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  • American Physiological Society  (41)
  • Leiter, J. C.  (41)
  • 1
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    Polycythemic responses to hypoxia: molecular and genetic mechanisms of chronic mountain sickness
    American Physiological Society ; 1998
    In:  Journal of Applied Physiology Vol. 84, No. 4 ( 1998-04-01), p. 1242-1251
    Details
    In: Journal of Applied Physiology, American Physiological Society, Vol. 84, No. 4 ( 1998-04-01), p. 1242-1251
    Abstract: We examined erythropoietin (EPO) gene expression and EPO production during hypoxia in two Sprague-Dawley rat strains with divergent polycythemic responses to hypoxia. Hilltop (H) rats develop severe polycythemia, severe hypoxemia, and pulmonary artery hypertension. The H rats often die from a syndrome indistinguishable from chronic mountain sickness (CMS) in humans. Madison (M) rats develop polycythemia and pulmonary artery hypertension that is modest and suffer no excess mortality. We tested the hypothesis that these rat strains have different stimulus-response characteristics governing EPO production. Rats of each strain were exposed to hypoxia (0.5 atm, 73 Torr inspired [Formula: see text]), and renal tissue EPO mRNA and EPO levels, plasma EPO, ventilation, arterial and renal venous blood gases, and indexes of renal function were measured at fixed times during a 30-day hypoxic exposure. During extended hypoxic exposure, H rats had significantly elevated renal EPO mRNA, renal EPO, and plasma EPO levels compared with M rats. Ventilatory responses and indexes of renal function were similar in the strains during the hypoxic exposure. H rats had greater arterial hypoxemia from the onset of hypoxia and more severe renal tissue hypoxemia and greater polycythemia after 14 days of hypoxic exposure. When EPO responses were expressed as functions of renal venous[Formula: see text] , the two strains appeared to lie on the same dose-response curves, but the responses of H rats were shifted along the curve toward more hypoxic values. We conclude that H rats have significantly greater polycythemia secondary to poorer renal tissue oxygenation, but the stimulus-response characteristics governing EPO gene expression and EPO production do not seem to differ between M and H rats. Finally, the regulation of EPO levels during hypoxia occurs primarily at the transcriptional level.
    Type of Medium: Online Resource
    ISSN: 8750-7587 , 1522-1601
    URL: Article
    DOI: 10.1152/jappl.1998.84.4.1242
    RVK:
    WA 15000
    RVK:
    XA 52094
    Language: English
    Publisher: American Physiological Society
    Publication Date: 1998
    detail.hit.zdb_id: 1404365-8
    SSG: 12
    SSG: 31
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  • 2
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    Pathophysiological effects of hemodilution in chronic mountain sickness in rats
    American Physiological Society ; 1996
    In:  Journal of Applied Physiology Vol. 80, No. 2 ( 1996-02-01), p. 574-582
    Details
    In: Journal of Applied Physiology, American Physiological Society, Vol. 80, No. 2 ( 1996-02-01), p. 574-582
    Abstract: We examined the effect of isovolemic hemodilution in a rat model of chronic mountain sickness (CMS). After 30 days at simulated high altitude (5,500 m), Hilltop rats had developed evidence of CMS: severe hypoxemia, polycythemia, and pulmonary arterial hypertension. Isovolemic hemodilution to a mean hematocrit of 46 +/- 5% was well tolerated by both the hypoxia-sensitive Hilltop rats and the companion Madison rat strain that does not develop CMS. After hemodilution, we found no evidence of sustained improvements in ventilation or gas exchange in either strain. Despite the fall in blood viscosity, cardiac output increased only marginally, and pulmonary arterial hypertension persisted in the Hilltop rats. Vascular hindrance increased after hemodilution, preventing a significant decline in pulmonary and systemic vascular resistances in the Hilltop rats. Blood O2 content and the coefficient of O2 delivery fell after hemodilution, but O2 consumption was sustained at a normal level after hemodilution by increasing the extraction fraction in the Hilltop strain. There was systemic hypotension through the first day of hemodilution, but this was the only apparent adverse effect of hemodilution. We conclude that isovolemic hemodilution was well tolerated despite the reduction in tissue O2 delivery. However, hemodilution failed to improve any of the respiratory and cardiovascular manifestations of CMS in Hilltop rats.
