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At least 343 records · Page 19Linked to original sources
PubMed1996

Chemosensitive medullary neurones in the brainstem--spinal cord preparation of the neonatal rat.

1. Using the isolated medulla and spinal cord of the neonatal rat, the response to CO2-induced changes in superfusate pH was examined in whole cell and perforated patch recordings from ventral medullary neurones which were identified by injection of Lucifer Yellow. The respiratory response to changing the CO2 concentration (from 2 to 8%) consisted of an increase in phrenic burst frequency, which could be accompanied by an increase, decrease or no change in burst amplitude. 2. Five classes of neurone - inspiratory, post-inspiratory, expiratory, respiration-modulated and ionic - were distinguished on the basis of their membrane potential and discharge patterns. Almost all (112 of 123) responded rapidly to 8% CO2 with a sustained change in membrane potential. Depolarizing responses (3-18 mV) occurred in inspiratory, respiration-modulated and 45% of tonic neurones. Hyperpolarizing responses (2-19 mV) occurred in expiratory and post-inspiratory neurones. The remaining tonic neurones were inhibited or showed no response. 3. In representatives of each class of neurone, membrane potential responses to 8% CO2 were retained when tested in the presence of tetrodotoxin (n = 7), low (0.2 mM) Ca(2+)-high (5 mM) Mg2+ (n = 23) or Cd2+ (0.2 mM) (n = 3)-containing superfusate, implying that they are mediated by intrinsic membrane or cellular mechanisms. 4. Neurones were distributed between 1200 microns rostral and 400 microns caudal to obex, and their cell bodies were located between 50 and 700 microns below the ventral surface (n = 104). Almost all responsive neurones (n = 78) showed dendritic projections to within 50 microns of the surface. 6. These experiments indicate that significant numbers of ventral medullary neurones, including respiratory neurones, are intrinsically chemosensitive. The consistency with which these neurones show surface dendritic projections suggests that this sensitivity may arise in part at this level.

Animals↗
PubMed1996

Dissociation of hypoxia-induced chemosensory responses and catecholamine efflux in cat carotid body superfused in vitro.

1. To examine the correlation between chemosensory response and dopamine release induced by hypoxic stimulation, we studied carotid bodies excised from anaesthetized cats. 2. The carotid bodies with their carotid (sinus) nerves were superfused in vitro with modified Tyrode solution (pH 7.40, at 37.5 degrees C) equilibrated with 20 or 100% O2. The PO2 of the superfusing channel was monitored polarographically. The frequency of chemosensory discharges (fx) was recorded from the whole carotid nerve. Catecholamine (CA) efflux-mostly consisting of dopamine-was measured by high-speed chronoamperometry, through Nafion-coated carbon electrodes placed on the carotid body tissue. Chemosensory stimulation was induced by intrastream injections of NaCN, by superfusion with 100% N2-equilibrated saline (lowering PO2 to 25-40 Torr) or by flow interruption. 3. Low doses of NaCN increased fx, but had no measurable effect on CA efflux, while larger doses produced fast increases in fx, preceding delayed and prolonged increases in CA efflux. Repeated injections of NaCN, still increasing fx, gave reduced CA effluxes. 4. Switching to hypoxic superfusion for 6-8 min produced large and fast fx increases, but delayed and prolonged augmentations of CA efflux. 5. Administration of three to four boluses of dopamine (7-15 micrograms; augmenting CA concentration by up to 35 microM) initially decreased fx, after which hypoxic stimulation resulted in enhanced and faster CA effluxes, without changing the speed and intensity of chemosensory responses. 6. Flow interruptions induced fast increases in fx and delayed increases in CA efflux. Repeated flow interruptions produced similar increases in fx but progressively attenuated CA effluxes. 7. Our results suggest that CA efflux is not essential for hypoxia-induced chemosensory excitation in the cat carotid body. They also suggest the presence of two pools of releasable CAs in the carotid body, one of slow turnover and release, and another of recently incorporated dopamine and fast release, both pools being rapidly depleted by repeated stimulation of the carotid body.

