RESUMEN
KEY POINTS: The action potential initiation in the nerve terminals and its subsequent conduction along the axons of afferent nerves are not necessarily dependent on the same voltage-gated sodium channel (NaV 1) subunits. The action potential initiation in jugular C-fibres within airway tissues is not blocked by TTX; nonetheless, conduction of action potentials along the vagal axons of these nerves is often dependent on TTX-sensitive channels. This is not the case for nodose airway Aδ-fibres and C-fibres, where both action potential initiation and conduction is abolished by TTX or selective NaV 1.7 blockers. The difference between the initiation of action potentials within the airways vs. conduction along the axons should be considered when developing NaV 1 blocking drugs for topical application to the respiratory tract. ABSTRACT: The action potential (AP) initiation in the nerve terminals and its subsequent AP conduction along the axons do not necessarily depend on the same subtypes of voltage-gated sodium channels (NaV 1s). We evaluated the role of TTX-sensitive and TTX-resistant NaV 1s in vagal afferent nociceptor nerves derived from jugular and nodose ganglia innervating the respiratory system. Single cell RT-PCR was performed on vagal afferent neurons retrogradely labelled from the guinea pig trachea. Almost all of the jugular neurons expressed the TTX-sensitive channel NaV 1.7 along with TTX-resistant NaV 1.8 and NaV 1.9. Tracheal nodose neurons also expressed NaV 1.7 but, less frequently, NaV 1.8 and NaV 1.9. NaV 1.6 were expressed in â¼40% of the jugular and 25% of nodose tracheal neurons. Other NaV 1 α subunits were only rarely expressed. Single fibre recordings were made from the vagal nodose and jugular nerve fibres innervating the trachea or lung in the isolated perfused vagally-innervated preparations that allowed for selective drug delivery to the nerve terminal compartment (AP initiation) or to the desheathed vagus nerve (AP conduction). AP initiation in jugular C-fibres was unaffected by TTX, although it was inhibited by NaV 1.8 blocker (PF-01247324) and abolished by combination of TTX and PF-01247324. However, AP conduction in the majority of jugular C-fibres was abolished by TTX. By contrast, both AP initiation and conduction in nodose nociceptors was abolished by TTX or selective NaV 1.7 blockers. Distinction between the effect of a drug with respect to inhibiting AP in the nerve terminals within the airways vs. at conduction sites along the vagus nerve is relevant to therapeutic strategies involving inhaled NaV 1 blocking drugs.
Asunto(s)
Potenciales de Acción , Nociceptores/metabolismo , Tetrodotoxina/farmacología , Nervio Vago/metabolismo , Bloqueadores del Canal de Sodio Activado por Voltaje/farmacología , Canales de Sodio Activados por Voltaje/metabolismo , Animales , Cobayas , Pulmón/inervación , Masculino , Nociceptores/fisiología , Tráquea/inervación , Nervio Vago/fisiologíaRESUMEN
We have fabricated and characterized 10,000 and 20,440 pixel Microwave Kinetic Inductance Detector (MKID) arrays for the Dark-speckle Near-IR Energy-resolved Superconducting Spectrophotometer (DARKNESS) and the MKID Exoplanet Camera (MEC). These instruments are designed to sit behind adaptive optics systems with the goal of directly imaging exoplanets in a 800-1400 nm band. Previous large optical and near-IR MKID arrays were fabricated using substoichiometric titanium nitride (TiN) on a silicon substrate. These arrays, however, suffered from severe non-uniformities in the TiN critical temperature, causing resonances to shift away from their designed values and lowering usable detector yield. We have begun fabricating DARKNESS and MEC arrays using platinum silicide (PtSi) on sapphire instead of TiN. Not only do these arrays have much higher uniformity than the TiN arrays, resulting in higher pixel yields, they have demonstrated better spectral resolution than TiN MKIDs of similar design. PtSi MKIDs also do not display the hot pixel effects seen when illuminating TiN on silicon MKIDs with photons with wavelengths shorter than 1 µm.