    Type of Medium: Online Resource
    ISSN: 8750-7587 , 1522-1601
    URL: Article
    DOI: 10.1152/jappl.1996.80.2.574
    RVK:
    WA 15000
    RVK:
    XA 52094
    Language: English
    Publisher: American Physiological Society
    Publication Date: 1996
    detail.hit.zdb_id: 1404365-8
    SSG: 12
    SSG: 31
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  • 3
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    Ventilatory and hematopoietic responses to chronic hypoxia in two rat strains
    American Physiological Society ; 1992
    In:  Journal of Applied Physiology Vol. 72, No. 6 ( 1992-06-01), p. 2354-2363
    Details
    In: Journal of Applied Physiology, American Physiological Society, Vol. 72, No. 6 ( 1992-06-01), p. 2354-2363
    Abstract: Hilltop (H) and Madison (M) strains of Sprague-Dawley rats exhibit strikingly different susceptibilities to the effects of chronic altitude exposure. The H rats develop greater polycythemia, hypoxemia, and pulmonary hypertension. We studied ventilation, pulmonary gas exchange, tissue oxygenation, and hematologic adaptations in the two rat strains during a 50-day exposure to a simulated altitude (HA) of 5,500 m (18,000 ft). There were no strain differences among the variables we studied under sea level (SL) conditions. Within the first 14 days of hypoxic exposure, the only significant strain differences were that erythropoietin (EPO) rose much higher and erythroid activity was greater in the H rats, even though arterial Po2 and PCo2 (Pao2 and PaCo2, respectively), renal venous PO2 (Prvo2), and ventilation (VE) were equivalent in the two strains during this time. By day 14 at HA, the H rats had significantly higher erythroid activity, hematocrit (Hct), and EPO levels, significantly lower PaO2 and PrvO2, but equivalent VE and PaCO2. These changes persisted for the remainder of the exposure, except that the Hct continued to rise and the increase was greater in H rats. Despite the greater O2-carrying capacity of H rats in the later stages of hypoxic exposure, PaO2 and PrvO2 were significantly lower in H rats. There were no strain differences at either SL or HA in ventilatory responses to hypercapnia or hypoxia, in blood O2 affinity or 2,3-diphosphoglycerate, in extrarenal production of EPO, or in EPO clearance. We conclude that early in the hypoxic exposure the H rats produce more EPO at apparently equivalent levels of hypoxia, and this is the first step in the pathogenesis of the maladaptation to HA manifest by H rats. We find no consistent evidence that differences in VE contribute to the variable susceptibility to hypoxia in the two rat strains.
    Type of Medium: Online Resource
    ISSN: 8750-7587 , 1522-1601
    URL: Article
    DOI: 10.1152/jappl.1992.72.6.2354
    RVK:
    WA 15000
    RVK:
    XA 52094
    Language: English
    Publisher: American Physiological Society
    Publication Date: 1992
    detail.hit.zdb_id: 1404365-8
    SSG: 12
    SSG: 31
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  • 4
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    Identification of respiratory vagal feedback in awake normal subjects using pseudorandom unloading
    American Physiological Society ; 2001
    In:  Journal of Applied Physiology Vol. 90, No. 6 ( 2001-06-01), p. 2330-2340
    Details
    In: Journal of Applied Physiology, American Physiological Society, Vol. 90, No. 6 ( 2001-06-01), p. 2330-2340
    Abstract: Evidence of the Hering-Breuer reflex has been found in humans during anesthesia and sleep but not during wakefulness. Cortical influences, present during wakefulness, may mask the effects of this reflex in awake humans. We hypothesized that, if lung volume were increased in awake subjects unaware of the stimulus, vagal feedback would modulate breathing on a breath-to-breath basis. To test this hypothesis, we employed proportional assist ventilation in a pseudorandom sequence to unload the respiratory system above and below the perceptual threshold in 17 normal subjects. Tidal volume, integrated respiratory muscle pressure per breath, and inspiratory time were recorded. Both sub- and suprathreshold stimulation evoked a significant increase in tidal volume and inspiratory flow rate, but a significant decrease in inspiratory time was present only during the application of a subthreshold stimulus. We conclude that vagal feedback modulates respiratory timing on a breath-by-breath basis in awake humans, as long as there is no awareness of the stimulus.
