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Biomedical subjects

N S Cherniack

Publications and source records attributed to N S Cherniack.

At least 37 records · Page 2Linked to original sources
PubMed1996

The brainstem network involved in coordination of inspiratory activity and cholinergic outflow to the airways.

The respiratory rhythm modulates cholinergic outflow to the tracheal smooth muscle through the parasympathetic nerves. To determine the basis of this modulation, we combined the retrograde tracer technique to identify bulbospinal cells projecting to phrenic motoneurons, and the transneuronal labeling method to visualize medullary neurons that innervate airway-related vagal preganglionic cells. Following injections of fluorogold into the ventral horns of the cervical spinal cord and injections of pseudorabies virus (PRV) into the wall of the extrathoracic trachea of superior cervical ganglioctomized Sprague-Dawley rats. A large number of the double-labeled cells were identified along the ventral aspect of the medulla oblongata. Most frequently, double-labeled neurons were seen in the medial tegmental field, particularly in the parapyramidal region, within the gigantocellular nuclei, and the caudal raphe nuclei. Less frequently, double-labeled neurons were found in the ventrolateral medulla. No double-labeled cell was observed in the dorsal aspect of the medulla oblongata. This study indicates that a subset of medullary neurons that project to phrenic motoneurons also innervate the airway-related vagal preganglionic cells, allowing the coupling of inspiratory activity and parasympathetic outflow to the airways.

Animals↗
PubMed1996

Effects of changes in ventilation on respiratory discomfort during isocapnic exercise.

We studied the effects of changes in the level of ventilation on respiratory discomfort during isocapnic exercise. Six subjects exercised at 60 W on a cycle ergometer. They initially breathed 2.5% CO2 in oxygen for 75 breaths. Ventilatory parameters of the last 10 breaths were used as controls. In 7 subsequent test sessions each lasting 2 min alternating with 2 min free breathing periods, subjects tried to achieve a target ventilation ranging from 0.7 to 1.3 times the control with a visual feedback system. End-tidal CO2 was regulated automatically at the control level by changing the inspired CO2. Breathing discomfort was measured at the end of each session using a visual analog scale. Isocapnic constraining of ventilation (0.7 times the control) during exercise significantly increased respiratory discomfort (p < 0.05). Increases in ventilation had no significant effect. These results indicate that respiratory discomfort during exercise is exaggerated when the level of ventilation falls below that spontaneously adopted even when chemical drives are held constant.

Adult↗
PubMed1996

CO2-induced c-fos expression in the CNS catecholaminergic neurons.

In these studies we examined c-fos expression in catecholaminergic neurons following exposure of unanesthetized rats to hypercapnic stress. Breathing a gas mixture with elevated CO2 (15% CO2, 21% O2 and 64% N2, or 15% CO2 balance O2) for 60 min, induced activation of the c-fos gene in widespread regions of the CNS, as indicated by the expression of Fos-like immunoreactive protein (Fos). Similar results were obtained in carotid body denervated animals. Colocalization studies of tyrosine hydroxylase (TH) and Fos protein revealed that in the brainstem, 73 to 85% of noradrenaline-containing cells expressed Fos immunoreactivity. Double-labeled neurons were found in the ventrolateral medullary reticular formation (A1 noradrenaline cells), in the dorsal aspect of medulla oblongata (A2 noradrenaline cells), in the ventrolateral pons (A5 noradrenaline cells), and in the locus coeruleus (A6 noradrenaline cells). However, over 90% of TH-immunoreactive neurons in the mesencephalon and diencephalon (dopaminergic cells) did not express Fos-like immunoreactivity in response to CO2. These results indicate that the brainstem noradrenaline-containing neurons are part of the neuronal networks that react to hypercapnic exposure.

Animals↗
PubMed1996

A strategy for coping with change: an affiliation between a medical school and a managed care health system.

Case Western Reserve University School of Medicine (CWRU), a private research-focused medical school, and Henry Ford Health System (HFHS), an integrated health system with a preponderance of managed care, have established a formal, broad affiliation that includes substantial commitments that bind the two organizations. Among them are formal full-time faculty appointments at CWRU for qualified professional staff of HFHS, designation of an associate dean for CWRU at HFHS, election of HFHS faculty to key medical school committees such as admission, curriculum, and promotions and tenure, and the commitment of funds to the affiliation by both organizations: a grant from HFHS to CWRU for curriculum development, and investment from CWRU to HFHS. The alliance of two such organizations is made complex by a number of issues. They include differences of institutional cultures as well as traditional issues in academic health centers such as departmental authority over curriculum and faculty appointments, competition for academic preeminence, and competition among hospitals for patients. The affiliation was facilitated by shared commitments to education, agreement on the need to adapt student education to the emerging managed care environment, a shared commitment to health services research, investment in the concept that learners add value to a health care delivery setting, and the desire to develop graduates with knowledge of practice in managed care. The authors conclude that medical schools and integrated managed care health systems gain sufficiently from such an affiliation that the investment of time, effort, and resources is readily justified.

