RESUMEN

INTRODUCTION: Bamlanivimab and etesevimab (BAM + ETE) are monoclonal antibodies (mAbs) effective in reducing COVID-19-related hospitalizations and all-cause mortality in adult participants at increased risk for severe disease. We present pharmacokinetic (PK), efficacy, and safety results from pediatric participants (< 18 years of age) with COVID-19 who were treated with BAM + ETE. METHODS: In an addendum to the phase 2/3 BLAZE-1 clinical trial (NCT04427501), pediatric participants received open-label weight-based dosing (WBD, n = 94) based on exposure-matching to the authorized dose of BAM + ETE in adult participants. For efficacy and safety assessments, placebo (n = 14) and BAM + ETE (n = 20)-treated adolescent participants (> 12 to < 18 years of age) from the BLAZE-1 trial were included in the overall pediatric population (N = 128). All participants had mild to moderate COVID-19 upon enrollment and ≥ 1 risk factor for severe COVID-19. The primary objective was to characterize the PK of BAM and ETE in the WBD population. RESULTS: The median age of the participants was 11.2 years, 46.1% were female, 57.9% were Black/African American, and 19.7% were Hispanic/Latino. The area under the curve for BAM and ETE in the WBD population was similar to that previously observed in adults. There were no COVID-19-related hospitalizations or deaths. All adverse events (AE) except one were mild or moderate, with one participant reporting a serious AE. CONCLUSION: WBD in pediatric participants achieved similar drug exposures compared to adult participants that received the authorized BAM + ETE dose. The pediatric efficacy and safety data were consistent with adults receiving mAbs for COVID-19. TRIAL REGISTRATION NUMBER: NCT04427501.

RESUMEN

OBJECTIVES: We performed a pilot study of upamostat, a serine protease inhibitor, in outpatients with symptomatic COVID-19 before a pivotal trial. METHODS: SARS-CoV-2 patients with ≥2 moderate-severe symptoms onset within 5 days were randomized to oral upamostat 200 or 400 mg or placebo daily for 14 days. Patients completed COVID-19 symptom questionnaires daily for 28 days, then thrice weekly for 4 weeks, and underwent physical and laboratory examinations periodically. RESULTS: A total of 61 patients enrolled of which 20 received a placebo or upamostat 200 mg daily; 21 received upamostat 400 mg daily. Treatment was well tolerated; only one patient (upamostat 400) reported a drug-related adverse event, mild skin rash; no patient discontinued owing to a drug-related adverse event. The median time to a sustained recovery from severe symptoms was 8, 4, and 3 days for the three treatment groups, respectively. New severe symptoms developed in 20% of the placebo group vs 2.4% in the combined upamostat groups, (P = 0.036). Three placebo patients (15%) versus no upamostat patients were hospitalized for worsening COVID (P= 0.03). The mean d-dimer level remained constant in placebo patients but decreased by 38% and 48% in upamostat 200 and 400 patients, respectively. CONCLUSION: Upamostat was well tolerated, shortened recovery time, and decreased new severe symptoms and hospitalization.

Asunto(s)

COVID-19 , Humanos , SARS-CoV-2 , Proyectos Piloto , Pacientes Ambulatorios , Inhibidores de Serina Proteinasa , Resultado del Tratamiento , Método Doble Ciego

