Curva dosis-respuesta a metacolina en niños normales hijos de asmáticos / Dose-response curves to methacholine in son of asthmatics normal children

Entre los parientes en primer grado de los enfermos conasma bronquial se ha demostrado una mayor prevalencia de esta enfermedad, la que crecería gradualmente hasta alcanzar cifras del orden de 43 por ciento a los 65 años. Con el propósito de establecer si los hijos de padres asmáticos(HPA) presentan alteraciones en la forma y posición de su curva dosis respuesta a metacolina, estudiamos 16 HPA y 16 controles sin antecedentes familiares de asma, escogidos por presentar edad (8,07 + - 0,45 años de edad, X + - ES)y hábito tabáquico familiar (3,8+ - 1,3 vs 2,9 + - 1,22 cigarrillos diarios)similares al grupo HPA. Ninguno de los niños presentaba enfermedades cardiorrespiratorias crónicas ni agudas durante los dos meses previos al estudio. Se efectuó una prueba de provocación administrando metacolina desde 0,03 hasta máxima (M), la posiciónde la curva a través de la dosis acumulativa que causa un 50 por ciento de M (ED50)y la PC20. No se observó diferencias significativas en M(39,8 promedio 3,89 vs 33,6 promedio 3,84 por ciento VEF1), enlogED50 (-1,29 + - 0,18 vs -1,22 + - 0,17mg)ni el logPC20(0,70 + - 0,22 vs 0,71 + - 0,22 mg/ml) al compararlas con su curva dosis-respuesta a metacolina respecto a niños sin antecedentes familiares de asma, lo que sugiere que la capacidad cantráctil de su músculo liso, las cargas que éste debe vencer y los factores que amplifican la respuesta de sus vías aéreas sonnormales en el estudio preasmático y que las alteraciones observadas en asmáticos serían adquiridas, probablemente por influencias ambientales

Bradycardic responses to vagal stimulation and methacholine injection in sinoaortic denervated rats.

The bradycardia that occurs in response to vagal stimulation or to methacholine after 6 h of sinoaortic denervation (SAD) was studied in SAD rats before and after adrenergic blockade to determine whether the peripheral vagal action was impaired by sympathetic hyperactivity. A marked attenuation in the responses to methacholine and no difference in the responses to vagal stimulation were observed in SAD rats compared to sham-operated controls. The adrenergic blockade attenuated the responses to both vagal stimulation and methacholine in control rats but not in SAD rats. These findings revealed an impairment of peripheral vagal function after 6 h of SAD, probably due to a decreased sensitivity of the muscarinic receptors.

Increase of muscarinic cholinergic receptors in the rat submandibular glands after parasympathectomy and repeated administration of haloperidol.

1. The mechanisms of the supersensitivity to cholinergic drugs after chronic haloperidol was studied in normal and parasympathectomized submandibular glands of the rats. 2. Both parasympathectomy and haloperidol treatment for 7 days (2 mg/kg/day, i.p.) increased the sialogogue response of the glands to methacholine, a cholinomimetic drug. 3. Both denervation and haloperidol administration induce up-regulation of the muscarinic receptors as expressed per gram of the tissue. 4. Haloperidol causes no further increase in sensitivity than denervation alone. 5. These data demonstrate that secretory supersensitivity to cholinergic drugs in the rat submandibular glands, after chronic haloperidol and parasympathectomy is related to an increase in muscarinic cholinergic receptors.

Effects of cadmium on the function and structure of the rat salivary glands.

The effects of sub-chronic cadmium (Cd) administration on the structure and subsequent secretory responses of the submaxillary and parotid glands to sialagogues were investigated. Female Wistar rats were injected subcutaneously with cadmium chloride (3.0 mg/kg body weight), 4 times a week for 2, 3 or 4 weeks. Functional and histopathological studies were done 3 days after the last injection. Dose-response curves for norepinephrine and methacholine were obtained. After 2 weeks of Cd administration significant changes in the secretory response to these sialogogues were observed. The dose-response curves after pretreatment with Cd for 3 weeks were also shifted to the right, but the response showed recovery when compared with that of 2-week treated animals. Parotid amylase concentration was also diminished by Cd. Treated rats had reduced acinar diameters, and an increase in acinar cell nuclei per field in both the submaxillary and parotid glands. Thus sub-chronic administration of ionized Cd produces morphological and functional changes in rat salivary glands. Moreover, the extent of tubular and acinar damage matches the degree of gland dysfunction as judged by the diminution of secretory responses to sialagogues.

Some pharmacological properties of the circular smooth muscle layer of the rat vas deferens.