RESUMEN
Murine noroviruses (MNVs) are highly prevalent in laboratory mice, can cause persistent infections, and have been shown to infect macrophages, dendritic cells, and B cells. To address the potential impact of MNV infection on research outcomes, numerous studies have been conducted with various mouse models of human disease and have generated mixed results, ranging from no impact to significant disease. Many of these studies included histologic evaluations after MNV infection, and these results have similarly been variable in terms of whether MNV induces lesions, despite the fact that localization of MNV by viral culture and molecular techniques have demonstrated systemic distribution regardless of mouse immune status. The aim of this review is to summarize the histologic findings that have been reported with MNV infection in several mouse models. The studies demonstrate that experimental infection of MNV in wild-type mice results in minimal to no histologic changes. In contrast, immunodeficient mice consistently have detectable MNV-induced lesions that are typically inflammatory and, in the most severe cases, accompanied by necrosis. In these, the liver is commonly affected, with more variable lesions reported in the lung, gastrointestinal tract, mesenteric lymph nodes, brain, and spleen. In specific disease models including atherosclerosis, MNV infection had a variable impact that was dependent on the mouse model, viral strain, timing of infection, or other experimental variables. It is important to recognize the reported MNV lesions to help discern the possible influence of MNV infection on data generated in mouse models.
Asunto(s)
Infecciones por Caliciviridae/virología , Norovirus/fisiología , Animales , Animales de Laboratorio , Encéfalo/patología , Encéfalo/virología , Infecciones por Caliciviridae/patología , Modelos Animales de Enfermedad , Tracto Gastrointestinal/patología , Tracto Gastrointestinal/virología , Inflamación/patología , Inflamación/virología , Hígado/patología , Hígado/virología , Ratones , Necrosis/patología , Necrosis/virología , Bazo/patología , Bazo/virologíaRESUMEN
Recent studies demonstrate that endothelin-1 (ET-1) constricts human pulmonary arteries (PA). In this study, we examined possible mechanisms by which ET-1 might constrict human PA. In smooth muscle cells freshly isolated from these arteries, whole cell patch-clamp techniques were used to examine voltage-gated K(+) (K(V)) currents. K(V) currents were isolated by addition of 100 nM charybdotoxin and were identified by current characteristics and inhibition by 4-aminopyridine (10 mM). ET-1 (10(-8) M) caused significant inhibition of K(V) current. Staurosporine (1 nM), a protein kinase C (PKC) inhibitor, abolished the effect of ET-1. Rings of human intrapulmonary arteries (0.8-2 mm OD) were suspended in tissue baths for isometric tension recording. ET-1-induced contraction was maximal at 10(-8) M, equal to that induced by K(V) channel inhibition with 4-aminopyridine, and attenuated by PKC inhibitors. These data suggest that ET-1 constricts human PA, possibly because of myocyte depolarization via PKC-dependent inhibition of K(V). Our results are consistent with data we reported previously in the rat, suggesting similar mechanisms may be operative in both species.
Asunto(s)
Endotelina-1/farmacología , Músculo Liso Vascular/efectos de los fármacos , Canales de Potasio con Entrada de Voltaje/metabolismo , Arteria Pulmonar/efectos de los fármacos , 4-Aminopiridina/farmacología , Adolescente , Adulto , Animales , Células Cultivadas , Caribdotoxina/farmacología , Niño , Inhibidores Enzimáticos/farmacología , Femenino , Humanos , Técnicas In Vitro , Indoles/farmacología , Masculino , Maleimidas/farmacología , Persona de Mediana Edad , Músculo Liso Vascular/citología , Músculo Liso Vascular/metabolismo , Técnicas de Placa-Clamp , Bloqueadores de los Canales de Potasio/farmacología , Arteria Pulmonar/citología , Arteria Pulmonar/metabolismo , Estaurosporina/farmacología , Vasoconstricción/efectos de los fármacos , Vasoconstricción/fisiologíaRESUMEN