Academic Medical Centers↗
PubMed1996

Decreased energy metabolism in brain stem during central respiratory depression in response to hypoxia.

Metabolic changes in the brain stem were measured at the time when oxygen deprivation-induced respiratory depression occurred. Eucapnic ventilation with 8% oxygen in vagotomized urethan-anesthetized rats resulted in cessation of respiratory drive, monitored by recording diaphragm electromyographic activity, on average within 11 min (range 5-27 min), presumably via central depressant mechanisms. At that time, the brain stems were frozen in situ for metabolic analyses. By using 20-microns lyophilized sections from frozen-fixed brain stem, microregional analyses of ATP, phosphocreatine, lactate, and intracellular pH were made from 1) the ventral portion of the nucleus gigantocellularis and the parapyramidal nucleus; 2) the compact and ventral portions of the nucleus ambiguus; 3) midline neurons; 4) nucleus tractus solitarii; and 5) the spinal trigeminal nucleus. At the time of respiratory depression, lactate was elevated threefold in all regions. Both ATP and phosphocreatine were decreased to 50 and 25% of control, respectively. Intracellular pH was more acidic by 0.2-0.4 unit in these regions but was relatively preserved in the chemosensitive regions near the ventral and dorsal medullary surfaces. These results show that hypoxia-induced respiratory depression was accompanied by metabolic changes within brain stem regions involved in respiratory and cardiovascular control. Thus it appears that there was significant energy deficiency in the brain stem after hypoxia-induce respiratory depression had occurred.

Animals↗
PubMed1996

Effects of willful ventilatory control on respiratory sensation during hypercapnia.

Remarkable augmentation of breathing discomfort has been noted when ventilation is constrained to the steady state level during progressive hypercapnia. However, the effect of willful enhancement of ventilation on breathing discomfort remains to be evaluated. The present study examined the effects of moderate willful increases or decreases in ventilation during progressive hypercapnia on breathing discomfort in 12 subjects. There were a total of 5 rebreathing trials. In the first (F1) and the fifth trials the subjects rebreathed freely. In the other trials subjects breathed by tracking a target to achieve hypercapnic ventilatory responses that were the same (HCVR-S), 25% higher (HCVR-H) and 25% lower (HCVR-L) than in the F1 trial. Breathing discomfort was assessed every 30 s by a 150-mm visual analog scale (VAS). The sensational response (dVAS/dPCO2) during HCVR-S [3.8 +/- (SE) 0.8 mm/Torr] was significantly smaller (p < 0.01) than that during the F1 (6.3 +/- 0.8 mm/Torr) trial. HCVR-H resulted in a further decrease in dVAS/dPCO2 to 3.1 +/- 0.7 mm/Torr as compared to HCVR-S (p < 0.05). HCVR-L significantly increased dVAS/dPCO2 to 4.9 +/- 0.7 mm/Torr compared to HCVR-S (p < 0.05). The final free rebreathing ventilatory response was significantly larger than the initial free rebreathing response (2.7 +/- 0.5 as compared to 2.1 +/- 0.4 liters/min/Torr, p < 0.01). However, the sensational response did not change (6.3 +/- 0.8 vs. 5.8 +/- 0.7 mm/Torr). These rebreathing studies indicate that willful control of respiration decreases respiratory sensation even at comparable levels of ventilation. In particular, moderate willful increases in ventilation produce an ameliorating effect on the sensation of breathing discomfort.

Adult↗
PubMed1995

Cell selective induction and transcriptional activation of immediate early genes by hypoxia.

c-fos and jun belong to the immediate early response genes (IERG) that initiate phenotypic changes in response to a variety of extracellular stimuli. In the present study, we examined whether hypoxia induces IERG expression in isolated cells. Experiments were performed on pheochromocytoma-12 (PC-12), hepatoblastoma (Hep3B), neuroblastoma and fibroblast cells that were exposed either to normoxia (21% O2) or to hypoxia (5% O2) for one hour. mRNAs for c-fos, c-jun, junB, junD were analyzed by northern blot assay. Increases in IERG mRNAs were seen in PC-12, Hep3B, and fibroblasts but not in neuroblastoma cells. Significant induction of c-fos mRNA was seen with hypoxic exposure as short as 15 min and the effects persisted at 10 h of low pO2 exposure. Hypoxia stimulated transcription from a 356 bp fragment of the c-fos promoter linked to a choloramphenicol acetyl transferase reporter in PC-12 but not in neuroblastoma cells. Fetal bovine serum, however, activated c-fos promoter both in PC-12 and neuroblastoma cells. These results demonstrate cell type selective mechanisms for c-fos promoter activation that require nucleic acid sequences with in the first 356 bp of the c-fos promoter. These observations suggest that increased IERG transcription is one of the early events in genomic adaptations to hypoxia.