    Type of Medium: Online Resource
    ISSN: 8750-7587 , 1522-1601
    URL: Article
    DOI: 10.1152/jappl.2001.90.6.2330
    RVK:
    WA 15000
    RVK:
    XA 52094
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2001
    detail.hit.zdb_id: 1404365-8
    SSG: 12
    SSG: 31
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  • 5
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    Diaphragmatic electromyography using a multiple electrode array
    American Physiological Society ; 1989
    In:  Journal of Applied Physiology Vol. 67, No. 4 ( 1989-10-01), p. 1525-1534
    Details
    In: Journal of Applied Physiology, American Physiological Society, Vol. 67, No. 4 ( 1989-10-01), p. 1525-1534
    Abstract: We have developed a new technique for diaphragmatic electromyography using an array of seven sequential electrode pairs at 1.0-cm spacing on an esophageal catheter. This array provides information about the spatial distribution of the electrical field generated by the diaphragm and reveals a sharply peaked variation of electrical potential with distance along the esophagus. The rectified and integrated information from each of the seven pairs is summed to give an approximation to the total electrical activity over the span of the array, providing a signal that is relatively insensitive to the position of the array over approximately 4 cm of catheter movement and removes the requirement for balloon stabilization of the catheter. With our array, we have confirmed the artifact in the evoked compound muscle action potential that seems to be related to diaphragmatic shape as reported by others who used supramaximal phrenic nerve stimulation, but the magnitude of this artifact (compared with the functional residual capacity level) was modest near functional residual capacity, averaging 12 +/- 14% (SD) for lung volumes 1.0 l above and -4 +/- 15% for lung volumes 1.0 l below functional residual capacity along the rib cage-abdomen relaxation line.
    Type of Medium: Online Resource
    ISSN: 8750-7587 , 1522-1601
    URL: Article
    DOI: 10.1152/jappl.1989.67.4.1525
    RVK:
    WA 15000
    RVK:
    XA 52094
    Language: English
    Publisher: American Physiological Society
    Publication Date: 1989
    detail.hit.zdb_id: 1404365-8
    SSG: 12
    SSG: 31
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  • 6
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    Role of the spleen in the exaggerated polycythemic response to hypoxia in chronic mountain sickness in rats
    American Physiological Society ; 1999
    In:  Journal of Applied Physiology Vol. 87, No. 5 ( 1999-11-01), p. 1901-1908
    Details
    In: Journal of Applied Physiology, American Physiological Society, Vol. 87, No. 5 ( 1999-11-01), p. 1901-1908
    Abstract: In a rat model of chronic mountain sickness, the excessive polycythemic response to hypoxic exposure is associated with profound splenic erythropoiesis. We studied the uptake and distribution of radioactive iron and red blood cell (RBC) morphology in intact and splenectomized rats over a 30-day hypoxic exposure. Retention of 59 Fe in the plasma was correlated with 59 Fe uptake by both spleen and marrow and the appearance of 59 Fe-labeled RBCs in the blood. 59 Fe uptake in both the spleen and the marrow paralleled the production of nucleated RBCs. Splenic 59 Fe uptake was ∼10% of the total marrow uptake under normoxic conditions but increased to 60% of the total marrow uptake during hypoxic exposure. Peak splenic 59 Fe uptake and splenomegaly occurred at the most intense phase of erythropoiesis and coincided with the rapid appearance of 59 Fe-labeled RBCs in the blood. The bone marrow remains the most important erythropoietic organ under both resting and stimulated states, but inordinate splenic erythropoiesis in this rat strain accounts in large measure for the excessive polycythemia during the development of chronic mountain sickness in chronic hypoxia.