The effect of selective tachykinin receptor agonists and antagonists on human isolated intralobar pulmonary arterial rings was investigated. Neither Substance P (SP) nor neurokinin A (NKA) contracted the arteries. Both of these agonists, however, were potent and efficacious at relaxing the arteries that were precontracted with phenylephrine. The negative log (M) EC(50) values for SP and NKA were 9.0 and 8.3, respectively. The neurokinin (NK)-3 selective agonist, senktide-analog, and the NK-2 receptor selective agonist, [beta-Ala(8)]NKA(4-10), caused neither contractions nor relaxations of the arteries, whereas the NK-1 receptor agonist Ac-[Arg6, Sar9, Met(O2)11]SP(6-11) (ASM-SP) relaxed the tissue with a potency similar to SP. The relaxations to SP, NKA, and ASM-SP were competitively antagonized by the selective NK-1 receptor antagonist CP 99994, with a pK(b) in the nanomolar range. Antagonism of the ASM-SP-induced relaxations was also noted with FK 888, RP 67580, and L 732,138, although these antagonists were much less potent than CP 99994 in this regard. Another NK-1 receptor selective antagonist, SR 140333, caused an insurmountable antagonism of the SP-induced relaxations. The NK-1 receptor-mediated relaxations could be blocked by removing the endothelium, or by a combination of N-nitro-L-arginine and indomethacin. Measurement of prostanoid generation revealed that in endothelial-intact but not endothelial-denuded tissue, ASM-SP caused a selective increase in the production of 6-keto-PGF1alpha, the stable metabolite of prostacyclin. The results indicate that stimulation of NK-1 receptors leads to relaxation of human intralobar pulmonary arteries, which is mediated largely by nitric oxide and prostacyclin released from the endothelium of these vessels.
Asunto(s)
Arteria Pulmonar/fisiología , Receptores de Neuroquinina-1/fisiología , Receptores de Taquicininas/agonistas , Receptores de Taquicininas/antagonistas & inhibidores , Vasodilatación/fisiología , Adolescente , Adulto , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Endotelio Vascular/fisiología , Epoprostenol/metabolismo , Epoprostenol/fisiología , Femenino , Humanos , Técnicas In Vitro , Pulmón/fisiología , Masculino , Persona de Mediana Edad , Neuroquinina A/farmacología , Óxido Nítrico/fisiología , Fragmentos de Péptidos/farmacología , Fenilefrina/farmacología , Sustancia P/análogos & derivados , Sustancia P/farmacología , Vasoconstricción/efectos de los fármacosRESUMEN
In vitro electrophysiological techniques were used to examine the effect of bradykinin on guinea pig trachea and bronchus afferent nerve endings arising from the nodose or jugular ganglia. The data reveal that bradykinin activates nerve terminals of jugular C and Adelta fibers. Although the fibers were too few in number to study rigorously, bradykinin also stimulated nodose C fibers innervating the trachea and bronchus. In contrast, Adelta fibers arising from the nodose ganglion were unresponsive to bradykinin challenge. The responses in both jugular C and Adelta fiber types were blocked by a selective bradykinin B2 receptor antagonist and were not dependent on the efferent release of sensory neuropeptides. These data indicate that the sensitivity of guinea pig airway afferent fibers to bradykinin is dependent more on the ganglionic origin of the cell body than on the conduction velocity of its axon.
Asunto(s)
Bradiquinina/farmacología , Neuronas Aferentes/efectos de los fármacos , Tráquea/inervación , Nervio Vago/efectos de los fármacos , Potenciales de Acción , Animales , Antagonistas de los Receptores de Bradiquinina , Relación Dosis-Respuesta a Droga , Electrofisiología , Cobayas , Técnicas In Vitro , Masculino , Fibras Nerviosas/efectos de los fármacos , Conducción Nerviosa/efectos de los fármacos , Ganglio Nudoso/citología , Ganglio Nudoso/efectos de los fármacos , Terminales Presinápticos/efectos de los fármacos , Receptor de Bradiquinina B2 , Estimulación Química , Nervio Vago/citologíaRESUMEN
We evaluated the ability of hyperosmolar stimuli to activate afferent nerves in the guinea pig trachea and main bronchi and investigated the neural pathways involved. By using electrophysiological techniques, studies in vitro examined the effect of hyperosmolar solutions of sodium chloride (hypertonic saline) on guinea pig airway afferent nerve endings arising from either vagal nodose or jugular ganglia. The data reveal a differential sensitivity of airway afferent neurons to activation with hypertonic saline. Afferent fibers (both A delta and C fibers) with cell bodies located in jugular ganglia were much more sensitive to stimulation with hypertonic saline, compared with afferent neurons with cell bodies located in nodose ganglia. Additional studies in vivo demonstrated that inhalation of aerosols of hypertonic saline induced plasma extravasation in guinea pig trachea that was mediated via tachykinin NK1 receptors. Identification of a differential sensitivity of guinea pig airway afferent nerves to hypertonic saline leads to the speculation that airway responses to hyperosmolar stimuli may result from activation of afferent neurons originating predominantly from the jugular ganglion.
