseline ventilation with no effect on the acute hypoxic ventilatory response indicates that acute pain interacted with ventilatory control without modifying the effect of low-dose sevoflurane on the peripheral chemoreflex loop. Acute pain increased the level of arousal significantly during sevoflurane inhalation but did not restore the approximately 30% depression of the acute hypoxic ventilatory response by sevoflurane. The central nervous system arousal state per se did not contribute to the impairment of the acute hypoxic ventilatory response by sevoflurane.

Acute Disease↗
PubMed1996

Influence of reduced carotid body drive during sustained hypoxia on hypoxic depression of ventilation in humans.

To evaluate whether the intact hypoxic drive from the carotid bodies during sustained hypoxia is required for the generation of hypoxic depression of ventilation (VE), 16 volunteers were exposed to two consecutive periods of isocapnic hypoxia (first period 20 min; second period 5 min; end-tidal PO2 45 Torr) separated by 6 min of normoxia. In study A, saline was given. In study B, 3 micrograms.kg-1.min-1 i.v. dopamine (DA), a carotid body inhibitor, was given during the first hypoxic exposure followed by saline during normoxia and the second hypoxic exposure. In study C, 20 min of normoxia with DA preceded 6 min of normoxia and 5 min of hypoxia without DA. The first peak hypoxic VE (PHV) in study A was approximately 100% above normoxic VE. After 20 min of hypoxia, VE declined to 60% above normoxic VE. The second PHV in study A was only 60% of the first PHV. We relate this delayed recovery from hypoxia to "ongoing" effects of hypoxic depression. During DA infusion, the changes in VE due to sustained hypoxia were insignificant (study B). The second PHV in study B was not different from the PHV after air breathing in studies A and C. This indicates that the recovery from sustained hypoxia with a suppressed carotid body drive was complete within 6 min. Our results show that despite central hypoxia the absence of ventilatory changes during 20 min of isocapnic hypoxia due to intravenous DA prevented the generation of central hypoxic depression and the depression of a subsequent hypoxic response.

Adult↗
PubMed1995

Influence of hypoxic duration and posthypoxic inspired O2 concentration on short term potentiation of breathing in humans.

1. Short term potentiation (STP) of breathing refers to respiratory activity at a higher level than expected just from the dynamics of the peripheral and central chemoreceptors. In humans STP is activated by hypoxic stimulation. 2. To investigate the effects of the duration of hypoxia and the posthypoxic inspired O2 concentration on STP, the ventilatory responses to 30 s and 1, 3 and 5 min of hypoxia (end-tidal PO2, P(ET.O2) approximately 6.5 kPa) followed by normoxia (P(ET.O2) approximately 14.5 kPa) and hyperoxia (P(ET.O2) approximately 70 kPa) were studied in ten healthy subjects. End-tidal PCO2 (P(ET.CO2)) was clamped during hypoxic and recovery periods at 5.7 kPa. 3. Steady-state ventilation (VE) was 13.7 +/- 0.6 l min-1 during normoxia and increased to 15.5 +/- 0.3 l min-1 during hyperoxia (P < 0.05) due to the reduced Haldane effect and some decrease in cerebral blood flow (CBF). 4. The mean responses following hypoxia reached normoxic baseline after 69, 54, 12 and 12 s when 30 s and 1, 3 and 5 min of hypoxia, respectively, were followed by normoxia. An undershoot of 10 and 20% below hyperoxic baseline was observed when 3 and 5 min of hypoxia, respectively, were followed by hyperoxia. Hyperoxic VE reached hyperoxic baseline after 9, 15, 12 and 9 s at the termination of 30 s and 1, 3 and 5 min of hypoxia, respectively. 5. Normoxic recovery from 30 s and 1 min of hypoxia displayed a fast and subsequent slow decrease towards normoxic baseline. The fast component was attributed to the loss of the hypoxic drive at the site of the peripheral chemoreceptors, and the slow component to the decay of the STP that had been activated centrally by the stimulus. A slow decrease at the termination of 30 s and 1 min of hypoxia by hyperoxia was not observed since this component was cancelled by the increase in ventilatory output due to the reduced Haldane effect and some decrease of CBF. 6. Decay of the STP was not apparent in the normoxic recovery from 3 and 5 min of hypoxia as a slow component since it cancelled against the slow ventilatory increase related to the increase of brain tissue PCO2 due to the reduction of CBF at the relief of hypoxia. The undershoot observed when hyperoxia followed 3 and 5 min of hypoxia reflects the stimulatory effects of hyperoxia on VE. 7. The manifestation of the STP as a slow ventilatory decrease depends on the duration of hypoxia and the subsequent inspired oxygen concentration. We argue that STP is not abolished by the central depressive effects of hypoxia, although the manifestation of the STP may be overridden or counteracted by other mechanisms.

