RESUMEN
We addressed the role of muscarinic receptor subtypes in neurally mediated bronchoconstriction in vivo and airway smooth muscle contraction in vitro in the newborn dog. The in vivo dose-response effects of "selective" muscarinic antagonists on changes in lung resistance (RL) and heart rate (HR) in response to electrical stimulation of the vagus nerves were obtained in four groups of newborns. Each group was exposed to a different muscarinic antagonist: M1-selective pirenzepine (pir), M2-selective AF-DX 116 (11-[2-[(diethylamino)methyl]-1-piperidinyl]acetyl-5,11-dihydro-6H-pyrid o- [2,3-b]-[1,4]-benzodiazepine-6-one), M3-selective p-F-HHSiD (p-fluoro-hexahydro-sila-difenidol), and nonselective atropine (atr). In vitro concentration-response effects of pir and AF-DX 116 were obtained for neurally induced contractions of tracheal smooth muscle, elicited by electrical field stimulation. In a separate series of experiments we measured the bronchoconstrictor response to the muscarinic agonist acetylcholine delivered by right heart injection. Muscarinic antagonists reduced RL and HR responses to vagal stimulation in a dose-dependant fashion; however, ED50 values and selectivity for airway and cardiac responses (HR/RL ED50 ratio) were significantly different between antagonists. The rank order of potencies for inhibition of the increase in RL was atr > pir, M1 > p-F-HHSiD, M3 > AF-DX 116, M2, while that for HR was atr > AF-DX 116 > pir > p-F-HHSiD. AF-DX 116 preferentially inhibited the HR response, as reflected by the lowest HR/RL ED50 ratio (p < 0.001). The remaining antagonists preferentially inhibited RL, with the highest HR/RL ED50 ratio seen for p-F-HHSiD. These data suggest that muscarinic receptor subtypes are differentiated at birth and mediate cardiac and airway responses to vagal stimulation. We did not find autoinhibitory actions of airway M2 receptors on either the in vivo bronchoconstrictor response or the in vitro contractile response to electrical field stimulation. This suggests that neonatal airway M2 receptors, but not myocardial M2 receptors, are reduced in number or weakly coupled to muscarinic signal transduction mechanisms. Direct activation of airway smooth muscle by acetylcholine caused dose-dependent increases in RL that reached a plateau at approximately 200% at 100 micrograms, similar to values reported for vagal stimulation.
Asunto(s)
Parasimpatolíticos/farmacología , Pirenzepina/análogos & derivados , Pirenzepina/farmacología , Nervio Vago/efectos de los fármacos , Resistencia de las Vías Respiratorias/efectos de los fármacos , Análisis de Varianza , Animales , Animales Recién Nacidos , Broncoconstricción/efectos de los fármacos , Perros , Relación Dosis-Respuesta a Droga , Estimulación Eléctrica , Frecuencia Cardíaca/efectos de los fármacos , Frecuencia Cardíaca/fisiología , Humanos , Técnicas In Vitro , Contracción Muscular/efectos de los fármacos , Músculo Liso/efectos de los fármacos , Mecánica Respiratoria/fisiología , Nervio Vago/fisiologíaRESUMEN
The rationale for the use of muscarinic antagonists in bronchopulmonary dysplasia (BPD) is based on the physiology and pharmacology of airway smooth muscle, the pathology of BPD, and the response of infants with BPD to bronchodilators, in vivo and in vitro studies of airway smooth muscle of newborn animals and humans indicate that vagal efferent airway innervation and/or muscarinic receptors are functional at birth, as well as early in gestation. Current concepts regarding muscarinic receptor subtypes suggest that M3 receptors mediate airway smooth muscle contraction, M2 receptors are autoinhibitory and limit vagally-mediated bronchoconstriction, and M1 receptors may play a facilitatory role in ganglionic transmission. Muscarinic receptor subtypes appear to be functionally expressed at birth but may undergo developmental regulation. Infants with BPD have an elevated pulmonary resistance that is accompanied by hypertrophy of airway smooth muscle, b2-agonists cause bronchodilation in BPD as does atropine in infants recovering from severe BPD. The synthetic congener of atropine, ipratropium bromide (IPB) causes bronchodilation in ventilator-dependent infants with BPD in a dose-dependent fashion. Nebulized IPB causes a decrease in respiratory resistance that reaches a maximum of 20% at 175 mg. The bronchodilation seen with muscarinic antagonists suggests that part of the elevated resistance associated with BPD is due to increased muscarinic tone, presumably vagal in origin. When IPB is combined with salbutamol (0.04 mg) the response is increased in magnitude and duration; reaching a slightly larger decreases in resistance (26%) that is now accompanied by an increase in compliance (20%).(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Displasia Broncopulmonar/metabolismo , Parasimpaticomiméticos/antagonistas & inhibidores , Parasimpaticomiméticos/metabolismo , Animales , Broncodilatadores/uso terapéutico , Displasia Broncopulmonar/tratamiento farmacológico , Esquema de Medicación , Humanos , Recién Nacido , Ipratropio/administración & dosificación , Ipratropio/uso terapéutico , Músculo Liso/metabolismo , Parasimpaticomiméticos/uso terapéutico , Sistema Respiratorio/metabolismoRESUMEN