Asunto(s)
Bronquios/efectos de los fármacos , Neuronas Aferentes/efectos de los fármacos , Solución Salina Hipertónica/farmacología , Tráquea/efectos de los fármacos , Nervio Vago/efectos de los fármacos , Administración por Inhalación , Animales , Bronquios/irrigación sanguínea , Bronquios/inervación , Bronquios/fisiología , Permeabilidad Capilar/efectos de los fármacos , Cobayas , Técnicas In Vitro , Masculino , Fibras Nerviosas/efectos de los fármacos , Fibras Nerviosas/fisiología , Neuronas Aferentes/fisiología , Ganglio Nudoso/efectos de los fármacos , Ganglio Nudoso/fisiología , Receptores de Neuroquinina-1/fisiología , Tráquea/irrigación sanguínea , Tráquea/inervación , Tráquea/fisiología , Nervio Vago/citología , Nervio Vago/fisiologíaRESUMEN
OBJECTIVE: To identify factors predicting prosthesis use and final speech quality in patients undergoing secondary tracheoesophageal puncture (TEP) for voice restoration alter laryngectomy. METHODS: We undertook a retrospective study of 168 patients who underwent secondary TEP at the Cleveland Clinic between June 1980 and October 1993. Factors examined were: patient demographics, extent of initial surgery, method of pharyngeal preparation, history of irradiation, insufflation test results, pharyngeal stricture, and concurrent medical conditions. Univariate and multivariate statistical analyses were performed to identify predictive factors. RESULTS: At last evaluation, 73.8% (124) of the patients were still using the prosthesis. Quality of speech was the only predictor of prosthesis use (p < .001). Phonation on the first day was achieved in 90% (151) of patients. Speech result improved significantly over the first 6 months (p < .001). Univariate analysis found that the need for reconstruction at laryngectomy (p = .04), the presence of pharyngeal stricture (p = .001), and continued prosthetic use (p < .001) were associated with the speech result. There was no significant advantage to the lack of approximation of the pharyngeal constrictors (p = .31). Stepwise logistic regression showed that only the absence of pharyngeal stricture was associated with a better-quality voice (p = .001). CONCLUSION: Tracheoesophageal puncture is a reliable method for restoring voice after laryngectomy. Prosthesis use decreases with time, and good voice quality is the only predictor of continued prosthesis use. In this series the absence of pharyngeal stricture was the only significant predictor of good to excellent speech.
Asunto(s)
Tráquea/cirugía , Trastornos de la Voz/rehabilitación , Adulto , Anciano , Distribución de Chi-Cuadrado , Femenino , Humanos , Laringectomía/métodos , Laringe Artificial/estadística & datos numéricos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Trastornos de la Voz/cirugía , Calidad de la VozRESUMEN
Carbon monoxide, formed as a product of heme oxygenase activity, has been postulated to act as an intra- and intercellular messenger molecule. We addressed the hypothesis that heme oxygenase is involved in the relaxation of the guinea pig trachealis elicited by vasoactive intestinal peptide (VIP) or by electrical field stimulation. Immunohistochemical studies revealed the presence of heme oxygenase-II in airway smooth muscle and epithelium. Zinc protoporphyrin-IX (ZnPPn), an inhibitor of heme oxygenase, effectively inhibited VIP-induced relaxations of tracheal smooth muscle. Surprisingly, the potency of ZnPPn was increased if the drug was preincubated with the VIP solution before addition to the tissue bath. The relaxant responses to 3-morpholinosydnonimine were unaffected by ZnPPn. Zinc deuteroporphyrin-IX 2,4 bisglycol, a more potent inhibitor of heme oxygenase than ZnPPn, did not affect the VIP responses. ZnPPn (300 microM) had no effect on nonadrenergic, noncholinergic relaxations of the guinea pig trachea. These data indicate that although ZnPPn is an efficacous inhibitor of VIP-induced relaxations of the guinea pig trachealis, it is unlikely that heme oxygenase plays an important role in this response. Rather, the data are consistent with the hypothesis that ZnPPn inhibits the VIP response via an interaction with the VIP molecules themselves. Although the results demonstrate the existence of heme oxygenase-II in the guinea pig trachealis, they do not support the hypothesis that it plays a role in electrical field stimulation-induced nonadrenergic, noncholinergic relaxations.