    Type of Medium: Online Resource
    ISSN: 8750-7587 , 1522-1601
    URL: Article
    DOI: 10.1152/jappl.1999.87.5.1901
    RVK:
    WA 15000
    RVK:
    XA 52094
    Language: English
    Publisher: American Physiological Society
    Publication Date: 1999
    detail.hit.zdb_id: 1404365-8
    SSG: 12
    SSG: 31
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  • 7
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    Control of segmental upper airway resistance in patients with obstructive sleep apnea
    American Physiological Society ; 1993
    In:  Journal of Applied Physiology Vol. 74, No. 6 ( 1993-06-01), p. 2694-2703
    Details
    In: Journal of Applied Physiology, American Physiological Society, Vol. 74, No. 6 ( 1993-06-01), p. 2694-2703
    Abstract: We sought to determine if the upper airway response to an added inspiratory resistive load (IRL) during wakefulness could be used to predict the site of upper airway collapse in patients with obstructive sleep apnea (OSA). In 10 awake patients with OSA, we investigated the relationship between resistance in three segments of the upper airway (nasal, nasopharyngeal, and oropharyngeal) and three muscles known to influence these segments (alae nasi, tensor veli palatini, and genioglossus) while the patient breathed with or without a small IRL (2 cmH2O.l–1.s). During IRL, patients with OSA exhibited increased nasopharyngeal resistance and no significant increase in either the genioglossus or tensor veli palatini activities. Neither nasal resistance nor alae nasi EMG activity was affected by IRL. We contrasted this to the response of five normal subjects, in whom we found no change in the resistance of either segment of the airway and no change in the genioglossus EMG but a significant activation of the tensor palatini. In six patients with OSA, we used the waking data to predict the site of upper airway collapse during sleep and we had limited success. The most successful index (correct in 4 of 6 patients) incorporated the greatest relative change in segmental resistance during IRL at the lowest electromyographic activity. We conclude, in patients with OSA, IRL narrows the more collapsible segment of the upper airway, in part due to inadequate activation of upper airway muscles. However, it is difficult to predict the site of upper airway collapse based on the waking measurements where upper airway muscle activity masks the passive airway characteristics.
    Type of Medium: Online Resource
    ISSN: 8750-7587 , 1522-1601
    URL: Article
    DOI: 10.1152/jappl.1993.74.6.2694
    RVK:
    WA 15000
    RVK:
    XA 52094
    Language: English
    Publisher: American Physiological Society
    Publication Date: 1993
    detail.hit.zdb_id: 1404365-8
    SSG: 12
    SSG: 31
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  • 8
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    Role of sex hormones in development of chronic mountain sickness in rats
    American Physiological Society ; 1994
    In:  Journal of Applied Physiology Vol. 77, No. 1 ( 1994-07-01), p. 427-433
    Details
    In: Journal of Applied Physiology, American Physiological Society, Vol. 77, No. 1 ( 1994-07-01), p. 427-433
    Abstract: After chronic exposure to hypoxia, Hilltop Sprague-Dawley rats developed excessive polycythemia and severe pulmonary hypertension and right ventricular (RV) hypertrophy, signs consistent with human chronic mountain sickness; however, there were gender differences in the magnitude of the polycythemia and susceptibility to the fatal consequence of chronic mountain sickness. Orchiectomy and ovariectomy were performed to evaluate the role of sex hormones in the gender differences in these hypoxic responses. After 40 days of exposure to simulated high altitude (5,500 m; barometric pressure of 370 Torr and inspired Po2 of 73 Torr), both sham-gonadectomized male and female rats developed polycythemia and had increased RV peak systolic pressure and RV hypertrophy. The hematocrit was slightly but significantly higher in males than in females. Orchiectomy did not affect these hypoxic responses, although total ventricular weight was less in the castrated high-altitude rats. At high altitude, the mortality rates were 67% in the sham-operated male rats and 50% in the castrated animals. In contrast, ovariectomy aggravated the high-altitude-associated polycythemia and increased RV peak systolic pressure and RV weight compared with the sham-operated high-altitude female rats. Both sham-operated control and ovariectomized females suffered negligible mortality at high altitude. The present study demonstrated that 1) the male sex hormones play no role in the development of the excessive polycythemia, pulmonary hypertension, and RV hypertrophy during chronic hypoxic exposure or in the associated high mortality and 2) the female sex hormones suppressed both the polycythemic and cardiopulmonary responses in vivo during chronic hypoxic exposure.