Animals↗
PubMed1997

Developmental loss of hypoxic chemosensitivity in rat adrenomedullary chromaffin cells.

1. We investigated whether adrenomedullary chromaffin cells (AMCs) derived from neonatal (postnatal day (P) 1-P2) and juvenile (P13-P20) rats, and maintained in short-term culture (1-3 days), express O2-chemoreceptive properties. 2. In whole-cell recordings, the majority (approximately 70%; n = 47) of neonatal AMCs were sensitive to hypoxia. Under voltage clamp, acute hypoxia (PO2 approximately 40 mmHg) suppressed voltage-dependent K+ current by 25.1 +/- 3.4% (mean +/- S.E.M.; n = 22); under current clamp, acute hypoxia caused a membrane depolarization of 14.1 +/- 1.3 mV (n = 13) from a resting potential of -54.8 +/- 2.8 mV (n = 13), and this was often sufficient to trigger action potentials. 3. Exposure of neonatal AMC cultures to a moderate (PO2 approximately 75 mmHg) or severe (PO2 approximately 35 mmHg) hypoxia for 1 h caused a dose-dependent stimulation (approximately 3 or 6 times normoxia, respectively) of catecholamine (CA) release, mainly adrenaline, determined by HPLC. This induced CA release was abolished by the L-type calcium channel blocker, nifedipine (10 microM). 4. In contrast to the above results in neonates, hypoxia had no significant effects on voltage-dependent K+ current, membrane potential, or CA release in juvenile AMCs. 5. We conclude that rat adrenal chromaffin cells possess a developmentally regulated O2-sensing mechanism, similar to carotid body type I cells.

Adrenal Medulla↗
PubMed2006

Hypersensitivity of pulmonary chemosensitive neurons induced by activation of protease-activated receptor-2 in rats.

This study was carried out to determine the effect of protease-activated receptor-2 (PAR2) activation on the pulmonary chemoreflex responses and on the sensitivity of isolated rat vagal pulmonary chemosensitive neurons. In anaesthetized, spontaneously breathing rats, intratracheal instillation of trypsin (0.8 mg ml(-1), 0.1 ml), an endogenous agonist of PAR2, significantly amplified the capsaicin-induced pulmonary chemoreflex responses. The enhanced responses were completely abolished by perineural capsaicin treatment of both cervical vagi, suggesting the involvement of pulmonary C-fibre afferents. In patch-clamp recording experiments, pretreatment with trypsin (0.1 microM, 2 min) potentiated the capsaicin-induced whole-cell inward current in isolated pulmonary sensory neurons. The potentiating effect of trypsin was mimicked by PAR2-activating peptide (PAR2-AP) in a concentration-dependent manner. PAR2-AP pretreatment (100 microM, 2 min) also markedly enhanced the acid-evoked inward currents in these sensory neurons. Furthermore, the sensitizing effect of PAR2 was completely abolished by pretreatment with either U73122 (1 microM, 4 min), a phospholipase C inhibitor, or chelerythrine (10 microM, 4 min), a protein kinase C (PKC) inhibitor. In summary, our results have demonstrated that activation of PAR2 upregulates the pulmonary chemoreflex sensitivity in vivo and the excitability of isolated pulmonary chemosensitive neurons in vitro, and this effect of PAR2 activation was mediated through the PKC-dependent transduction pathway. These results further suggest that the hypersensitivity of these neurons may play a part in the development of airway hyper-responsiveness resulting from PAR2 activation.

Action Potentials↗
PubMed1977

A response regulator model in a simple sensory system.

Bacterial behavior is shown to be modulated through a simple on-off switching device which directs migration toward favorable conditions and away from unfavorable ones. The behavioral response is controlled by a rudimentary memory which allows the bacteria to sense gradients over time. The memory can be explained by a biochemical system involving a response regulator whose level relative to a threshold controls flagellar function. The level of the response regulator is itself controlled by factors such as enzyme levels and environmental stimuli. The molecular basis of the model appears to be relevant to more complex hormonal and neural signaling systems.

