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1.
Handb Exp Pharmacol ; (187): 129-54, 2009.
Artículo en Inglés | MEDLINE | ID: mdl-18825339

RESUMEN

Cough plays a vital role in protecting the lower airways from inhaled irritants, pollutants, and infectious agents. The cough reflex exhibits remarkable plasticity, such that in the context of infectious or inflammatory respiratory diseases such as asthma, chronic bronchitis, and idiopathic pulmonary fibrosis the cough reflex can become dysregulated, leading to a chronic cough. A chronic, nonproductive (dry) cough can rob sufferers of quality of life. Plasticity of the cough reflex likely involves multiple intersecting pathways within the airways, the peripheral nerves that supply them, and the central nervous system. While further studies are needed to determine the presence and relevance of many of these specific pathways in cough associated with chronic respiratory disease, the last decade has yielded unprecedented insight into the molecular identity of the ion channels and associated proteins that initiate and conduct action potentials in the primary sensory nerves involved in reflexes such as cough. We now know, for instance, that members of the transient receptor potential superfamily of nonselective cation channels function as transducers that convert specific external stimuli into neuronal activation. We also know that certain Na+ and K+ channels play specialized roles in regulating action potential discharge in irritant-sensing afferent nerves. In this chapter, we summarize the available information regarding factors that may modulate afferent neuron function acutely, via posttranslational modifications and over the longer term through neurotrophin-dependent alterations of the transcriptional programs of adult sensory neurons.


Asunto(s)
Tos/fisiopatología , Plasticidad Neuronal/fisiología , Sistema Nervioso Periférico/fisiopatología , Animales , Humanos , Canales Iónicos/efectos de los fármacos , Canales Iónicos/fisiología , Mecanotransducción Celular/efectos de los fármacos , Mecanotransducción Celular/fisiología , Factores de Crecimiento Nervioso/fisiología , Plasticidad Neuronal/efectos de los fármacos , Sistema Respiratorio/inervación , Sistema Respiratorio/fisiopatología
2.
J Physiol ; 586(14): 3447-59, 2008 Jul 15.
Artículo en Inglés | MEDLINE | ID: mdl-18499726

RESUMEN

Transient receptor potential (TRP) A1 channels are cation channels found preferentially on nociceptive sensory neurones, including capsaicin-sensitive TRPV1-expressing vagal bronchopulmonary C-fibres, and are activated by electrophilic compounds such as mustard oil and cinnamaldehyde. Oxidative stress, a pathological feature of many respiratory diseases, causes the endogenous formation of a number of reactive electrophilic alkenals via lipid peroxidation. One such alkenal, 4-hydroxynonenal (4HNE), activates TRPA1 in cultured sensory neurones. However, our data demonstrate that 100 microm 4HNE was unable to evoke significant action potential discharge or tachykinin release from bronchopulmonary C-fibre terminals. Instead, another endogenously produced alkenal, 4-oxononenal (4ONE, 10 microm), which is far more electrophilic than 4HNE, caused substantial action potential discharge and tachykinin release from bronchopulmonary C-fibre terminals. The activation of mouse bronchopulmonary C-fibre terminals by 4ONE (10-100 microm) was mediated entirely by TRPA1 channels, based on the absence of responses in C-fibre terminals from TRPA1 knockout mice. Interestingly, although the robust increases in calcium caused by 4ONE (0.1-10 microm) in dissociated vagal neurones were essentially abolished in TRPA1 knockout mice, at 100 microm 4ONE caused a large TRPV1-dependent response. Furthermore, 4ONE (100 microm) was shown to activate TRPV1 channel-expressing HEK cells. In conclusion, the data support the hypothesis that 4-ONE is a relevant endogenous activator of vagal C-fibres via an interaction with TRPA1, and at less relevant concentrations, it may activate nerves via TRPV1.