RESUMEN

OBJECTIVE: To evaluate the long-term safety of NKTR-181, a novel mu-opioid receptor agonist that may have reduced human abuse potential, in patients with moderate to severe chronic low back pain (CLBP) or other chronic noncancer pain (CNP). DESIGN: Uncontrolled, multicenter, open-label, long-term study of NKTR-181 comprised of three periods: screening (≤21 days), treatment (52 weeks), and safety follow-up (∼14 days after the last dose of NKTR-181). SETTING: Multicenter, long-term clinical research study. METHODS: NKTR-181 administered at doses of 100-600 mg twice daily (BID) was evaluated in opioid-naïve and opioid-experienced patients. Patients were enrolled de novo or following completion of the randomized, placebo-controlled phase 3 efficacy study (SUMMIT-07). Safety assessments included adverse event documentation, measurements of opioid withdrawal, and clinical laboratory tests. Effectiveness was assessed using the modified Brief Pain Inventory Short Form (mBPI-SF). RESULTS: The study enrolled 638 patients. The most frequently reported treatment-emergent adverse events (TEAEs) were constipation (26%) and nausea (12%). Serious TEAEs, reported in 5% of patients, were deemed by investigators to be unrelated to NKTR-181. There were no deaths or reported cases of respiratory depression. A sustained reduction in mBPI-SF pain intensity and pain interference from baseline to study termination was observed throughout treatment. Only 2% of patients discontinued NKTR-181 due to lack of efficacy, and 11% discontinued due to treatment-related AEs. NKTR-181 doses of up to 600 mg BID were generally well tolerated, and patients experienced low rates of opioid-related adverse events. CONCLUSIONS: The study results support the premise that NKTR-181 is a safe and effective option for patients with moderate to severe CLBP or CNP.

Asunto(s)

Dolor Crónico , Dolor de la Región Lumbar , Analgésicos Opioides/efectos adversos , Dolor Crónico/tratamiento farmacológico , Método Doble Ciego , Humanos , Dolor de la Región Lumbar/tratamiento farmacológico , Morfinanos , Dimensión del Dolor , Resultado del Tratamiento

RESUMEN

OBJECTIVES: Buprenorphine HCl buccal film has been developed for treating chronic pain utilizing BioErodible MucoAdhesive (BEMA(®)) delivery technology. Buccal buprenorphine (BBUP; Belbuca(TM), Endo Pharmaceuticals) was evaluated for the management of moderate to severe chronic low back pain (CLBP) requiring around-the-clock analgesia in a multicenter, double-blind, placebo-controlled, enriched-enrollment, randomized-withdrawal study in opioid-naive patients. METHODS: Patients (n = 749) were titrated to a dose of BBUP (range, 150-450 µg every 12 h) that was generally well tolerated and provided adequate analgesia for ≥14 days, and then randomized to BBUP (n = 229) or placebo (n = 232), respectively. The primary efficacy variable was the change from baseline to week 12 of double-blind treatment in the mean of daily average pain intensity scores (numeric rating scale from 0 [no pain] to 10 [worst pain imaginable]). RESULTS: Patients were experiencing moderate to severe pain at study entry: mean (SD) = 7.15 (1.05). Following titration, pain was reduced to the mild range; 2.81 (1.07). After randomization, mean (SD) pain scores increased from baseline to week 12 more with placebo (1.59 [2.04]) versus BBUP: (0.94 [1.85]) with a significant between-group difference (-0.67 [95% CI: -1.07 to -0.26]; p = 0.0012). A significantly larger percentage of patients receiving BBUP versus placebo had ≥30% pain reduction (63% vs 47%; p = 0.0012). During double-blind treatment, the most frequent adverse events (AEs) with BBUP were nausea (10%), constipation (4%) and vomiting (4%). The most common AEs with placebo were nausea (7%), upper respiratory tract infection (4%), headache (3%) and diarrhea (3%). CONCLUSIONS: These findings demonstrate the efficacy and tolerability of BBUP among opioid-naive patients requiring around-the-clock opioid treatment for CLBP.

Asunto(s)

Analgésicos Opioides/administración & dosificación , Buprenorfina/administración & dosificación , Dolor Crónico/tratamiento farmacológico , Dolor de la Región Lumbar/tratamiento farmacológico , Administración Bucal , Adulto , Anciano , Anciano de 80 o más Años , Analgésicos Opioides/uso terapéutico , Buprenorfina/uso terapéutico , Dolor Crónico/diagnóstico , Método Doble Ciego , Femenino , Estudios de Seguimiento , Humanos , Dolor de la Región Lumbar/diagnóstico , Masculino , Persona de Mediana Edad , Dimensión del Dolor , Índice de Severidad de la Enfermedad , Resultado del Tratamiento