Adult↗
PubMed1995

The cyclosome, a large complex containing cyclin-selective ubiquitin ligase activity, targets cyclins for destruction at the end of mitosis.

The ubiquitin-mediated degradation of mitotic cyclins is required for cells to exit from mitosis. Previous work with cell-free systems has revealed four components required for cyclin-ubiquitin ligation and proteolysis: a nonspecific ubiquitin-activating enzyme E1, a soluble fraction containing a ubiquitin carrier protein activity called E2-C, a crude particulate fraction containing a ubiquitin ligase (E3) activity that is activated during M-phase, and a constitutively active 26S proteasome that degrades ubiquitinated proteins. Here, we identify a novel approximately 1500-kDa complex, termed the cyclosome, which contains a cyclin-selective ubiquitin ligase activity, E3-C. E3-C is present but inactive during interphase; it can be activated in vitro by the addition of cdc2, enabling the transfer of ubiquitin from E2-C to cyclin. The kinetics of E3-C activation suggest the existence of one or more intermediates between cdc2 and E3-C. Cyclosome-associated E3-C acts on both cyclin A and B, and requires the presence of wild-type N-terminal destruction box motifs in each cyclin. Ubiquitinated cyclins are then rapidly recognized and degraded by the proteasome. These results identify the cyclosome-associated E3-C as the component of the cyclin destruction machinery whose activity is ultimately regulated by cdc2 and, as such, the element directly responsible for setting mitotic cyclin levels during early embryonic cell cycles.

Animals↗
PubMed1995

Halothane affects ventilatory afterdischarge in humans.

In awake humans, when ventilatory stimulation is suddenly removed, the subsequent change in minute ventilation (which remains at higher levels for longer times than expected from the dynamics of the chemoreceptors) is termed ventilatory after discharge. In this study we investigated the effects of subanaesthetic concentrations of halothane on afterdischarge. The ventilatory pattern after sudden termination of brief periods (90-180 s) of isocapnic hypoxia (PE'cO2 approximately 0.1 kPa above initial resting values; PE'O2 6.5 kPa) by normoxia (PE'O2 14 kPa) was determined in healthy volunteers. Six subjects underwent 13 studies without halothane (control) and six others 10 studies during inhalation of 0.22% halothane. Isocapnic hypoxia caused a mean increase in ventilation of 10.8 (SD 2.4) litre min-1 in the control and 4.2 (2.4) litre min-1 in the halothane studies (P < 0.01). The transition to normoxia caused a slow ventilatory decay in the control and a fast decay in the halothane groups: the interval that occurred between the "last hypoxic" breath and the time required for ventilation to return to 110% of baseline was 60.7 (23) s for the control and 12.3 (6.0) s for the halothane studies (P < 0.05). Taking into consideration the different factors that determine the pattern of breathing immediately after termination of a brief period of hypoxia by normoxia (PE'O2 waveform, transport delay time between lungs and carotid bodies, time constant of the peripheral chemoreflex loop and afterdischarge), the faster ventilatory decay observed with halothane is probably related to suppression of afterdischarge.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

Influences of subanesthetic isoflurane on ventilatory control in humans.