Adaptation, Physiological↗
PubMed1994

Inhibition of human immunodeficiency virus type 1 in human T cells by a potent Rev response element decoy consisting of the 13-nucleotide minimal Rev-binding domain.

Intracellular immunization is an anti-viral gene therapy strategy based on the introduction of DNA templates into cells to stably express genetic elements which inhibit viral gene expression and replication. We have recently developed an intracellular immunization strategy for human immunodeficiency virus (HIV) infection that uses RNA decoys. RNA decoys are short RNA oligonucleotides corresponding to the HIV trans activation response element (TAR) or Rev response element (RRE) sequences, which function by inhibiting the binding of the HIV regulatory proteins Tat and Rev to the authentic HIV RNA TAR and RRE regions, respectively. In this report we describe the characterization of potent RRE decoys containing the minimal 13-nucleotide primary Rev binding domain of the RRE. Using an improved tRNA cassette to express high levels of RRE transcripts in CEM cells, we found that this new generation of minimal RRE decoys were more potent inhibitors of HIV in isolated cell lines than previously described TAR or RRE decoys. CEM cells expressing RRE decoys exhibited diminished Rev function in cotransfection assays, confirming the specificity of inhibition of HIV by RRE decoys and indicating that the 13-nucleotide minimal Rev binding domain defined by using in vitro binding studies also binds Rev in vivo. Significant differences in the degree of HIV inhibition between individual CEM cell lines transduced with RRE decoy vectors which were not due to sequence alterations in the tRNA-RRE DNA template, differences in RRE decoy expression level, or endogenous variations in the resistance of CEM clonal cell lines to HIV were observed. In order to evaluate the efficacy of RRE decoys in a more realistic fashion than by comparison of individual clonal cell lines, polyclonal populations of transduced CEM cells were infected with HIV. By using a novel flow cytometric method for quantitating intracellular p24 expression, one version of the RRE decoys tested in this study was found to be capable of durably protecting polyclonal populations of CEM cells from HIV.

Bacterial Proteins↗
PubMed2001

Strict control of human immunodeficiency virus type 1 replication by a genetic switch: Tet for Tat.

Live-attenuated human immunodeficiency virus type 1 (HIV-1) variants have shown great promise as AIDS vaccines, but continued replication can lead to the selection of faster-replicating variants that are pathogenic. We therefore designed HIV-1 genomes that replicate exclusively upon addition of the nontoxic effector doxycycline (dox). This was achieved by replacement of the viral TAR-Tat system for transcriptional activation by the Escherichia coli-derived Tet system for inducible gene expression. These designer "HIV-rtTA" viruses replicate in a strictly dox-dependent manner both in a T-cell line and in primary blood cells, and the rate of replication can be fine-tuned by simple variation of the dox concentration. These HIV-rtTA viruses provide a tool to perform genetics, e.g., selection and optimization experiments, with the E. coli-derived Tet reagents in a eukaryotic background. Furthermore, such viruses may represent improved vaccine candidates because their replication can be turned on and off at will.

Bacterial Proteins↗
PubMed2001

Human GLI-2 is a tat activation response element-independent Tat cofactor.

Zinc finger-containing GLI proteins are involved in the development of Caenorhabditis elegans, Xenopus, Drosophila, zebrafish, mice, and humans. In this study, we show that an isoform of human GLI-2 strongly synergizes with the Tat transactivating proteins of human immunodeficiency virus types 1 and 2 (HIV-1 and -2) and markedly stimulates viral replication. GLI-2 also synergizes with the previously described Tat cofactor cyclin T1 to stimulate Tat function. Surprisingly, GLI-2/Tat synergy is not dependent on either a typical GLI DNA binding site or an intact Tat activation response element but does require an intact TATA box. Thus, GLI-2/Tat synergy results from a mechanism of action which is novel both for a GLI protein and for a Tat cofactor. These findings link the GLI family of transcriptional and developmental regulatory proteins to Tat function and HIV replication.

Animals↗
PubMed1975

Chemotaxis in bacteria.