RESUMEN

In the present study, we used atomic force microscopy (AFM) to examine the ligand-binding properties of α7-containing nicotinic acetylcholine receptors (nAChRs) expressed on neurons from the ventral respiratory group. We also determined the effect of acute and prolonged exposure to nicotine on the binding probability of nAChRs. Neurons from neonatal (postnatal day 5-10) and juvenile rats (3-4 weeks old) were cultured. Internalization of Alexa Fluor 488-conjugated substance P was used to identify respiratory neurons that expressed the neurokinin-1 receptor (NK1-R), a recognized marker of ventral respiratory group neurons. To assess functional changes in nAChRs, AFM probes conjugated with anti-α7 subunit nAChR antibody were used to interact cyclically with the surface of the soma of NK1-R-positive neurons. Measurements were made of the frequency of antibody adhesion to the α7 receptor subunit and of the detachment forces between the membrane-attached receptor and the AFM probe tip. Addition of α-bungarotoxin (a specific antagonist of α7 subunit-containing nAChRs) to the cell bath produced a 69% reduction in binding to the α7 subunit (P < 0.05, n = 10), supporting specificity of binding. Acute exposure to nicotine (1 µM added to culture media) produced an 80% reduction in nAChR antibody binding to the α7 subunit (P < 0.05, n = 9). Prolonged incubation (72 h) of the cell culture in nicotine significantly reduced α7 binding in a concentration-dependent manner. Collectively, these findings demonstrate that AFM is a sensitive tool for assessment of functional changes in nAChRs expressed on the surface of living NK1-R-expressing medullary neurons. Moreover, these data demonstrate that nicotine exposure decreases the binding probability of α7 subunit-containing nAChRs.

Asunto(s)

Microscopía de Fuerza Atómica , Neuronas/metabolismo , Receptores de Neuroquinina-1/metabolismo , Receptores Nicotínicos/metabolismo , Centro Respiratorio/metabolismo , Factores de Edad , Animales , Animales Recién Nacidos , Bungarotoxinas/metabolismo , Bungarotoxinas/farmacología , Células Cultivadas , Relación Dosis-Respuesta a Droga , Colorantes Fluorescentes/metabolismo , Ligandos , Masculino , Neuronas/efectos de los fármacos , Nicotina/metabolismo , Nicotina/farmacología , Agonistas Nicotínicos/metabolismo , Agonistas Nicotínicos/farmacología , Antagonistas Nicotínicos/metabolismo , Antagonistas Nicotínicos/farmacología , Unión Proteica , Ratas , Ratas Sprague-Dawley , Receptores Nicotínicos/efectos de los fármacos , Centro Respiratorio/citología , Centro Respiratorio/efectos de los fármacos , Sustancia P/análogos & derivados , Sustancia P/metabolismo , Factores de Tiempo , Receptor Nicotínico de Acetilcolina alfa 7

RESUMEN

Chemically modified graphene (CMG) nanoplatelets have shown great promise in various applications due to their electrical properties and high surface area. Chemical doping is one of the most effective methods to tune the electronic properties of graphene materials. In this work, novel B-doped nanoplatelets (borane-reduced graphene oxide, B-rG-O) were produced on a large scale via the reduction of graphene oxide by a borane-tetrahydrofuran adduct under reflux, and their use for supercapacitor electrodes was studied. This is the first report on the production of B-doped graphene nanoplatelets from a solution process and on the use of B-doped graphene materials in supercapacitors. The B-rG-O had a high specific surface area of 466 m(2)/g and showed excellent supercapacitor performance including a high specific capacitance of 200 F/g in aqueous electrolyte as well as superior surface area-normalized capacitance to typical carbon-based supercapacitor materials and good stability after 4500 cycles. Two- and three-electrode cell measurements showed that energy storage in the B-rG-O supercapacitors was contributed by ion adsorption on the surface of the nanoplatelets in addition to electrochemical redox reactions.