Asunto(s)
Relajación Muscular/efectos de los fármacos , Tráquea/efectos de los fármacos , Péptido Intestinal Vasoactivo/farmacología , Zinc/farmacología , Animales , Relación Dosis-Respuesta a Droga , Cobayas , Inmunohistoquímica , Isoproterenol/farmacología , MasculinoRESUMEN
We examined the pharmacology of ZM253,270 and two representative examples of the pyrrolopyrimidines, a new class of nonpeptide, NK-2 receptor (NK-2R) antagonists. ZM253,270 competitively inhibited [3H]NKA binding to native or cloned NK-2R from hamster urinary bladder (Ki = 2 nM), but was a weaker (48-fold) inhibitor of [3H]NKA binding to cloned human NK-2R. A similar species selectivity was observed with less potent analogs of ZM253,270. The pyrrolopyrimidines demonstrated only marginal inhibition of [3H]SP binding to NK-1R in guinea pig lung membranes (Ki > 2 microM). In hamster trachea, ZM253,270 competitively antagonized the contractile response evoked by neurokinin A (NKA, -logKB = 7.5). In human bronchus, ZM253,270 was about 90-fold less potent as a competitive antagonist of NKA. The data from ligand binding assays in cloned receptors combined with functional receptor assays in airway smooth muscles, demonstrate that the nonpeptide antagonist ZM253,270 is selective for the NK2 receptor species that are prevalent in hamster, compared with those found in human tissues.
Asunto(s)
Pirimidinas/farmacología , Pirroles/farmacología , Receptores de Neuroquinina-2/antagonistas & inhibidores , Animales , Línea Celular , Cricetinae , Cobayas , Humanos , Técnicas In Vitro , Pulmón/efectos de los fármacos , Pulmón/metabolismo , Contracción Muscular/efectos de los fármacos , Músculo Liso/efectos de los fármacos , Músculo Liso/metabolismo , Músculo Liso/fisiología , Unión Proteica , Receptores de Neuroquinina-2/metabolismo , Especificidad de la Especie , Tráquea/efectos de los fármacos , Tráquea/metabolismo , Células Tumorales CultivadasRESUMEN
The effect of human recombinant stem cell factor (SCF) on inflammatory mediator release and smooth muscle contraction was evaluated in human isolated intralobar bronchi. Bronchi from 21 of 26 donors contracted in response to SCF. The threshold concentration was approximately 0.01 micrograms/ml. At 1 micrograms/ml, the tissues contracted to about 60% of the carbamylcholine-induced maximum contraction. The responses to SCF mimicked those obtained with anti-IgE. Thus, the contractions to SCF and anti-IgE were inhibited to a similar extent by a combination of a cysteinyl-leukotriene receptor antagonist and a histamine H1 receptor antagonist. SCF also mimicked the effect of anti-IgE in releasing histamine, i-LTD4, and PGD2 from the bronchi. At a threshold concentration for contraction (0.01 micrograms/ml), SCF had no effect on subsequent responses to anti-IgE in the bronchi. The data suggest that human recombinant SCF contracts airway smooth muscle by stimulating the release of contractile mediators from bronchial mast cells. The data fail to support the hypothesis that SCF primes bronchial mast cells to subsequent immunologic stimuli.