Bacteria swim by rotating their flagella. They alter course by abruptly changing the direction of this rotation. The probability of the occurrence of this event is biased by chemoreception. The bias depends on the way in which the concentration of the attractant or repellent changes with time. Sugars are detected as they bind to specific proteins which also play a role in transport. The way in which the receptors are coupled to the flagella is not known. The coupling may involve changes in membrane potential.

Amino Acids↗
PubMed2005

Sensitization of pulmonary chemosensitive neurons by bombesin-like peptides in rats.

Small cell lung cancer (SCLC) patients suffer from pulmonary stresses such as dyspnea and chest pain, and the pathogenic mechanisms are not known. SCLC cells secrete a variety of bioactive neuropeptides, including bombesin-like peptides. We hypothesize that these peptides may enhance the sensitivity of the pulmonary chemosensitive nerve endings, contributing to the development of these pulmonary stresses in SCLC patients. This study was therefore carried out to determine the effects of bombesin and gastrin-releasing peptide (GRP), a major bombesin-like peptide, on the sensitivities of pulmonary chemoreflex and isolated pulmonary vagal chemosensitive neurons. In anesthetized, spontaneously breathing rats, intravenous infusion of bombesin or GRP significantly amplified the pulmonary chemoreflex responses to chemical stimulants such as capsaicin and ATP. The enhanced responses were completely abolished by perineural capsaicin treatment of both cervical vagi, suggesting the involvement of pulmonary C-fiber afferents. In isolated pulmonary vagal chemosensitive neurons, pretreatment with bombesin or GRP potentiated the capsaicin-induced Ca(2+) transient. This sensitizing effect was further demonstrated in patch-clamp recording studies; the sensitivities of these neurons to both chemical (capsaicin and ATP) and electrical stimuli were significantly enhanced by the presence of either bombesin or GRP. In summary, our results have demonstrated that bombesin and GRP upregulate the pulmonary chemoreflex sensitivity in vivo and the excitability of isolated pulmonary chemosensitive neurons in vitro.

Animals↗
PubMed1991

Factors affecting distribution of alveolar surfactant during resting ventilation.

Few studies have been done to establish the ventilatory factors affecting alveolar surfactant under resting conditions. Experiments in which ventilatory variables were recorded for 4 h were performed in 12 adult cats breathing spontaneously under pentobarbital sodium anesthesia. After the animals were killed and bronchoalveolar lavages (BALs) were performed, the resulting fluid was subjected to differential centrifugation and determinations of proteins, phospholipids (PL), and disaturated phosphatidylcholine (DSPC). Pellet P1+2 was obtained by two centrifugations at 140 g; the supernatant was centrifuged at 1,000 g to obtain pellet P3 and subsequently at 60,000 g to obtain P4. Pellets P3 and P4 had the higher contents of PL and DSPC. Bivariate and multivariate correlational analyses indicate that 1) total PL in BAL was not related to any of the ventilatory variables studied, 2) PL in P3 and P4 fractions was directly correlated to the physiological range of variations in the frequency of large spontaneous gasps (fL), and 3) PL in P1+2 fraction was inversely related to fL. Cats subjected to bilateral section of carotid nerves, although presenting reduced chemosensory drive and ventilatory chemoreflexes, did not exhibit significant differences in resting ventilatory variables nor in alveolar surfactant components. Present results indicate that the total content of alveolar surfactant is not modified by ventilatory variations within physiological range but that the spontaneous occurrence of large gasps increases the proportion of more active forms of alveolar surfactant. This may mediate the role of augmented breaths in keeping lung compliance and preventing atelectasis under resting ventilatory conditions.

Animals↗
PubMed1999

Postnatal maturation of carotid body and type I cell chemoreception in the rat.