BACKGROUND: The purpose of this study was to quantify in humans the effects of subanesthetic isoflurane on the ventilatory control system, in particular on the peripheral chemoreflex loop. Therefore we studied the dynamic ventilatory response to carbon dioxide, the effect of isoflurane wash-in upon sustained hypoxic steady-state ventilation, and the ventilatory response at the onset of 20 min of isocapnic hypoxia. METHODS: Study 1: Square-wave changes in end-tidal carbon dioxide tension (7.5-11.5 mmHg) were performed in eight healthy volunteers at 0 and 0.1 minimum alveolar concentration (MAC) isoflurane. Each hypercapnic response was separated into a fast, peripheral component and a slow, central component, characterized by a time constant, carbon dioxide sensitivity, time delay, and off-set (apneic threshold). Study 2: The ventilatory changes due to the wash-in of 0.1 MAC isoflurane, 15 min after the induction of isocapnic hypoxia, were studied in 11 healthy volunteers. Study 3: The ventilatory responses to a step decrease in end-tidal oxygen (end-tidal oxygen tension from 110 to 44 mmHg within 3-4 breaths; duration of hypoxia 20 min) were assessed in eight healthy volunteers at 0, 0.1, and 0.2 MAC isoflurane. RESULTS: Values are reported as means +/- SF. Study 1: The peripheral carbon dioxide sensitivities averaged 0.50 +/- 0.08 (control) and 0.28 +/- 0.05 l.min-1.mmHg-1 (isoflurane; P < 0.01). The central carbon dioxide sensitivities (control 1.20 +/- 0.12 vs. isoflurane 1.04 +/- 0.11 l.min-1.mmHg-1) and off-sets (control 36.0 +/- 0.1 mmHg vs. isoflurane 34.5 +/- 0.2 mmHg) did not differ between treatments. Study 2: Within 30 s of exposure to 0.1 MAC isoflurane, ventilation decreased significantly, from 17.7 +/- 1.6 (hypoxia, awake) to 15.0 +/- 1.5 l.min-1 (hypoxia, isoflurane). Study 3: At the initiation of hypoxia ventilation increased by 7.7 +/- 1.4 (control), 4.1 +/- 0.8 (0.1 MAC; P < 0.05 vs. control), and 2.8 +/- 0.6 (0.2 MAC; P < 0.05 vs. control) l.min-1. The subsequent ventilatory decrease averaged 4.9 +/- 0.8 (control), 3.4 +/- 0.5 (0.1 MAC; difference not statistically significant), and 2.0 +/- 0.4 (0.2 MAC; P < 0.05 vs. control) l.min-1. There was a good correlation between the acute hypoxic response and the hypoxic ventilatory decrease (r = 0.9; P < 0.001). CONCLUSIONS: The results of all three studies indicate a selective and profound effect of subanesthetic isoflurane on the peripheral chemoreflex loop at the site of the peripheral chemoreceptors. We relate the reduction of the ventilatory decrease of sustained hypoxia to the decrease of the initial ventilatory response to hypoxia.

Adult↗
PubMed1994

Components of a system that ligates cyclin to ubiquitin and their regulation by the protein kinase cdc2.

Cyclin B, a positive regulatory subunit of the cdc2 protein kinase complex, is synthesized across the cell cycle and then rapidly degraded at the end of mitosis. Degradation of cyclin B is triggered by increased levels of active cdc2 and is required for exit from mitosis. It was shown previously that cyclin degradation is carried out by the ubiquitin system, but the components responsible for the specificity and regulation of cyclin-ubiquitin ligation have not been identified. The formation of ubiquitin-protein conjugates usually requires the sequential action of three enzymes: a ubiquitin-activating enzyme (E1), a ubiquitin-carrier protein (E2), and a ubiquitin-protein ligase (E3). In this work we employed a fractionation approach to identify the components of a clam oocyte system responsible for specific ubiquitination of cyclin and to determine which components are regulated by cdc2. Experimental conditions were established under which a fusion protein containing an amino-terminal fragment of cyclin B is ligated to ubiquitin only in extracts from M-phase but not from interphase cells. Fractionation of M-phase extracts by DEAE-cellulose and high speed centrifugation yielded three fractions that were all required for cell cycle stage-specific cyclin-ubiquitin ligation. Only one of these fractions could be replaced by a previously known enzyme of the ubiquitin system, E1. A second fraction contained a novel species of E2, termed E2-C, which acts in the ligation of ubiquitin to cyclin but not to other endogenous proteins. A third component is associated with particulate material. Whereas E2-C from either M-phase or interphase extracts is active, the particulate component is active only in M-phase. Incubation of the particulate fraction from interphase cells with the protein kinase cdc2 activates it for cyclin-ubiquitin ligation, after a lag of about 30 min. These findings suggest that the particulate fraction may contain an E3 enzyme that acts on cyclin, as well as additional factors activated by cdc2.