Asunto(s)
Bronquios/fisiología , Factores de Crecimiento de Célula Hematopoyética/farmacología , Mastocitos/efectos de los fármacos , Contracción Muscular/efectos de los fármacos , Músculo Liso/fisiología , Anticuerpos Antiidiotipos/farmacología , Autacoides/metabolismo , Bronquios/inmunología , Carbacol/farmacología , Ácidos Dicarboxílicos/farmacología , Antagonistas de los Receptores Histamínicos , Humanos , Inmunoglobulina E , Técnicas In Vitro , Leucotrieno D4/antagonistas & inhibidores , Mastocitos/inmunología , Músculo Liso/inmunología , Pirilamina/farmacología , Proteínas Recombinantes/farmacología , Factor de Células MadreRESUMEN
We studied the effect of inhibiting phosphodiesterase (PDE) isozyme types III, IV and V on the cholinergic and noncholinergic (tachykinergic) contractile responses to electrical field stimulation (EFS) in the guinea pig isolated bronchus. SKF 94836, a PDE III inhibitor, had a slight (approximately 30%) but significant inhibitory effect on the noncholinergic contractions. Rolipram, an inhibitor of PDE IV isozymes, dramatically inhibited the noncholinergic contractions by nearly 70%. The EC50 for rolipram was approximately 20 nM. Rolipram (1 microM) had no effect on contractions elicited by either capsaicin or neurokinin A. EFS, but not direct vagus nerve stimulation, elicits small nonadrenergic, noncholinergic relaxations of the bronchus that were potentiated by rolipram. Rolipram had the same inhibitory effect on EFS- and vagus nerve stimulation-induced noncholinergic contractions. The effect of rolipram was mimicked by another PDE IV inhibitor, RO-201724. Inhibition of PDE V with zaprinast (3 microM) had no effect on the tachykinergic contractile response. None of the PDE inhibitors affected the EFS-induced cholinergic contractions. The data suggest that the contraction due to stimulation of tachykinergic fibers is significantly reduced by selective inhibition of PDE IV and, to a lesser extent, PDE III isozymes. This is unlikely to be due to functional antagonism at the level of the smooth muscle. It is also unlikely to be due to potentiation of the nonadrenergic relaxant response to nerve stimulation. Rather, the data are in agreement with the hypothesis that selective inhibition of PDE isozymes leads to inhibition of electrically evoked tachykinin release from capsaicin-sensitive fibers in the guinea pig bronchus.
Asunto(s)
Broncoconstricción/efectos de los fármacos , Isoenzimas/antagonistas & inhibidores , Inhibidores de Fosfodiesterasa/farmacología , 4-(3-Butoxi-4-metoxibencil)-2-imidazolidinona/farmacología , Animales , Bronquios/inervación , Estimulación Eléctrica , Guanidinas/farmacología , Cobayas , Masculino , Purinonas/farmacología , Piridazinas/farmacología , Pirrolidinonas/farmacología , Rolipram , Nervio Vago/fisiologíaRESUMEN
The ability of antigen to contract passively sensitized tissues was examined in human central (5 to 12 mm) and peripheral (0.5 to 2 mm) bronchi. Both central and peripheral bronchi contracted to ragweed antigen E (RW AgE), and these contractions were virtually abolished by a combination of indomethacin, cysteinyl-leukotriene, and histamine antagonists. There were, however, quantitative differences in contractile responses and in mediator release to RW AgE between central and peripheral bronchi. RW AgE was approximately 20-fold more potent in contracting peripheral bronchi compared with central bronchi. On a per weight of tissue basis, RW AgE released six-fold more histamine, 15- to 20-fold more immunoreactive leukotriene D4 (i-LTD4) and two- to 10-fold more prostanoids in the peripheral bronchi compared with central bronchi. Anti-IgE mimicked the effect of RW AgE with respect to inflammatory mediator release and with respect to the magnitude of the contractile response in peripheral and central bronchi. Anti-IgE, however, was more potent in contracting central than peripheral bronchi. Moreover, in peripheral bronchi, contractile responses to anti-IgE were only partially inhibited by a combination of indomethacin, cysteinyl-leukotriene, and histamine antagonists. These results indicate that the qualitative characteristics of antigen-induced mediator release and muscle contraction are similar in central versus peripheral bronchi. However, RW AgE is much more potent in causing smooth muscle constriction, and is capable of releasing a greater quantity of inflammatory mediators in peripheral bronchi/bronchioles than in the more central bronchi.