The purpose of the present study was to examine the pattern of changes in respiratory system mechanics induced by dexamethasone (Dex) in infants with bronchopulmonary dysplasia (BPD) and to determine whether dosages that produce these changes induce adrenal suppression. We examined mechanics in seven ventilator-dependent premature infants (age, 33 +/- 4.8 days) with BPD, before and daily during Dex therapy. Dex (0.5 mg/kg/day) was given intravenously for 7 days unless complications necessitated early termination. Respiratory system resistance (Rrs) and compliance (Crs) were measured by the passive expiratory flow-volume technique during the course of dexamethasone therapy or until extubation. Adrenocorticotrophic hormone (ACTH) stimulation tests were done at baseline and following Dex therapy to evaluate adrenal function. Dex therapy caused a 77 +/- 18% increase in Crs (from 0.97 +/- 0.09 SEM mL/cmH2O to 1.6 +/- 0.16 mL/cmH2O; P less than 0.025) and a 33 +/- 5% decrease in Rrs (from 0.20 +/- 0.02 cmH2O/mL/s to 0.14 +/- 0.01 cmH2O/mL/s; P less than 0.01). Concurrently, ventilator rate, mean airway pressure, and FIO2 all decreased significantly (P less than 0.025). Extubation occurred later in infants with the lowest Crs and highest Rrs at baseline. At extubation, all Crs values were greater than 1.33 mL/cmH2O and Rrs values were less than 0.15 cmH2O/mL/s. Systolic blood pressure increased from 61 +/- 6.3 mmHg to 84 +/- 17 mmHg, 72-96 h after the start of Dex (P less than 0.025). There were no episodes of culture-positive sepsis. Neither basal nor ACTH-stimulated levels of cortisol were suppressed as a result of Dex therapy (P greater than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Glándulas Suprarrenales/efectos de los fármacos , Resistencia de las Vías Respiratorias/efectos de los fármacos , Displasia Broncopulmonar/tratamiento farmacológico , Dexametasona/uso terapéutico , Recien Nacido Prematuro , Rendimiento Pulmonar/efectos de los fármacos , Dexametasona/farmacología , Humanos , Hidrocortisona/sangre , Lactante , Recién Nacido de Bajo Peso , Recién Nacido , Respiración Artificial , Resultado del TratamientoRESUMEN
Although the muscarinic antagonist Ipratropium bromide is used clinically as a bronchodilator in infants ventilated because of bronchopulmonary dysplasia (BPD), no studies have compared the response or efficacy of different dosages or its effectiveness in combination with beta-adrenergic agonists. We measured the response of respiratory system mechanics in 10 ventilated infants (25 +/- 2 days of age) to 75, 125, and 175 micrograms ipratropium bromide (IB), 125 micrograms IB plus 0.04 mg salbutamol (SAL), 175 micrograms IB plus 0.04 mg SAL, and saline vehicle, delivered via nebulizer into the ventilator circuit. Respiratory system resistance (Rrs) and compliance (Crs) were measured by the passive flow-volume technique. Rrs and Crs were measured before and at 1 to 2 h and at 4 h after delivery of the five drug dosages or saline. All six studies were completed within a 72-h period. Saline had no significant effect on mechanics. Significant responses to ipratropium alone were seen only after 175 micrograms where Rrs decreased 20 +/- 3% (SEM) (p less than 0.05) at 1 to 2 h and 16 +/- 5% (p less than 0.05) at 4 h. After 125 micrograms IB + SAL and 175 micrograms IB + SAL, Rrs was significantly decreased both at 1 to 2 h and at 4 h, and Crs was significantly increased 20 +/- 6% and 20 +/- 4%, respectively, at 1 to 2 h. The greatest decrease in Rrs (26 +/- 6%) was seen 1 to 2 h after 175 micrograms IB + salbutamol.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Broncodilatadores/uso terapéutico , Displasia Broncopulmonar/tratamiento farmacológico , Ipratropio/uso terapéutico , Resistencia de las Vías Respiratorias , Bronquios/efectos de los fármacos , Bronquios/fisiopatología , Displasia Broncopulmonar/fisiopatología , Adaptabilidad , Humanos , Lactante , Recién NacidoRESUMEN
Although several studies have examined the pulmonary response to muscarinic agonists in the newborn, none has addressed the functional capabilities or "maturity" of vagal innervation to airway smooth muscle in the newborn. The purpose of the present study was to provide a quantitative analysis of the ability of vagal excitatory innervation (encompassing the pre- and postganglionic fibers, airway ganglia, and airway smooth muscle) to alter pulmonary mechanics in the newborn. We measured the changes in pulmonary mechanics elicited by electrical stimulation of the vagus nerves in 20 newborn cats and 18 puppies anesthetized with chloralose urethan. Animals were tracheotomized and ventilated (chest open), and the cervical vagus nerves were sectioned and placed on stimulating electrodes. Animals were placed in a flow plethysmograph, and mean inspiratory resistance (RL,I) and dynamic compliance were measured on a breath-by-breath basis. In each animal RL,I increased, dynamic compliance decreased, and heart rate slowed during 10 s of vagal stimulation at frequencies ranging from 2 to 20 pulses/s. At each stimulus frequency there was a spectrum of responses with respect to the percent change in RL,I. At 15 pulses/s there was a fourfold difference in the RL,I response of the most- and least-sensitive animals. In both species, higher stimulus frequencies caused greater increases in RL,I; at 2 pulses/s RL,I increased on average approximately 40%, compared with approximately 250% at 20 pulses/s. The increase in RL,I was similar in the kitten and puppy at stimulus frequencies of 6 and 15 pulses/s but was less in the kitten at 2 pulses/s (P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)