Animals↗
PubMed1994

Effects of 20% nitrous oxide on the ventilatory response to hypercapnia and sustained isocapnic hypoxia in man.

To examine the effects of a sub-anaesthetic concentration of nitrous oxide on ventilation, we have studied the ventilatory response to carbon dioxide and isocapnic hypoxia (FIN2O 0.2). In five subjects, we performed step decreases in PE'O2 to 6.7 kPa for 15 min and step increases in PE'CO2 (delta PE'CO2 1.5 kPa). The carbon dioxide responses were partitioned into a fast peripheral and slow central component. All control oxygen responses were biphasic: the acute hypoxic response was 7.2 (4.6) litre min-1 and the subsequent decline 4.2 (2.6) litre min-1. With nitrous oxide, the acute hypoxic response was 10.3 (6.7) litre min-1, but was followed by a nonsignificant decline of 3.8 (3.0) litre min-1 because of a progressive increase in breathing frequency in the hypoxic period. None of the variables obtained from the carbon dioxide responses differed between groups. Our data indicate that a sub-anaesthetic concentration of nitrous oxide did not affect the peripheral chemoreflex loop. The hyperventilatory response to prolonged hypoxia was sustained better with nitrous oxide compared with control.

Adult↗
PubMed1994

Effects of subanesthetic halothane on the ventilatory responses to hypercapnia and acute hypoxia in healthy volunteers.

BACKGROUND: The peripheral chemoreceptors are responsible for the ventilatory response to hypoxia (acute hypoxic response) and for 30% of the normoxic hypercapnic ventilatory response. To quantify the effects of subanesthetic concentrations of halothane on the respiratory control system, in particular on the peripheral chemoreceptors, we studied the response of humans to carbon dioxide and oxygen at two subanesthetic concentrations of halothane. METHODS: Square-wave changes in end-tidal carbon dioxide tension (7.5-11.3 mmHg) and step decreases in end-tidal oxygen tension (arterial hemoglobin oxygen saturation 82 +/- 2%; duration of hypoxia 5 min) were performed in nine healthy male subjects during 0, 0.05 (HA-1), and 0.1 minimum alveolar concentration (HA-2) halothane. Each hypercapnic response was separated into a fast, peripheral component and a slow, central component, characterized by a time constant, carbon dioxide sensitivity, time delay, and off-set. RESULTS: Fifty-six carbon dioxide responses and 27 oxygen responses were obtained. The peripheral carbon dioxide sensitivities averaged to 0.76 +/- 0.14 l.min-1.mmHg-1 (control), 0.50 +/- 0.12 l.min-1.mmHg-1 (HA-1), and 0.30 +/- 0.08 l.min-1.mmHg-1 (HA-2; P < 0.01 vs. control). The central carbon dioxide sensitivity did not differ significantly among treatment groups (control, 1.47 +/- 0.22 l.min-1.mmHg-1; HA-1, 1.41 +/- 0.51 l.min-1.mmHg-1; and HA-2, 1.23 +/- 0.30 l.min-1.mmHg-1). The time constants of the central chemoreflex loop showed a large decrease during the administration of 0.1 minimum alveolar concentration halothane. The acute hypoxic response declined from 15.0 +/- 3.9 l.min-1 to 10.9 +/- 2.9 l.min-1 (HA-1) and 4.8 +/- 1.4 l.min-1 (HA-2; P < 0.01 vs. control and HA-1). All values are means +/- SEM. CONCLUSIONS: The results show depression of the ventilatory responses to hypoxia and hypercapnia during inhalation of subanesthetic concentrations of halothane. The depression is attributed to a selective effect of halothane on the peripheral chemoreflex loop. The oxygen and carbon dioxide responses mediated by the peripheral chemoreceptors are affected proportionally. It is argued that the decrease in central time constants is caused by an effect of halothane on central neuronal dynamics.