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Alérgenos/inmunología , Anticuerpos Antiidiotipos/inmunología , Bronquios/inmunología , Inmunoglobulina E/inmunología , Proteínas de Plantas/inmunología , Polen/inmunología , Adulto , Antígenos de Plantas , Bronquios/efectos de los fármacos , Relación Dosis-Respuesta Inmunológica , Interacciones Farmacológicas , Femenino , Humanos , Hipersensibilidad Inmediata/inmunología , Técnicas In Vitro , Masculino , Contracción Muscular/efectos de los fármacos , Músculo Liso/efectos de los fármacos , Músculo Liso/inmunología , Factores de TiempoRESUMEN
1. We examined effects of bradykinin (BK) receptor antagonists on airway hyperresponsiveness and eosinophilia in sensitized guinea-pigs that had been administered single, as well as repeated (chronic) challenges with inhaled ovalbumin. In addition, the effects of BK antagonists on antigen-induced respiratory distress during the chronic study were noted. 2. At 24 h following single antigen challenge, guinea-pigs exhibited airway hyperresponsiveness to the bronchoconstrictor effect of i.v. histamine, characterized by a left shift in the dose-response curve. In addition, responses to the maximum dose of histamine that could be used were significantly increased in hyperresponsive guinea-pigs. The percentages of bronchoalveolar fluid, eosinophil and neutrophils also increased. 3. A BK B1 receptor antagonist, desArg9-[Leu8]-BK, significantly inhibited airway hyperresponsiveness induced by single antigen challenge. A B2 receptor antagonist, D-Arg-[Hyp3, Thi5,8,D-Phe7]-BK (NPC 349) had a small, but statistically significant inhibitory effect on responsiveness to the highest histamine dose in challenged animals. DesArg9-[Leu8]-BK significantly inhibited the neutrophilia, whereas NPC 349 inhibited infiltration by both cell types. 4. Chronic antigen challenge also caused airway hyperresponsiveness to i.v. acetylcholine (ACh), distinguished by an increase in the slope of the dose-response curve. Thus, the magnitude of the bronchoconstrictor responses to the maximum dose of ACh that could be used was significantly increased. No change in sensitivity to ACh was evident. Marked eosinophilia was also noted in the trachea, bronchi and lung parenchyma. 5. Airway hyperresponsiveness and eosinophilia, induced by chronic antigen challenge, were markedly inhibited by the B2 antagonists, D-Arg-[Hyp3,D-Phe7]-BK (NPC 567) or D-Arg-[Hyp3,Thi5d-Tic7,Tic8]-BK (NPC 16731).NPC 16731 also abolished antigen-induced cyanosis, and delayed the onset of dyspnoea,doubling the time taken for animals to exhibit respiratory distress.6. The ability of BK receptor antagonists to inhibit antigen-induced airway hyperresponsiveness, in addition to eosinophilia, indicates an important role for endogenous kinins. Moreover, the abrogation of eosinophil infiltration suggests that BK has a significant function in maintaining allergic inflammation of the airways.
Asunto(s)
Hiperreactividad Bronquial/patología , Eosinofilia Pulmonar/tratamiento farmacológico , Receptores de Neurotransmisores/antagonistas & inhibidores , Síndrome de Dificultad Respiratoria del Recién Nacido/tratamiento farmacológico , Acetilcolina/farmacología , Animales , Bradiquinina/análogos & derivados , Bradiquinina/antagonistas & inhibidores , Bradiquinina/farmacología , Relación Dosis-Respuesta a Droga , Femenino , Cobayas , Humanos , Recién Nacido , Masculino , Ovalbúmina/inmunología , Eosinofilia Pulmonar/inducido químicamente , Eosinofilia Pulmonar/patología , Receptores de Bradiquinina , Síndrome de Dificultad Respiratoria del Recién Nacido/inducido químicamente , Síndrome de Dificultad Respiratoria del Recién Nacido/patologíaRESUMEN
One hundred forty-six secondary tracheoesophageal puncture (TEP) procedures were performed on 132 patients at the Cleveland Clinic Foundation in the past 10 years. The complications of these procedures are reviewed, along with assessment of potential risk factors such as irradiation, esophageal/hypopharyngeal stricture, alcoholism, diabetes, or chronic obstructive pulmonary disease. Among the subgroups studied, only stricture dilation was associated with an increased incidence of postsurgical complications. The majority of these, however, were immediate, and were probably related to the esophagoscopy or dilation itself. The incidence of TEP-related complications in all groups of patients may be higher than previously suspected.