Asunto(s)

Capacidad Eléctrica , Suministros de Energía Eléctrica , Electrodos , Electrónica/instrumentación , Grafito/química , Nanoestructuras/química , Nanoestructuras/ultraestructura , Diseño de Equipo , Análisis de Falla de Equipo , Tamaño de la Partícula

RESUMEN

Here, we demonstrate that the assembly of nanostructures with different dimensionalities yields "multicomponent hybrid" transparent conductive films (TCFs) with sheet resistance and optical transmittance comparable to that of indium tin oxide (ITO) films. It was shown that sheet resistance of single-component Ag nanowire (NW) films can be further decreased by introducing gold-decorated reduced graphene oxide (RG-O) nanoplatelets that bridge the closely located noncontacting metal NWs. RG-O nanoplatelets can act as a protective and adhesive layer for underneath metal NWs, resulting in better performance of hybrid TCFs compared to single-component TCFs. Additionally, these hybrid TCFs possess antibacterial properties, demonstrating their multifunctional characteristics that might have a potential for biomedical device applications. Further development of this strategy paves a way toward next generation TCFs composed of different nanostructures and characterized by multiple (or additional) functionalities.

Asunto(s)

Fenómenos Fisiológicos Bacterianos/efectos de los fármacos , Membranas Artificiales , Nanopartículas/administración & dosificación , Nanopartículas/química , Antibacterianos/farmacología , Conductividad Eléctrica , Ensayo de Materiales , Refractometría

RESUMEN

Chemically activated graphene ('activated microwave expanded graphite oxide', a-MEGO) was used as a cathode material for Li-ion hybrid supercapacitors. The performance of a-MEGO was first verified with Li-ion electrolyte in a symmetrical supercapacitor cell. Hybrid supercapacitors were then constructed with a-MEGO as the cathode and with either graphite or Li(4)Ti(5)O(12) (LTO) for the anode materials. The results show that the activated graphene material works well in a symmetrical cell with the Li-ion electrolyte with specific capacitances as high as 182 F g(-1). In a full a-MEGO/graphite hybrid cell, specific capacitances as high as 266 F g(-1) for the active materials at operating potentials of 4 V yielded gravimetric energy densities for a packaged cell of 53.2 W h kg(-1).

RESUMEN

Chemically modified graphene platelets, produced via graphene oxide, show great promise in a variety of applications due to their electrical, thermal, barrier and mechanical properties. Understanding the chemical structures of chemically modified graphene platelets will aid in the understanding of their physical properties and facilitate development of chemically modified graphene platelet chemistry. Here we use (13)C and (15)N solid-state nuclear magnetic resonance spectroscopy and X-ray photoelectron spectroscopy to study the chemical structure of (15)N-labelled hydrazine-treated (13)C-labelled graphite oxide and unlabelled hydrazine-treated graphene oxide, respectively. These experiments suggest that hydrazine treatment of graphene oxide causes insertion of an aromatic N(2) moiety in a five-membered ring at the platelet edges and also restores graphitic networks on the basal planes. Furthermore, density-functional theory calculations support the formation of such N(2) structures at the edges and help to elucidate the influence of the aromatic N(2) moieties on the electronic structure of chemically modified graphene platelets.

Asunto(s)

Grafito/química , Hidrazinas/química , Nitrógeno/química , Óxidos/química , Isótopos de Carbono/química , Química/métodos , Calor , Espectroscopía de Resonancia Magnética/métodos , Modelos Químicos , Espectroscopía de Fotoelectrones/métodos , Agua/química

RESUMEN

There is intense interest in graphene in fields such as physics, chemistry, and materials science, among others. Interest in graphene's exceptional physical properties, chemical tunability, and potential for applications has generated thousands of publications and an accelerating pace of research, making review of such research timely. Here is an overview of the synthesis, properties, and applications of graphene and related materials (primarily, graphite oxide and its colloidal suspensions and materials made from them), from a materials science perspective.