Vas deferens preparations were perfused in-vitro through the lumen and externally with a modified Tyrode solution alone or containing drugs. Contractions of the circular (internal) smooth muscle layer were recorded as changes in the pressure of internal perfusion. Contractions of the longitudinal (external) layer were simultaneously recorded through a tension transducer. When the organ was perfused through the lumen, the circular layer contracted after addition of methacholine (pD2 = 4.13), and noradrenaline (pD2 = 5.00), and relaxed after addition of isoprenaline (pD2 = 5.22). These effects were also observed when the drugs were perfused externally, although with lower values of pD2 for noradrenaline and methacholine. The circular fibres were less sensitive when compared with the longitudinal fibres perfused externally with the above agonists. Methacholine-induced contractions of the circular layer were competitively antagonized by atropine (pA2 = 8.53), indicating the presence of muscarinic receptors. The effects induced by noradrenaline and isoprenaline were antagonized by indoramin (pA2 = 7.78), and timolol (pA2 = 8.68), respectively, indicating the presence of alpha- and beta-adrenoceptors. The effect of noradrenaline was potentiated by cocaine and denervation, indicating the presence of neuronal uptake, and by corticosterone, indicating the presence of extraneuronal uptake in the circular layer.

Lack of cholinergic modulation of tyrosine hydroxylase activation by potassium.

Cholinergic modulation on the regulation of tyrosine hydroxylase was studied in guinea pig atria depolarized with high potassium concentration. In these conditions there was an increment in tyrosine hydroxylase activity as well as in the release of radioactivity from atria preincubated with 3H-noradrenaline. Both effects were concentration-dependent. Incubation in the presence of 10 microM methacholine, 31 microM 1,1 dimethyl-4-phenylpiperazinium iodide (DMPP), 0.15 microM atropine or 83 microM hexamethonium did not affect tyrosine hydroxylase activation by 100 mM K+. The percentage of activation was reduced however, when 7 microM physostigmine (acetylcholinesterase inhibitor) was present during depolarization. This effect is unlikely to be related to the increase of acetylcholine concentration in the interface, but more probably to a direct effect on the enzyme. In conclusion, tyrosine hydroxylase activation induced by 100 mM potassium appears to be unrelated to the stimulation of nicotinic and muscarinic presynaptic receptors.

Influence of castration upon trophism and reactivity of rat seminal vesicles.

1. Castration-induced time-dependent changes in trophism and reactivity of rat seminal vesicles were studied by measuring vesicle weight, spontaneous contractility, apparent sensitivity (pD2) to acetylcholine and acetyl-beta-methylcholine and intrinsic reactivity (alpha) to acetyl-beta-methylcholine 5, 10, 15 and 30 days after surgery. 2. The wet and dry weights of the seminal vesicles from castrated rats were less than those from the controls 5 days after castration, and decreased with time after gonadectomy. Spontaneous contractility was observed 15 days after surgery. The pD2 for acetyl-beta-methylcholine was significantly higher than normal control values (5.81 +/- 0.09 vs. 5.34 +/- 0.12) 10 days after orchidectomy, whereas the change in sensitivity to acetylcholine (from 5.04 +/- 0.15 to 5.95 +/- 0.95) was detected only 30 days after castration. In contrast, a change in alpha from 0.75 +/- 0.04 (normal control) to 0.90 +/- 0.02 was detected on the 5th day after castration. 3. These data show that atrophy and spontaneous contractility of rat seminal vesicles, as well as increased sensitivity and reactivity to parasympathetic drugs are detectable at different times after castration.

Increased incidence of bronchial reactivity in children with a history of bronchiolitis.

To assess bronchial reactivity in children who have had bronchiolitis, we studied 48 children by challenging them with methacholine nine or ten years after admission to hospital with bronchiolitis. Pulmonary function was also evaluated. Fifty-seven percent of children studied had bronchial hyperreactivity. Thirty-three percent of first-degree relatives of those with a positive MCH challenge had a positive response. There was a significant correlation between the occurrence of a positive MCH challenge and a history of recurrent bronchiolitis. Pulmonary function tests demonstrated lower flow rates in the positive responders. Fourteen children had a history of asthma or wheezing, but this did not appear to be severe or frequent, and few required long-term therapy. There appears to be a strong genetic component in the prevalence of bronchial reactivity in these children. Bronchial hyperreactivity may be a risk factor in the development of COPD.

Lung function in children following repair of tracheoesophageal fistula.

Lung function and bronchial reactivity by methacholine challenge were studied in 24 patients seven to 18 years after repair of type I tracheoesophageal fistula. Only one patient had no abnormalities of the variables tested. Thirteen patients had obstructive airways disease, five had a restrictive defect, and 15 had a positive methacholine challenge. It is postulated that continuing subclinical aspiration of esophageal contents causes lung damage and renders the airways hyperreactive.

Bronchial hyperreactivity in cystic fibrosis and asthma.

We studied 113 patients with CF and compared their responsiveness to inhaled methacholine to that of 50 asthmatic children and 26 normal children. Positive responses to MCh occurred in 51% of the patients with CF and 98% of those with asthma. There was a significant correlation between a positive response to MCh in CF and poor pulmonary function. There was no relationship between allergic rhinitis or positive allergen skin tests and a positive MCh response. Dose-response curves and time course to MCh challenge differed in CF and asthma. Bronchial hyperreactivity is thus common in CF but is different from that in asthma.