Administration, Inhalation↗
PubMed1994

Influence of a subanesthetic concentration of halothane on the ventilatory response to step changes into and out of sustained isocapnic hypoxia in healthy volunteers.

BACKGROUND: In humans the ventilatory response to isocapnic hypoxia is biphasic: an initial increase in minute ventilation (VE) from baseline, the acute hypoxic response, is followed after 3-5 min by a slow ventilatory decay, the hypoxic ventilatory decline, and a new steady state, 25-40% greater than baseline VE, is reached in about 15-20 min. The transition from 20 min of isocapnic hypoxia into normoxia results in a rapid decrease in VE, the off-response. In humans, halothane, at subanesthetic concentrations, is known to decrease the acute hypoxic response. In order to investigate the effects of halothane on sustained hypoxia we quantified the effects of 0.15 minimum alveolar concentration halothane on the ventilatory response at the onset of 20 min of hypoxia and at the termination of 20 min of hypoxia by normoxia in healthy volunteers. METHODS: Step changes in end-tidal oxygen tension were performed against a background of constant mild hypercapnia (end-tidal carbon dioxide tension about 1 mmHg above individual resting values) in fourteen male subjects. The end-tidal oxygen tension was forced as follows: 5-10 min at 110 mmHg, 20 min at 44 mmHg, and 10 min at 110 mmHg. In each subject we performed one trial before and one during 0.15 minimum alveolar concentration halothane administration. RESULTS: Ten responses into hypoxia and nine out of hypoxia were considered for analysis. All control trials were performed during wakefulness. Using behavioral characteristics, the central nervous system arousal state of the subjects during halothane inhalation was defined as "anesthesia-induced hypnosis." The acute hypoxic response averaged 10.4 +/- 4.7 l/min for control versus 3.7 +/- 2.4 l/min for halothane trials (P < 0.01). The hypoxic ventilatory decline was 4.8 +/- 2.5 l/min versus 3.9 +/- 2.9 l/min (NS), the off-response was 6.7 +/- 3.2 l/min versus 3.7 +/- 3.0 l/min (P < 0.05) for control versus halothane, respectively. All values are mean +/- SD. CONCLUSIONS: Our results indicate that halothane caused VE to be less than control levels during acute and sustained hypoxia as well as when sustained hypoxia is replaced by normoxia. It is argued that the depression of VE during acute hypoxia is attributed to an effect of halothane on the peripheral chemoreceptors. During sustained hypoxia halothane had no effect on the magnitude of the hypoxic ventilatory decrease, which is probably related to an increase by halothane of inhibitory neuromodulators within the central nervous system. With halothane, the ventilatory decrease when sustained hypoxia is replaced by normoxia is related to the removal of the hypoxic drive at the site of the peripheral chemoreceptors.

Adult↗
PubMed1994

Does subanesthetic isoflurane affect the ventilatory response to acute isocapnic hypoxia in healthy volunteers?

BACKGROUND: Differences in results studying the effects of subanesthetic concentrations of volatile agents on the hypoxic ventilatory response may be related to the conditions under which the subjects were tested. In this study we investigated the effects of 0.1 minimum alveolar concentration (MAC) of isoflurane on the hypoxic ventilatory response without and with audiovisual stimulation. METHODS: Step decreases in arterial hemoglobin oxygen saturation from normoxia into hypoxia (arterial hemoglobin oxygen saturation 80% +/- 2%; duration of hypoxia 5 min) were performed in ten healthy subjects. We obtained four responses per subject: one without isoflurane in a darkened, quiet room; one without isoflurane with audiovisual input (music videos); one in a darkened room at 0.1 MAC isoflurane; and one at 0.1 MAC isoflurane with audiovisual input (subjects were addressed to keep their eyes open). Experiments were performed against a background of isocapnia (end-tidal carbon dioxide tension 1-1.4 mmHg above initial resting values). RESULTS: The hypoxic responses averaged 0.54 +/- 0.09 1.min-1.%-1 (without isoflurane in a darkened, quiet room), 0.27 +/- 0.06 l-min-1.%-1 (in a darkened room at 0.1 MAC isoflurane; P < 0.01), 0.56 +/- 0.131.min-1.%-1 (without isoflurane with audiovisual input), and 0.47 +/- 0.13 l.min-1.%-1 (at 0.1 MAC isoflurane with audiovisual input). Values are means +/- SE. During 0.1 MAC isoflurane administration, all subjects showed a depressed hypoxic response when not stimulated, while with stimulation two subjects had an increased response, four a decreased response and four an unchanged response compared to control. CONCLUSIONS: We observed an important effect of the study conditions on the effects that 0.1 MAC isoflurane has on the hypoxic ventilatory response. A depressant effect of subanesthetic isoflurane was found only when external stimuli to the subjects were absent. With extraneous audiovisual stimuli the effect of isoflurane on the response to hypoxia was more variable. On the average, however, the response then was not depressed by isoflurane.