Asunto(s)
Aldehídos/farmacología , Canales de Calcio/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Canales Catiónicos TRPV/metabolismo , Canales de Potencial de Receptor Transitorio/metabolismo , Nervio Vago/fisiología , Potenciales de Acción , Animales , Autacoides/farmacología , Calcio/metabolismo , Canales de Calcio/genética , Capsaicina/farmacología , Línea Celular , Relación Dosis-Respuesta a Droga , Células Endoteliales/metabolismo , Cobayas , Humanos , Pulmón/inervación , Ratones , Ratones Noqueados , Proteínas del Tejido Nervioso/genética , Neuronas Aferentes/efectos de los fármacos , Neuronas Aferentes/fisiología , Canal Catiónico TRPA1 , Canales Catiónicos TRPV/genética , Canales de Potencial de Receptor Transitorio/genética
3.
J Biol Chem ; 276(2): 1439-49, 2001 Jan 12.
Artículo en Inglés | MEDLINE | ID: mdl-11022038

RESUMEN

The goal of this study was to examine arachidonic acid (AA) metabolism by murine bone marrow-derived mast cells (BMMC) during apoptosis induced by cytokine depletion. BMMC deprived of cytokines for 12-48 h displayed apoptotic characteristics. During apoptosis, levels of AA, but not other unsaturated fatty acids, correlated with the percentage of apoptotic cells. A decrease in both cytosolic phospholipase A(2) expression and activity indicated that cytosolic phospholipase A(2) did not account for AA mobilization during apoptosis. Free AA accumulation is also unlikely to be due to decreases in 5-lipoxygenase and/or cyclooxygenase activities, since BMMC undergoing apoptosis produced similar amounts of leukotriene B(4) and significantly greater amounts of PGD(2) than control cells. Arachidonoyl-CoA synthetase and CoA-dependent transferase activities responsible for incorporating AA into phospholipids were not altered during apoptosis. However, there was an increase in arachidonate in phosphatidylcholine (PC) and neutral lipids concomitant with a 40.7 +/- 8.1% decrease in arachidonate content in phosphatidylethanolamine (PE), suggesting a diminished capacity of mast cells to remodel arachidonate from PC to PE pools. Further evidence of a decrease in AA remodeling was shown by a significant decrease in microsomal CoA-independent transacylase activity. Levels of lyso-PC and lyso-PE were not altered in cells undergoing apoptosis, suggesting that the accumulation of lysophospholipids did not account for the decrease in CoA-independent transacylase activity or the induction of apoptosis. Together, these data suggest that the mole quantities of free AA closely correlated with apoptosis and that the accumulation of AA in BMMC during apoptosis was mediated by a decreased capacity of these cells to remodel AA from PC to PE.


Asunto(s)
Apoptosis/fisiología , Ácido Araquidónico/metabolismo , Citocinas/farmacología , Peroxidación de Lípido/efectos de los fármacos , Mastocitos/citología , Mastocitos/fisiología , Animales , Células de la Médula Ósea/citología , Células Cultivadas , Coenzima A Ligasas/metabolismo , Medios de Cultivo , ADN/biosíntesis , Eicosanoides/metabolismo , Ácidos Grasos no Esterificados/metabolismo , Interleucina-3/farmacología , Cinética , Mastocitos/efectos de los fármacos , Ratones , Ratones Endogámicos CBA , Modelos Químicos , Fosfatidilcolinas/metabolismo , Fosfatidiletanolaminas/metabolismo , Fosfolipasas A/metabolismo , Factor de Células Madre/farmacología
4.
J Auton Nerv Syst ; 78(2-3): 158-64, 2000 Jan 14.
Artículo en Inglés | MEDLINE | ID: mdl-10789695