    Type of Medium: Online Resource
    ISSN: 8750-7587 , 1522-1601
    URL: Article
    DOI: 10.1152/jappl.1994.77.1.427
    RVK:
    WA 15000
    RVK:
    XA 52094
    Language: English
    Publisher: American Physiological Society
    Publication Date: 1994
    detail.hit.zdb_id: 1404365-8
    SSG: 12
    SSG: 31
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  • 9
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    Heterogeneous patterns of pH regulation in glial cells in the dorsal and ventral medulla
    American Physiological Society ; 2004
    In:  American Journal of Physiology-Regulatory, Integrative and Comparative Physiology Vol. 286, No. 2 ( 2004-02), p. R289-R302
    Details
    In: American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, American Physiological Society, Vol. 286, No. 2 ( 2004-02), p. R289-R302
    Abstract: We examined pH regulation in two chemosensitive areas of the brain, the retrotrapezoid nucleus (RTN) and the nucleus tractus solitarius (NTS), to identify the proton transporters involved in regulation of intracellular pH (pH i ) in medullary glia. Transverse brain slices from young rats [postnatal day 8 (P8) to P20] were loaded with the pH-sensitive probe 2′,7′-bis (2-carboxyethyl)-5,6-carboxyfluorescein after kainic acid treatment removed neurons. Cells were alkalinized when they were depolarized (extracellular K + increased from 6.24 to 21.24 mM) in the RTN but not in the NTS. This alkaline shift was inhibited by 0.5 mM DIDS. Removal of [Formula: see text] or Na + from the perfusate acidified the glial cells, but the acidification after Na + removal was greater in the RTN than in the NTS. Treatment of the slice with 5-( N-ethyl- N-isopropyl)amiloride (100 μM) in saline containing [Formula: see text] acidified the cells in both nuclei, but the acidification was greater in the NTS. Restoration of extracellular Cl - after Cl - depletion during the control condition acidified the cells. Immunohistochemical studies of glial fibrillary acid protein demonstrated much denser staining in the RTN compared with the NTS. We conclude that there is evidence of [Formula: see text] cotransport and Na + /H + exchange in glia in the RTN and NTS, but the distribution of glia and the distribution of these pH-regulatory functions are not identical in the NTS and RTN. The differential strength of glial pH regulatory function in the RTN and NTS may also alter CO 2 chemosensory neuronal function at these two chemosensitive sites in the brain stem.
    Type of Medium: Online Resource
    ISSN: 0363-6119 , 1522-1490
    URL: Article
    DOI: 10.1152/ajpregu.00245.2003
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2004
    detail.hit.zdb_id: 1477297-8
    SSG: 12
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  • 10
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    Chemosensory Responses to CO 2 in Multiple Brain Stem Nuclei Determined Using a Voltage-Sensitive Dye in Brain Slices From Rats
    American Physiological Society ; 2009
    In:  Journal of Neurophysiology Vol. 102, No. 3 ( 2009-09), p. 1577-1590
    Details
    In: Journal of Neurophysiology, American Physiological Society, Vol. 102, No. 3 ( 2009-09), p. 1577-1590
    Abstract: We used epifluorescence microscopy and a voltage-sensitive dye, di-8-ANEPPS, to study changes in membrane potential during hypercapnia with or without synaptic blockade in chemosensory brain stem nuclei: the locus coeruleus (LC), the nucleus of the solitary tract, lateral paragigantocellularis nucleus, raphé pallidus, and raphé obscurus and, in putative nonchemosensitive nuclei, the gigantocellularis reticular nucleus and the spinotrigeminal nucleus. We studied the response to hypercapnia in LC cells to evaluate the performance characteristics of the voltage-sensitive dye. Hypercapnia depolarized many LC cells and the voltage responses to hypercapnia were diminished, but not eradicated, by synaptic blockade (there were intrinsically CO 2 -sensitive cells in the LC). The voltage response to hypercapnia was substantially diminished after inhibiting fast Na + channels with tetrodotoxin. Thus action potential–related activity was responsible for most of the optical signal that we detected. We systematically examined CO 2 sensitivity among cells in brain stem nuclei to test the hypothesis that CO 2 sensitivity is a ubiquitous phenomenon, not restricted to nominally CO 2 chemosensory nuclei. We found intrinsically CO 2 sensitive neurons in all the nuclei that we examined; even the nonchemosensory nuclei had small numbers of intrinsically CO 2 sensitive neurons. However, synaptic blockade significantly altered the distribution of CO 2 -sensitive cells in all of the nuclei so that the cellular response to CO 2 in more intact preparations may be difficult to predict based on studies of intrinsic neuronal activity. Thus CO 2 -sensitive neurons are widely distributed in chemosensory and nonchemosensory nuclei and CO 2 sensitivity is dependent on inhibitory and excitatory synaptic activity even within brain slices. Neuronal CO 2 sensitivity important for the behavioral response to CO 2 in intact animals will thus be determined as much by synaptic mechanisms and patterns of connectivity throughout the brain as by intrinsic CO 2 sensitivity.
    Type of Medium: Online Resource
    ISSN: 0022-3077 , 1522-1598
    URL: Article
    DOI: 10.1152/jn.00381.2009
    RVK:
    XA 10000 ; XA 552555
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2009
    detail.hit.zdb_id: 80161-6
    detail.hit.zdb_id: 1467889-5
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