Acoustic Stimulation↗
PubMed1994

The ecdysone response enhancer of the Fbp1 gene of Drosophila melanogaster is a direct target for the EcR/USP nuclear receptor.

The transcription of the Drosophila melanogaster Fbp1 gene is induced by the steroid hormone 20-hydroxyecdysone and restricted to the late-third-instar fat body tissue. In a previous study we showed that the -68 to -138 region relative to the transcription start site acts as an ecdysone-dependent third-instar fat body-specific enhancer in a transgenic assay. Here we report that seven nucleoprotein complexes are formed in vitro on this enhancer when a nuclear extract from late-third-instar fat body is used in a gel shift assay. Accurate mapping of the binding sites of the complexes revealed a remarkably symmetrical organization. Using specific antibodies, one of the complexes was identified as a heterodimer consisting of the ecdysone receptor (EcR) and Ultraspiracle (USP) proteins. The binding site of the heterodimer as defined by mutagenesis and methylation interference experiments bears strong sequence similarity to the canonical hsp27 ecdysone response element, including an imperfect palindromic structure. The two elements diverge at three positions in both half-sites, indicating that the structure of an active EcR/USP binding site allows considerable sequence variations. In vivo footprinting experiments using ligation-mediated PCR and wild-type or ecdysteroid-deficient larvae show that occupancy of the Fbp1 EcR/USP binding site and adjacent region is dependent on a high concentration of ecdysteroids. These results provide strong evidence for a direct role of the EcR/USP heterodimer in driving gene expression in response to changes of the ecdysteroid titer during Drosophila larval development.

Adipose Tissue↗
PubMed1992

Modelling the dynamic ventilatory response to hypoxia in humans.

A two-component dynamic model was used to describe the ventilatory response to sustained hypoxia in humans. One component (Xs) represents the stimulating effects of hypoxia and the other component (Xd), the hypoxic ventilatory decline. The total ventilatory response to hypoxia is represented by the sum of the two components. A nonlinearity is included to account for the nonlinear steady-state ventilatory response to hypoxia. A sensitivity analysis of the model indicates that, with a step change in F(ETO2) as the input, all the parameters can be estimated from the data except for the nonlinearity. The relative sensitivity of the parameters from the model analysis was confirmed in an experimental study. However, comparing steps into hypoxia versus steps out of hypoxia we found a decrease in the gains of both components. The most likely explanation for the decrease in the gains is that the combination of Xs and Xd is not entirely additive. Other models may be required to completely describe the ventilatory response to inputs more complex than steps.

Adult↗
PubMed1992

The ventilatory response to CO2 of the peripheral and central chemoreflex loop before and after sustained hypoxia in man.