Asunto(s)

Carbono/química , Óxidos/química , Óxidos/síntesis química , Fenómenos Mecánicos , Nanocompuestos/química , Fenómenos Ópticos , Temperatura

RESUMEN

GABAergic neurones are interspersed throughout the nucleus tractus solitarii (NTS), and their tonic activity is crucial to the maintenance of cardiorespiratory homeostasis. However, the mechanisms that regulate the magnitude of GABAergic inhibition in the NTS remain unknown. We hypothesized that the level of GABAergic inhibition is proportionally regulated by the level of excitatory synaptic input to the NTS from baroreceptors. Using the in situ working heart-brainstem preparation in normotensive and spontaneously hypertensive rats, we blocked GABA(A) receptor-mediated neurotransmission in the NTS with gabazine (a specific GABA(A) receptor antagonist) at two levels of perfusion pressure (low PP, 60-70 mmHg; and high PP, 105-125 mmHg) while monitoring the immediate changes in cardiorespiratory variables. In normotensive rats, gabazine produced an immediate bradycardia consistent with disinhibition of NTS circuit neurones that regulate heart rate (HR) which was proportional to the level of arterial pressure (HR at low PP, 57 +/- 9 beats min(1); at high PP, 177 +/- 9 beats min(1); P < 0.001), suggesting that GABAergic circuitry in the NTS modulating heart rate was arterial pressure dependent. In contrast, there was no significant difference in the magnitude of gabazine-induced bradycardia in spontaneously hypertensive rats at low or high PP (HR at low PP, 45 +/- 10 beats min(1); at high PP, 58 +/- 7 beats min(1)). With regard to thoracic sympathetic nerve activity (tSNA), at high PP there was a significant reduction in tSNA during the inspiratory (I) phase of the respiratory cycle, but only in the normotensive rat (tSNA = 18.7 +/- 10%). At low PP, gabazine caused an elevation of the postinspiration phase of tSNA in both normotensive (tSNA = 23.7 +/- 2.9%) and hypertensive rats (tSNA = 44.2 +/- 14%). At low PP, gabazine produced no change in tSNA during the mid-expiration phase in either rat strain, but at high PP we observed a significant reduction in the mid-expiration phase tSNA, but only in the spontaneously hypertensive rat (tSNA = 25.2 +/- 8%). Gabazine at both low and high PP produced a reduction in the late expiration phase of tSNA in the hypertensive rat (low PP, tSNA = 29.4 +/- 4.4%; high PP, tSNA = 22.8 +/- 3%), whereas in the normotensive rat this was only significant at high PP (tSNA = 42.5 +/- 6.1%). Therefore, in the spontaneously hypertensive rat, contrary to the GABA(A) receptor-mediated control of HR, it appears that GABA(A) receptor-mediated control of tSNA in the NTS is arterial pressure dependent. This study provides new insight into the origin of GABAergic inhibition in NTS circuitry affecting heart rate and sympathetic activity.

Asunto(s)

Barorreflejo , Sistema Cardiovascular/inervación , Hipertensión/metabolismo , Neuronas/metabolismo , Núcleo Solitario/metabolismo , Ácido gamma-Aminobutírico/metabolismo , Animales , Barorreflejo/efectos de los fármacos , Presión Sanguínea , Sistema Cardiovascular/efectos de los fármacos , Modelos Animales de Enfermedad , Antagonistas de Receptores de GABA-A/administración & dosificación , Frecuencia Cardíaca , Hipertensión/fisiopatología , Microinyecciones , Inhibición Neural , Neuronas/efectos de los fármacos , Perfusión , Nervio Frénico/fisiopatología , Piridazinas/administración & dosificación , Ratas , Ratas Endogámicas SHR , Ratas Wistar , Mecánica Respiratoria , Núcleo Solitario/efectos de los fármacos , Núcleo Solitario/fisiopatología , Factores de Tiempo