RESUMEN

Electrophysiological studies of vagal sensory nerves with cell bodies in the nodose ganglion and mechanically sensitive receptive fields in the guinea-pig trachea/bronchus, were performed. Exposure of the mechanically sensitive receptive fields to 4-aminopyridine (100 microM-1 mM) caused pronounced action potential discharge in all fibres studied. Action potential generation was also produced by alpha-dendrotoxin, and in a subset of fibres, by barium. By contrast, neither iberiotoxin, tetraethyl ammonium, glybenclamide, BDS-II, nor apamin caused action potential generation in the vagal afferent nerve fibres. Tetramethylrhodamine dextran was instilled into the trachea to retrogradely label cell bodies within the nodose ganglion. In these cells, 4-aminopyridine caused a large depolarization of the resting membrane potential, concomitant with an increase in input impedance. The data suggest 4-aminopyridine- and alpha-dendrotoxin-sensitive ion channels within the airway afferent nerve membrane hold the resting membrane potential below the threshold for action potential generation. Mechanisms that lead to an inhibition of these channels will likely lead to an increase in excitability of the airway afferent neurones.


Asunto(s)
Potenciales de Acción/efectos de los fármacos , Potenciales de Acción/fisiología , Vías Aferentes/efectos de los fármacos , Vías Aferentes/metabolismo , Bronquios/efectos de los fármacos , Bronquios/inervación , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Ganglio Nudoso/efectos de los fármacos , Ganglio Nudoso/metabolismo , Canales de Potasio/efectos de los fármacos , Canales de Potasio/metabolismo , 4-Aminopiridina/farmacología , Vías Aferentes/citología , Animales , Bronquios/metabolismo , Cobayas , Masculino , Potenciales de la Membrana/efectos de los fármacos , Potenciales de la Membrana/fisiología , Fibras Nerviosas/efectos de los fármacos , Fibras Nerviosas/metabolismo , Fibras Nerviosas/ultraestructura , Neuronas/citología , Ganglio Nudoso/citología , Bloqueadores de los Canales de Potasio
5.
J Physiol ; 521 Pt 1: 239-47, 1999 Nov 15.
Artículo en Inglés | MEDLINE | ID: mdl-10562348

RESUMEN

1. Intracellular and extracellular electrophysiological recording techniques were employed to examine the mechanisms involved in adaptation of guinea-pig airway sensory neurones to suprathreshold mechanical stimulation in vitro. Extracellular recordings performed using an in vitro airway preparation revealed two unambiguously distinct subsets of mechanically sensitive nerve endings in the trachea/bronchus. In one group of fibres, the mechanical stimulus caused a brief burst of action potentials, after which the nerve rapidly adapted. In the other group of fibres, repetitive action potentials were evoked as long as the stimulus was maintained above threshold. 2. The adaptation response strictly correlated with ganglionic origin of the soma. Those fibres derived from the nodose ganglion adapted rapidly, whereas those derived from the jugular ganglion were slowly or non-adapting. 3. Intracellular recordings from airway-identified neurones in isolated intact ganglia revealed that the majority of neurones within either the nodose or jugular ganglion adapted rapidly to prolonged suprathreshold depolarizing current injections. 4. The electrophysiological adaptation of nodose ganglion-derived neurones following prolonged suprathreshold current steps was greatly reduced by 4-aminopyridine. However, 4-aminopyridine did not affect the adaptation of rapidly adapting nodose ganglion-derived nerve endings in response to mechanical stimuli. 5. The data suggest that ganglionic origin dictates adaptive characteristics of guinea-pig tracheal and mainstem bronchial afferent neurones in response to mechanical stimulation. Also, the rapid adaptation of nodose nerve endings in the trachea observed during a mechanical stimulus does not appear to be related to the adaptation observed at the soma during prolonged suprathreshold depolarizing current injections.