1. The ventilatory response to sustained hypoxia is characterized by a fast increase due to the peripheral chemoreceptors followed by a slow decline. The mechanism of this decline is unknown. 2. To investigate the characteristics of the ventilatory response to sustained hypoxia ten healthy subjects were exposed to two consecutive periods of isocapnic hypoxia (arterial saturation 78%) separated by a 5 min exposure to isocapnic normoxia. 3. The acute hypoxic response to the second exposure to hypoxia (mean increase in ventilation +/- S.E.M., 7.2 +/- 0.8 l min-1) was significantly depressed (P = 0.04) compared to the first one (9.5 +/- 1.3 l min-1). 4. To investigate whether this depression was due to central or peripheral effects or both we measured, in the same ten subjects, the normoxic ventilatory response to CO2 before and after a period of 25 min of hypoxia using the technique of dynamic end-tidal forcing. 5. Each response was separated into a fast peripheral and slow central component characterized by a CO2 sensitivity, time constant, time delay and an off-set. 6. A total of thirty-six prehypoxic and thirty posthypoxic responses were analysed. The ventilatory CO2 sensitivities of the peripheral and central chemoreflex loops and the overall off-set (apnoeic threshold) after 25 min of hypoxia were somewhat larger than their prehypoxic values, but this effect was not significant. 7. We argue that the hypoxic ventilatory decline in man is due to a change in the off-set of the peripheral chemoreflex loop.

Adult↗
PubMed1991

Effect of i.v. midazolam on the ventilatory response to sustained hypoxia in man.

The ventilatory response to isocapnic, sustained hypoxia is characterized by initial hyperventilation followed by ventilatory decline. The ventilatory response to isocapnic sustained hypoxia during i.v. administration of midazolam was assessed in five healthy subjects. Compared with control experiments, the hyperventilatory effect of hypoxia was not decreased following administration of midazolam. The hypoxic ventilatory change was significantly greater with midazolam because of a decrease in tidal volume.

Adult↗
PubMed1990

Receptor binding of somatostatin-14 and somatostatin-28 in rat brain: differential modulation by nucleotides and ions.

The tissue-selective binding of the two principal bioactive forms of somatostatin, somatostatin-14 (SS-14) and somatostatin-28 (SS-28), their ability to modulate cAMP-dependent and -independent regulation of post-receptor events to different degrees and the documentation of specific labelling of SS receptor subtypes with SS-28 but not SS-14 in discrete regions of rat brain suggest the existence of distinct SS-14 and SS-28 binding sites. Receptor binding of SS-14 ligands has been shown to be modulated by nucleotides and ions, but the effect of these agents on SS-28 binding has not been studied. In the present study we investigated the effects of adenine and guanine nucleotides as well as monovalent and divalent cations on rat brain SS receptors quantitated with radioiodinated analogs of SS-14 ([125I-Tyr11]SS14, referred to in this paper as SS-14) and SS-28 ([Leu8, D-Trp22, 125I-Tyr25] SS-28, referred to as LTT* SS-28) in order to determine if distinct receptor sites for SS-14 and SS-28 could be distinguished on the basis of their modulation by nucleotides and ions. GTP as well as ATP exerted a dose-dependent inhibition (over a concentration range of 10(-7)-10(-3) M) of the binding of the two radioligands. The nucleotide inhibition of binding resulted in a decrease the Bmax of the SS receptors, the binding affinity remaining unaltered. GTP (10(-4) M) decreased the Bmax of LTT* SS-28 binding sites to a greater extent than ATP (145 +/- 10 and 228 +/- 16 respectively, compared to control value of 320 +/- 20 pmol mg-1). Under identical conditions GTP was less effective than ATP in reducing the number of T* SS-14 binding sites (Bmax = 227 +/- 8 and 182 +/- 15, respectively, compared to 340 +/- 15 pmol mg-1 in the absence of nucleotides). Monovalent cations inhibited the binding of both radioligands, Li+ and Na+ inhibited the binding of T* SS-14 to a greater extent than K+. The effect of divalent cations on the other hand was varied. At low concentration (2 mM) Mg2+, Ba2+, Mn2+, Ca2+ and Co2+ augmented the binding of both T* SS-14 and LTT* SS-28, while higher than 4 mM Co2+ inhibited binding of both ligands. LTT* SS-28 binding was reduced in the presence of high concentrations of Ba2+ and Mn2+ also. Interestingly Ca2+ at higher than 10 mM preferentially inhibited LTT* SS-28 binding and increased the affinity of SS-14 but not SS-28 for LTT* SS-28 binding sites.(ABSTRACT TRUNCATED AT 400 WORDS)

Adenosine Triphosphate↗