RESUMEN

RATIONALE: Central angiotensin (Ang) II inhibits baroreflex and plays an important role in the pathogenesis of hypertension. However, the underlying molecular mechanisms are still not fully understood. OBJECTIVE: Our objective in the present study was to characterize the signal transduction mechanism of phosphatidylinositol 3-kinase (PI3K) involvement in Ang II-induced stimulation of central neuronal activity in cultured neurons and Ang II-induced inhibition of baroreflex in spontaneously hypertensive rats (SHR) versus WKY rats. METHODS AND RESULTS: Application of Ang II to neurons produced a 42% greater increase in neuronal firing in cells from the SHR than the WKY rat. Although the Ang II-mediated increase in firing rate was abolished entirely by the protein kinase (PK)C inhibitor GF109230 in the WKY, blockade of both PKC and PI3K activity was necessary in the SHR. This was associated with an increased ability of Ang II to stimulate NADPH oxidase-reactive oxygen species (ROS)-mediated signaling involving phosphorylation of the p47phox subunit of the NADPH oxidase and was dependent on the activation of PI3K in the SHR. Inhibition of PI3K resulted in the reduction of levels of p47phox phosphorylation, NADPH oxidase activity, ROS levels, and ultimately neuronal activity in cells from the SHR but not the WKY rat. In addition, in working heart-brainstem preparations, inhibition of PKC activity in the nucleus of the solitary tract in situ abolished the Ang II-mediated depression of cardiac and sympathetic baroreceptor reflex gain in the WKY. In contrast, PKC inhibition in the nucleus of the solitary tract of SHR only partially reduced the effect of Ang II on the baroreceptor reflex gain. CONCLUSIONS: These observations demonstrate that PI3K in the cardiovascular brainstem regions of the SHR may be selectively involved in Ang II-mediated signaling that includes a reduction in baroreceptor reflex function, presumably via a NADPH-ROS mediated pathway.

Asunto(s)

Angiotensina II/metabolismo , Barorreflejo , Corazón/inervación , Hipertensión/enzimología , Fosfatidilinositol 3-Quinasas/metabolismo , Transducción de Señal , Núcleo Solitario/enzimología , Sistema Nervioso Simpático/fisiopatología , Potenciales de Acción , Angiotensina II/administración & dosificación , Animales , Barorreflejo/efectos de los fármacos , Células Cultivadas , Modelos Animales de Enfermedad , Hipertensión/fisiopatología , Microinyecciones , NADPH Oxidasas/metabolismo , Fosfatidilinositol 3-Quinasas/genética , Inhibidores de las Quinasa Fosfoinosítidos-3 , Fosforilación , Proteína Quinasa C/antagonistas & inhibidores , Proteína Quinasa C/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Especies Reactivas de Oxígeno/metabolismo , Receptor de Angiotensina Tipo 1/metabolismo , Reproducibilidad de los Resultados , Transducción de Señal/efectos de los fármacos , Núcleo Solitario/efectos de los fármacos , Núcleo Solitario/fisiopatología , Sistema Nervioso Simpático/efectos de los fármacos , Transducción Genética

RESUMEN

We studied the role of neurokinin-1 receptors (NK1-R) on the excitability of expiratory (E) neurons (tonic discharge, E(TONIC); augmenting, E(AUG); decrementing, E(DEC)) throughout the ventral respiratory group, including Bötzinger Complex (BötC) using extracellular single-unit recording combined with pressurized picoejection in decerebrate, arterially perfused juvenile rats. Responses evoked by picoejection of the NK1-R agonist, [Sar9-Met(O2)11]-substance P (SSP) were determined before and after the selective NK1-R antagonist, CP99,994. SSP excited 20 of 35 expiratory neurons by increasing the number of action potentials per burst (+33.7 +/- 6.5% of control), burst duration (+20.6 +/- 7.9% of control), and peak firing frequency (+16.2 +/- 4.8% of control; means +/- SE). Pretreatment with CP99,994 completely blocked SSP-evoked excitation in a subset of neurons tested, supporting the notion that SSP excitation was mediated through NK1-R activation. Because we had previously shown that E(AUG) neurons were crucial to locomotor-respiratory coupling (LRC), we reasoned that blockade of NK1-R would alter LRC by preventing somatic-evoked excitation of E(AUG) neurons. Blockade of NK1-Rs by CP99,994 in the BötC severely disrupted LRC and prevented somatic-evoked excitation of E(AUG) neurons. These findings demonstrate that LRC is dependent on endogenous SP release acting via NK1-Rs on E(AUG) neurons of the BötC. Taken together with our earlier finding that inspiratory off-switching by the Hering-Breuer Reflex requires endogenous activation of NK1-Rs through activation of NK1-Rs on E(DEC) neurons, we suggest that endogenous release of substance P in the BötC provides a reflex pathway-dependent mechanism to selectively modulate respiratory rhythm.