The site of postnatal maturation of carotid body chemoreception is unclear. To test the hypothesis that maturation occurs synchronously in type I cells and the whole carotid body, the development of changes in the intracellular Ca2+ concentration responses to hypoxia, CO2, and combined challenges was studied with fluorescence microscopy in type I cells and compared with the development of carotid sinus nerve (CSN) responses recorded in vitro from term fetal to 3-wk animals. Type I cell responses to all challenges increased between 1 and 8 days and then remained constant, with no multiplicative O2-CO2 interaction at any age. The CSN response to hypoxia also matured by 8 days, but CSN responses to CO2 did not change significantly with age. Multiplicative O2-CO2 interaction occurred in the CSN response at 2-3 wk but not in younger groups. We conclude that type I cell maturation underlies maturation of the CSN response to hypoxia. However, because development of responses to CO2 and combined hypoxia-CO2 challenges differed between type I cells and the CSN, responses to these stimuli must mature at other, unidentified sites within the developing carotid body.

Aging↗
PubMed2001

Reflex cardiovascular responses originating in exercising muscles of mice.

The cardiovascular responses induced by exercise are initiated by two primary mechanisms: central command and reflexes originating in exercising muscles. Although our understanding of cardiovascular responses to exercise in mice is progressing, a murine model of cardiovascular responses to muscle contraction has not been developed. Therefore, the purpose of this study was to characterize the cardiovascular responses to muscular contraction in anesthetized mice. The results of this study indicate that mice demonstrate significant increases in blood pressure (13.8 +/- 1.9 mmHg) and heart rate (33.5 +/- 11.9 beats/min) to muscle contraction in a contraction-intensity-dependent manner. Mice also demonstrate 23.1 +/- 3.5, 20.9 +/- 4.0, 21.7 +/- 2.6, and 25.8 +/- 3.0 mmHg increases in blood pressure to direct stimulation of tibial, peroneal, sural, and sciatic hindlimb somatic nerves, respectively. Systemic hypoxia (10% O(2)-90% N(2)) elicits increases in blood pressure (11.7 +/- 2.6 mmHg) and heart rate (42.7 +/- 13.9 beats/min), while increasing arterial pressure with phenylephrine decreases heart rate in a dose-dependent manner. The results from this study demonstrate the feasibility of using mice to study neural regulation of cardiovascular function during a variety of autonomic stimuli, including exercise-related drives such as muscle contraction.

Animals↗
PubMed2005

Heterogeneity of voltage- and chemosignal-activated response profiles in vomeronasal sensory neurons.

Liolaemus lizards were explored to ascertain whether they would make an amenable model to study single-cell electrophysiology of neurons in the vomeronasal organ (VNO). Despite a rich array of chemosensory-related behaviors chronicled for this genus, no anatomical or functional data exist for the VNO, the organ mediating these types of behaviors. Two Liolaemus species (L. bellii and L. nigroviridis) were collected in Central Chile in the Farellones Mountains and transported to the United States. Lizards were subjected to hypothermia and then a lethal injection of sodium pentabarbitol prior to all experiments described in the following text. Retrograde dye perfusion combined with histological techniques demonstrated a compartmentalization of the proportionally large VNO from the main olfactory epithelium (MOE) in cryosections of L. bellii. SDS-PAGE analysis of the VNO of both species demonstrated the expression of three G protein subunits, namely, G(alphao), G(alphai2), and G(beta), and the absence of G(alphaolf), G(alpha11), and G(q), the latter of which are traditionally found in the MOE. Vomeronasal (VN) neurons were enzymatically isolated for whole cell voltage-clamp electrophysiology of single neurons. Both species demonstrated a tetrodotoxin (TTX)-sensitive, rapidly inactivating sodium current and a tetraethylammonium (TEA)-sensitive potassium current that had a transient and sustained component. VN neurons were classified into two types dependent on the ratio of sodium over sustained potassium current. VN neurons exhibited outward and inward chemosignal-evoked currents when stimulated with pheromone-containing secretions taken from the feces, skin, and precloacal pores. Fifty-nine percent of the neurons were responsive to at least one compound when presented with a battery of five different secretions. The breadth of responsiveness (H metric) demonstrated a heterogeneous population of tuning with a mean of 0.29.

Anesthetics, Local↗