Animals↗
PubMed1995

The N-methyl-D-aspartate receptor pathway is involved in hypoxia-induced c-Fos protein expression in the rat nucleus of the solitary tract.

Immediate early genes, like c-fos, are believed to be involved in triggering the expression of other genes such as those involved in the synthesis of neurochemicals. Exposure of unanesthetized rats to oxygen deprivation induces activation of the c-fos gene within the nucleus tractus solitarius, resulting in expression of fos-like immunoreactive protein (Fos). Prior administration of MK-801, a nonselective antagonist of the N-methyl-D-aspartate (NMDA)-sensitive glutamate receptor (1 or 2 mg/kg), significantly attenuated but did not completely block hypoxia-induced Fos expression. However, blockade of muscarinic receptors by atropine sulfate (2, 10 or 25 mg/kg) had no measurable effects on Fos expression induced by oxygen deprivation. These results suggest that an NMDA receptor signalling pathway is partly involved in programming the expression of early response genes that regulate various aspects of the response to oxygen deprivation.

Acetylcholine↗
PubMed1995

Model of respiratory sensation and wilful control of ventilation.

A mathematical model has been developed that includes sensations of breathlessness and a dynamic CO2 respiratory controller. Breathing sensations, which are represented as a discomfort index, are assumed to depend on arterial PCO2 level, automatic and wilful motor commands and mechanoreceptor feedback. Wilful control is assumed to arise from cortical centres of the brain and is independent of the reflex control system. The bulbopontine respiratory controller produces the automatic motor command, which is determined by chemical and mechanical feedback. Simulations demonstrate how the controller output and breathing sensations change when wilful motor commands disturb spontaneous breathing. Simulations include isocapnic hyper- and hypoventilation and deliberate hypoventilation during CO2 rebreathing. Simulations are compared with experimental data from human subjects. Simulations predict that the discomfort index intensifies when ventilation is either voluntarily raised or lowered from the optimal level; and discomfort is greater when ventilation is lowered than when it is raised at a given level of PCO2. The simulated results agree with those obtained experimentally. The simulations suggest that respiratory drive integration may depend not only on the direct effects of chemical and mechanical feedback, but also on the perceptual consequences of these stimuli.

Carbon Dioxide↗
PubMed1995

Nitric oxide and ventilatory response to hypoxia.

It is believed that hypoxia results in the release of neurotransmitters in the central nervous system, which can excite or inhibit breathing. Recent evidence indicates that nitric oxide (NO) is a physiological messenger molecule that may serve as a neurotransmitter in the CNS. In this study we examined (1) the localization of nitric oxide synthase (NOS) within the nucleus tractus solitarius, and (2) the role of the NO-cGMP pathway in the respiratory response to oxygen deprivation. Nicotinamide adenine dinucleotide phosphate (NADPH)-diaphorase histochemistry was used to determine the distribution of neurons that express NOS, an enzyme involved in NO formation. The NOS inhibitor N omega-nitro-L-arginine was used as tool to assess the NOS activity in the medulla, and to define the role of NO in the respiratory response to acute oxygen deprivation. In the rat and the cat brainstem, histochemical studies showed the presence of NADPH-diaphorase reactive neurons within subnuclei of the nucleus tractus solitarius which receive peripheral chemoreceptor inputs. Chronic pretreatment of rats with N omega-nitro-L-arginine (75 mg/kg, ip, twice daily for 7 days) caused a significant decrease in cGMP, and attenuated the ventilatory response to hypoxia. In anesthetized, paralyzed, vagotomized and artificially ventilated cats with intact carotid sinus nerves (n = 8), administration of N omega-nitro-L-arginine (30-100 mg/kg) attenuated the response to hypoxia, and caused the hypoxia induced roll-off of phrenic nerve activity to occur significantly earlier than when NOS activity was not inhibited. In sinoaortic denervated cats (n=9) blockage of NOS potentiated the decline of the phrenic nerve output. The data suggest that oxygen deprivation leads to activation of NO-cGMP pathway in the central nervous system, which contributes to the induction and maintenance of hypoxia-induced increase in respiratory output. In addition, these findings indicate that NO may inhibit inhibitory synaptic transmission that is triggered by CNS hypoxia, and this is not directly related to peripheral chemoreceptor inputs.

Animals↗
PubMed1995

Effect of hypoxia on reflex responses of tracheal submucosal glands.