Asunto(s)

Espiración/fisiología , Neuronas/fisiología , Receptores de Neuroquinina-1/fisiología , Centro Respiratorio/citología , Potenciales de Acción/efectos de los fármacos , Vías Aferentes/fisiología , Vías Aferentes/efectos de la radiación , Análisis de Varianza , Animales , Relación Dosis-Respuesta a Droga , Estimulación Eléctrica/métodos , Espiración/efectos de los fármacos , Homocisteína/análogos & derivados , Homocisteína/farmacología , Masculino , Modelos Biológicos , Antagonistas del Receptor de Neuroquinina-1 , Neuronas/efectos de los fármacos , Piperidinas/farmacología , Ratas , Ratas Wistar , Sustancia P/análogos & derivados , Sustancia P/farmacología

RESUMEN

The role of substance P (SP) and its receptor, the neurokinin-1 (NK1R), in the generation of respiratory rhythm has received considerable attention, particularly at the Pre-Bötzinger Complex of the ventral respiratory group (VRG). However, the functional role of SP and NK1R in other VRG regions has not been explored in detail. We review the current literature and describe recent data demonstrating that selective activation of NK1R in the Bötzinger Complex (BötC) of the VRG evoked bradypnea by lengthening expiratory period. In addition, endogenous activation of NK1R in the BötC participates in the expiratory lengthening effect of the Hering-Breuer reflex. These data suggest that NK1R expressing neurons in different subregions of the VRG have functionally diverse roles and provide new insight on the modulatory role of SP on respiratory reflexes.

Asunto(s)

Espiración/fisiología , Bulbo Raquídeo/fisiología , Receptores de Neuroquinina-1/fisiología , Fenómenos Fisiológicos Respiratorios , Sustancia P/fisiología , Humanos , Neurotransmisores/fisiología

Asunto(s)

Relojes Biológicos/fisiología , Bulbo Raquídeo/fisiología , Neuronas/fisiología , Insuficiencia Respiratoria/fisiopatología , Mecánica Respiratoria/fisiología , Animales , Mamíferos/fisiología , Periodicidad , Centro Respiratorio/fisiología , Fenómenos Fisiológicos Respiratorios

RESUMEN

In the present study, we examined the role of the neurokinin-1 receptor (NK1R) in the modulation of respiratory rhythm in a functionally identified bradypnoeic region of the ventral respiratory group (VRG) in the in situ arterially perfused juvenile rat preparation. In electrophysiologically and functionally identified bradypnoeic sites corresponding to the Bötzinger complex (BötC), microinjection of the selective NK1R agonist [Sar(9)-Met(O(2))(11)]-substance P (SSP) produced a significant reduction in phrenic frequency mediated exclusively by an increase in expiratory duration (T(E)). The reduction was characterized by a significant increase in postinspiratory (post-I) duration with no effect on either late-expiratory duration (E2) or inspiratory duration (T(I)). In contrast, in a functionally identified tachypnoeic region, corresponding to the preBötzinger complex (Pre-BötC), control microinjection of SSP elicited tachypnoea. Pretreatment with the NK1R antagonist CP99994 in the BötC significantly attenuated the bradypnoeic response to SSP injection and blunted the increase in T(E) duration. This effect of SSP mimicked the extension of T(E) produced by activation of the Hering-Breuer reflex. Therefore, we hypothesized that activation of NK1Rs in the BötC is requisite for the expiratory-lengthening effect of the Hering-Breuer reflex. Unilateral electrical stimulation of the cervical vagus nerve produced bradypnoea by exclusively extending T(E). Ipsilateral blockade of NK1Rs by CP99994 following blockade of the contralateral BötC by the GABA(A) receptor agonist muscimol significantly reduced the extension of T(E) produced by vagal stimulation. Results from the present study demonstrate that selective activation of NK1Rs in a functionally identified bradypnoeic region of the VRG can depress respiratory frequency by selectively lengthening post-I duration and provide evidence that endogenous activation of NK1Rs in the BötC appears to be involved in the expiratory-lengthening effect of the Hering-Breuer reflex. In conclusion, our findings demonstrate that selective activation of NK1Rs in discrete regions of the VRG can exert functionally diverse effects on breathing.