Asunto(s)
Complicaciones Posoperatorias , Voz Alaríngea , Voz Esofágica , Dilatación/efectos adversos , Esofagoscopía/efectos adversos , Humanos , Laringectomía/efectos adversos , Estudios Retrospectivos , Factores de Riesgo , Voz Alaríngea/métodos , Factores de TiempoRESUMEN
Five decapeptides were prepared, each having the generic primary sequence D-Arg0-Arg1-Pro2-Hyp3-Gly4-Thi5-Ser6-X7 -Y8-Arg9. A C-terminal beta-turn was anticipated when X was an alkyl ether of D-4-hydroxyproline in either the cis or trans geometric state and Y was either a Tic or Oic residue. Whereas cis ethers have only very weak receptor affinities, the trans ethers are significantly more potent in binding to guinea pig smooth muscle having Ki values as low as 0.16 nM. Notably, these peptides do not contain a D-aromatic amino acid at position 7 of the primary sequence.
Asunto(s)
Oligopéptidos/metabolismo , Receptores de Neurotransmisores/metabolismo , Secuencia de Aminoácidos , Animales , Sitios de Unión , Bradiquinina/análogos & derivados , Bradiquinina/química , Bradiquinina/metabolismo , Cobayas , Hidroxiprolina/química , Técnicas In Vitro , Cinética , Datos de Secuencia Molecular , Músculo Liso/metabolismo , Oligopéptidos/química , Conformación Proteica , Receptores de Bradiquinina , Relación Estructura-Actividad , TermodinámicaRESUMEN
Antigen arthritis in rabbits was associated with induction of bradykinin B1 receptors in isolated aorta smooth muscle 24 h following intra-articular injection of antigen in sensitized animals. Control tissues developed responsiveness to desArg9-bradykinin or bradykinin during 3 h incubation, but failed to respond to either kinin at the beginning of experiments. Aorta from rabbits 24 h after induction of arthritis not only developed responsiveness to kinins more rapidly than controls, but also responded at the outset of experiments. Antigen arthritis was characterized by acute phase protein synthesis and joint swelling. This is the first demonstration of induction of smooth muscle responsiveness to desArg9-bradykinin during an immune complex disease.
Asunto(s)
Artritis/metabolismo , Bradiquinina/metabolismo , Músculo Liso Vascular/metabolismo , Receptores de Neurotransmisores/metabolismo , Animales , Antígenos , Aorta/efectos de los fármacos , Bradiquinina/análogos & derivados , Bradiquinina/farmacología , Fibrina/inmunología , Masculino , Contracción Muscular/efectos de los fármacos , Fenilefrina/farmacología , Conejos , Receptores de BradiquininaAsunto(s)
Bradiquinina/antagonistas & inhibidores , Hidroxiprolina/análogos & derivados , Oligopéptidos/metabolismo , Receptores de Neurotransmisores/metabolismo , Secuencia de Aminoácidos , Animales , Sitios de Unión , Bradiquinina/análogos & derivados , Bradiquinina/química , Bradiquinina/metabolismo , Fenómenos Químicos , Química Física , Fibroblastos/metabolismo , Cobayas , Íleon/metabolismo , Datos de Secuencia Molecular , Oligopéptidos/química , Conformación Proteica , Receptores de Bradiquinina , Receptores de Neurotransmisores/química , Relación Estructura-Actividad , TermodinámicaRESUMEN
D-Arg[Hyp3-Thi5-D-Tic7-Tic8]-bradykinin (NPC 16731) inhibited bradykinin (BK) binding and BK-induced contraction in guinea-pig ileum, being markedly more potent than D-Phe7-BK analogues as a BK2 receptor antagonist. In isolated trachea NPC 16731, unlike other BK2 antagonists, inhibited BK binding and BK-induced contraction, and 45Ca2+ efflux in tracheal smooth muscle cells. That NPC 16731 potently inhibits BK effects in trachea provides further evidence for the existence of the airway BK3 receptor.