The effects of moderate sustained normocapnic hypoxia on tracheal submucosal gland reflex responses were studied. Experiments were performed in anesthetized, paralyzed, and mechanically ventilated dogs. The changes in the number of secreting glands and volume of secreted fluid in the subsequent period of time were recorded after 15-30 min of controlled ventilation with room air [arterial PO2 (PaO2) 86 +/- 3 Torr], hypoxic gas mixture (PaO2 49 +/- 4 Torr), or 100% O2 (PaO2 339 +/- 39 Torr), under isocapnic and isohydric conditions. The hillocks method was used to quantify the changes in submucosal gland secretion. The changes in secretion 30 s after stimulation of pulmonary C-fiber receptors by right atrial injection of capsaicin (10 micrograms/kg; n = 10) were markedly lower during moderate hypoxia than in normoxia or hyperoxia. Differences in the number of liquid droplets and the volume of secreted fluid were statistically significant (P < 0.05 and P < 0.001, respectively). Stimulation of airway rapidly adapting receptors by lung deflation increased airway secretion; the number of "hillocks" and the volume of secreted fluid were lower in hypoxic than in hyperoxic state. Differences between response curves for the number of glands activated and secreted volume were statistically significant (P < 0.05 and P < 0.001). The number of glands activated by substance P given locally by arterial infusion was not affected by the state of oxygenation, but the calculated volume of secreted fluid was lower during the hypoxic state than under hyperoxic condition (P = 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

CNS innervation of airway-related parasympathetic preganglionic neurons: a transneuronal labeling study using pseudorabies virus.

The CNS cell groups that innervate the tracheal parasympathetic preganglionic neurons were identified by the viral retrograde transneuronal labeling method. Pseudorabies virus (PRV) was injected into the tracheal wall of C8 spinal rats and after 4 days survival, brain tissue sections from these animals were processed for immunohistochemical detection of PRV. Retrogradely labeled parasympathetic preganglionic neurons were seen in three sites in the medulla: the compact portion of the nucleus ambiguus, the area ventral to the nucleus ambiguus, and the rostralmost portion of the medial nucleus tractus solitarius (NTS); this labeling pattern correlated well with the retrograde cell body labeling seen following cholera toxin beta-subunit injections in the tracheal wall. PRV transneuronally labeled neurons were found throughout the CNS with the most abundant labeling concentrated in the ventral medulla oblongata. Labeled neurons were identified along the ventral medullary surface, and in nearby areas including the parapyramidal, retrotrapezoid, gigantocellular and lateral paragigantocellular reticular nuclei as well as the caudal raphe nuclei (raphe pallidus, obscurus, and magnus). Serotonin (5-HT) neurons of the caudal raphe complex (B1-B3 cell groups) and ventromedial medulla were labeled as well as a few C1 adrenergic neurons. The A5 cell group was the major noradrenergic area labeled although a small number of locus coeruleus neurons were also labeled. Several NTS regions contained labeled cells including the commissural, intermediate, medial, central, ventral, and ventrolateral subnuclei. PRV infected neurons were present in the Kölliker-Fuse and Barrington's nuclei. In the rostral mesencephalon, the precommissural nucleus of the dorsal periventricular gray matter was labeled. Labeling was present in the dorsal, lateral and paraventricular hypothalamic nuclei. In summary, the airway parasympathetic preganglionic neurons are innervated predominantly by a network of lower brainstem neurons that lie in the same regions known to be involved in respiratory and cardiovascular regulation. These findings are discussed in relationship to some of the potential CNS mechanisms that may be operative in airway disorders as well as potentially involved in certain fatal respiratory conditions such as Ondine's curse and sudden infant death syndrome (SIDS).

Animals↗
PubMed1993

Intramedullary sodium cyanide injection on respiratory and vasomotor responses in cats.

To examine the effect of hypoxia confined to the ventrolateral medulla we microinjected NaCN into the cat medulla (1.0 mm below the ventral surface) unilaterally and investigated cardio-respiratory changes. We studied anesthetized artificially ventilated animals and measured the electrical activity of phrenic and cervical sympathetic nerves and blood pressure. Histotoxic hypoxia depressed phrenic amplitude and elevated sympathetic tone and blood pressure. These responses were obtained predominantly from the region 5.0-8.0 mm caudal to the foramen caecum and 3.0-5.0 mm lateral to the midline (intermediate area). A study with 14C-cyanide showed that total and covalently bound cyanide was confined within a 1 mm diffusion sphere following microinjection. Isolated areas in both rostral and caudal medulla responded to cyanide with elevated sympathetic tone in the absence of phrenic nerve depression, suggesting dissociation of respiratory and vasomotor responses to hypoxia. Thus, the respiratory depression and vasomotor excitation produced by central hypoxia can be reproduced by hypoxia limited to discrete regions of the ventrolateral medulla.

Animals↗