Asunto(s)

Diafragma/inervación , Receptores de Neuroquinina-1/efectos de los fármacos , Centro Respiratorio/efectos de los fármacos , Mecánica Respiratoria , Sustancia P/análogos & derivados , Animales , Estimulación Eléctrica , Masculino , Microinyecciones , Nervio Frénico/efectos de los fármacos , Piperidinas/farmacología , Ratas , Ratas Wistar , Receptores de Neuroquinina-1/metabolismo , Reflejo , Centro Respiratorio/metabolismo , Pruebas de Función Respiratoria , Sustancia P/farmacología , Nervio Vago/fisiología

RESUMEN

In severe hypoxia, respiratory rhythm is shifted from an eupneic, ramp-like motor pattern to gasping characterized by a decrementing pattern of phrenic motor activity. However, it is not known whether hypoxia reconfigures the spatiotemporal organization of the central respiratory rhythm generator. Using the in situ arterially perfused juvenile rat preparation, we investigated whether the shift from eupnea to gasping was associated with a reconfiguration of the spatiotemporal pattern of respiratory neuronal activity in the ventral medullary respiratory network. Optical images of medullary respiratory network activity were obtained from male rats (4-6 weeks of age). Part of the medullary network was stained with a voltage-sensitive dye (di-2 ANEPEQ) centred both within, and adjacent to, the pre-Bötzinger complex (Pre-BötC). During eupnea, optical signals initially increased prior to the onset of phrenic activity and progressively intensified during the inspiratory phase peaking at the end of inspiration. During early expiration, fluorescence was also detected and slowly declined throughout this phase. In contrast, hypoxia shifted the respiratory motor pattern from eupnea to gasping and optical signals were restricted to inspiration only. Areas active during gasping showed fluorescence that was more intensive and covered a larger region of the rostral ventrolateral medulla compared to eupnea. Regions exhibiting peak inspiratory fluorescence did not coincide spatially during eupnea and gasping. Moreover, there was a recruitment of additional medullary regions during gasping that were not active during eupnea. These results provide novel evidence that the shift in respiratory motor pattern from eupnea to gasping appears to be associated with a reconfiguration of the central respiratory rhythm generator characterized by changes in its spatiotemporal organization.

Asunto(s)

Hipoxia/fisiopatología , Bulbo Raquídeo/fisiopatología , Red Nerviosa/fisiopatología , Respiración , Análisis de Varianza , Animales , Conducta Animal , Diagnóstico por Imagen/métodos , Colorantes Fluorescentes/farmacocinética , Hipoxia/metabolismo , Hipoxia/patología , Procesamiento de Imagen Asistido por Computador/métodos , Inmunohistoquímica/métodos , Masculino , Bulbo Raquídeo/metabolismo , Bulbo Raquídeo/patología , Red Nerviosa/metabolismo , Red Nerviosa/patología , Ratas , Ratas Wistar , Receptores de Neuroquinina-1/metabolismo , Mecánica Respiratoria/fisiología

Asunto(s)

Ejercicio Físico/fisiología , Hipotálamo/fisiopatología , Actividad Motora/fisiología , Respiración , Mecánica Respiratoria/fisiología , Vías Aferentes/fisiología , Animales , Retroalimentación Fisiológica/fisiología , Humanos , Músculo Esquelético/inervación , Músculo Esquelético/fisiopatología , Condicionamiento Físico Animal/fisiología , Intercambio Gaseoso Pulmonar/fisiología , Ventilación Pulmonar/fisiología , Sistema Respiratorio/inervación , Sistema Respiratorio/fisiopatología , Transducción de Señal/fisiología

Asunto(s)

Ejercicio Físico/fisiología , Hipotálamo/fisiopatología , Actividad Motora/fisiología , Respiración , Mecánica Respiratoria/fisiología , Animales , Dióxido de Carbono/fisiología , Homeostasis , Humanos , Condicionamiento Físico Animal/fisiología , Potasio/fisiología , Intercambio Gaseoso Pulmonar/fisiología , Ventilación Pulmonar/fisiología , Ovinos , Médula Espinal/fisiopatología , Subtálamo/fisiopatología