Asunto(s)
Bronquios/inervación , Tráquea/inervación , Nervio Vago/fisiología , 4-Aminopiridina/farmacología , Potenciales de Acción/efectos de los fármacos , Adaptación Fisiológica/efectos de los fármacos , Vías Aferentes/efectos de los fármacos , Vías Aferentes/fisiología , Animales , Estimulación Eléctrica , Cobayas , Técnicas In Vitro , Nervios Laríngeos/efectos de los fármacos , Nervios Laríngeos/fisiología , Masculino , Ganglio Nudoso/efectos de los fármacos , Ganglio Nudoso/fisiología , Estimulación Física , Nervio Vago/efectos de los fármacos
6.
J Pharmacol Exp Ther ; 285(2): 602-7, 1998 May.
Artículo en Inglés | MEDLINE | ID: mdl-9580604

RESUMEN

The role of endogenous 5-lipoxygenase products in modulating tachykinergic neurotransmission in guinea pig isolated trachea was investigated. Tachykinin-containing afferent nerve fibers were stimulated with either electrical field stimulation or antidromic stimulation of the right vagus nerve. This resulted in contractions of the isolated caudal trachea and bronchus that could be blocked with either tetrodotoxin or a combination of neurokinin-1 and neurokinin-2 receptor antagonists. The 5-lipoxygenase inhibitor ZD 2138 (1 microM) significantly inhibited these neurally mediated tachykinergic contractions, by approximately 50%, yet had no effect on the contractions evoked by stimulating tachykinergic fibers in an action potential-independent fashion with capsaicin or by exogenously applied neurokinin A. The effect of ZD 2138 on action potential-driven tachykinergic contractions was mimicked by pobilukast, pranlukast, montelukast and zafirlukast, four structurally unrelated antagonists of the cysteinyl leukotriene 1 receptor subtype. Pobilukast had no effect on the tachykinergic contraction in tissues pretreated with ZD 2138. Likewise, ZD 2138 had no effect on the tachykinergic contractions in tissues pretreated with pobilukast. Intracellular electrophysiological recording of the membrane properties of jugular ganglion neurons, the source of tachykinins in the guinea pig trachea/bronchus, demonstrated that leukotriene D4 caused a membrane depolarization of vagal afferent C-fiber neurons and an increase in input impedance, both of which were abolished by zafirlukast. Taken together, these data indicate that in the resting guinea pig isolated trachea/bronchus, endogenous 5-lipoxygenase activity leads to the production of cysteinyl leukotrienes that amplify action potential-dependent release of tachykinins from airway afferent nerve fibers.


Asunto(s)
Araquidonato 5-Lipooxigenasa/fisiología , Taquicininas/fisiología , Tráquea/inervación , Animales , Estimulación Eléctrica , Cobayas , Técnicas In Vitro , Leucotrieno C4/farmacología , Inhibidores de la Lipooxigenasa , Masculino , Contracción Muscular , Piranos/farmacología , Quinolonas/farmacología , Tráquea/fisiología , Nervio Vago/fisiología
7.
Neuropeptides ; 31(4): 293-9, 1997 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-9308014

RESUMEN

The effect of corticotropin-releasing factor (CRF) on contractions of guinea pig isolated airways in response to electrical or chemical stimulation of tachykinergic nerve fibers was studied. CRF (1 microgram/ml) caused a 70% enhancement of the peak magnitude of the response to electrical field stimulation (EFS). CRF had a similar effect on contractions of the isolated bronchus evoked by capsaicin. CRF also potentiated contractions evoked by exogenously applied substance P. This effect was selective, as CRF has no effect on contractions evoked by neurokinin A or the substance P analog ASMSP. The potentiation of the substance P-induced contractions of airway smooth muscle was blocked by the CRF receptor antagonist alpha helical (9-41) CRF. These data support the hypothesis that CRF enhances the airway smooth muscle response to stimulation of tachykinin-containing nerve fibers and that this effect is due to a post-junctional mechanism of action.


Asunto(s)
Bronquios/efectos de los fármacos , Hormona Liberadora de Corticotropina/farmacología , Contracción Muscular/efectos de los fármacos , Taquicininas/farmacología , Animales , Sinergismo Farmacológico , Estimulación Eléctrica , Cobayas , Técnicas In Vitro , Masculino , Músculo Liso/efectos de los fármacos
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