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PubMed1985

Age-related changes in the reactivity of the rat jejunum to cholinoceptor agonists.

The contractile effects of barium, potassium, acetylcholine and acetyl-beta-methylcholine were studied in jejunum of 4, 12 and 20 month-old rats. The effects of age on the sensitivity and responsiveness of the jejunum to the agonists were examined using cumulative dose administration and measuring the pD2. The maximum contraction produced by the agonists and the sensitivity to barium and potassium were not modified by aging. In the middle-aged animals, the jejunum sensitivity to acetylcholine decreased while the sensitivity to acetyl-beta-methylcholine was not statistically different from that of 4 month-old rats. Since at this age (12 months) the acetylcholinesterase activity increased, the reduction in the sensitivity to acetylcholine could have been due to the increase in the activity of the metabolizing enzyme. Otherwise, in the jejunum from the older animals the sensitivity for both cholinoceptor agonists, acetylcholine and acetyl-beta-methylcholine, increased 5-fold when compared with the middle-aged animals. However, compared with the jejunum of 4 month-old rats the sensitivity to acetylcholine, to 20 month-old animals, was not altered while the sensitivity to acetyl-beta-methylcholine was increased. At this age (20 months), the jejunum acetylcholinesterase activity was increased when compared with that of 4 month-old rats and was not modified when compared with that of 12 month-old rats. The change in supersensitivity to cholinoceptor agonists could not have been due to an alteration in muscarinic receptor affinity, since the pA2 for atropine was not modified with increasing age. These results suggest that after an increase in acetylcholinesterase activity around month 12, the jejunum develops an adaptative supersensitivity to cholinoceptor agonists.

Acetylcholine↗
PubMed1986

Agonist-induced contractile responses of human bronchial muscle in vitro: effects of Ca2+ removal, La3+ and PY108068.

The effects of reducing the extracellular Ca2+ concentration ([Ca2+]0), the effects of La3+ and the dihydropyridine Ca2+ entry blocker PY108068 on contractile responses in human isolated bronchial strips have been compared. Reducing [Ca2+]0 or the presence of La3+ (1 mM) caused a reduction in basal tone, whereas PY108068 (1 microM) had no effect on unstimulated preparations. Response to KCl and A23187 were, in general, more markedly depressed by reducing the entry of extracellular Ca2+, with La3+ or PY108068 than were those to histamine, methacholine and LTD4. The effects of reducing [Ca2+]0, La3+ and PY108068 on responses to the receptor-mediated agents suggest that intracellular Ca2+ may be mobilized upon receptor activation, whereas responses to KCl and A23187 appear to be dependent upon the influx of extracellular Ca2+. More than one source of activator Ca2+ can therefore be involved in the development of contractions in human airway smooth muscle. These findings are in accord with those observed for in vitro airways preparations from experimental animals.

Bronchi↗
PubMed1986

Epithelium modulates the reactivity of ovalbumin-sensitized guinea-pig airway smooth muscle.

Mechanical removal of the airway epithelium alters the in vitro reactivity of airway smooth muscle. The modulation of reactivity may involve the release of inhibitory and excitatory factors from epithelial cells. Guinea pigs sensitized with ovalbumin have been used as an animal model of airway hyperreactivity. We evaluated the influence of the epithelium on the reactivity of in vitro tracheal smooth muscle from control and ovalbumin-sensitized guinea pigs, and the extent to which the presence of the epithelium affects the contractile response to in vitro challenge with ovalbumin. In both control and ovalbumin-sensitized tissues, epithelium removal increased the sensitivity of the preparations to histamine, methacholine and isoproterenol to a similar extent, i.e., 2- to 2.5-fold. Epithelium removal resulted in an 8.1-fold increase in sensitivity to ovalbumin in sensitized tissues. The epithelium appears not only to modulate the reactivity of the tissues to bronchoactive agents, but it also influences the magnitude of the contractile response following antigen challenge.

Animals↗
PubMed1986

Methacholine inhalation challenge after rapid saline infusion in healthy subjects.

Five healthy subjects were challenged with methacholine on 2 different days, 1 week apart, the second day after acute intravenous 30 ml/kg 0.9% saline infusion. After infusion, we observed a significant reduction in vital capacity (VC), maximal expiratory volume in 1 s (FEV1), provocation dose producing a 35% fall in SGaw (PD35SGaw) and in 25% of maximal expiratory flow (MEF25), and an increase in the slopes of log dose-response curves. Our results suggest an increased bronchial reactivity in acute minimal interstitial lung edema.

Adult↗
PubMed1975

Myotonic pupils in Charcot-Marie-Tooth disease. Successful relief of symptoms with 0.025% pilocarpine.

Twenty-seven members of a family with dominantly inherited Charcot-Marie-Tooth disease (CMTD) were examined. Fifteen members had CMTD and 13 of these had varying amounts of myotonic pupillary abnormalities similar in some ways to Adie tonic pupil syndrome. Those with graver neurologic disease showed greater pupillary abnormalities. Ten of the 15 patients had pupillary constriction with methacholine chloride (Mecholyl) and some of these had extensive iris atrophy. Several affected patients received symptomatic relief from 0.025% pilocarpine. Seven other patients with CMTD who were not related to our initial family were checked for myotonic pupils; two had findings similar to our initial family. Pupillary abnormalities in certain patients with CMTD appear secondary to a parasympathetic denervation of the iris sphincter and ciliary muscle, as shown by a positive methacholine test, and probably represent part of the autonomic nervous system dysfunction associated with the polyneuropathy in CMTD.

Adult↗
PubMed1987

Methacholine responsiveness increases after ultrasonically nebulized water but not after ultrasonically nebulized hypertonic saline in patients with asthma.

Airway obstruction can be induced in patients with asthma by the inhalation of ultrasonically nebulized aerosols of nonisotonic solutions. It is the change in osmolarity of the periciliary fluid that is believed to be the stimulus for bronchoconstriction. However, it is not known whether hyperosmolar and hypo-osmolar aerosols induce asthma via the same mechanism. We have previously reported that patients with asthma have a reduction in the dose of provoking agent that induces a 20% fall in FEV1 (PD20) for methacholine after challenge with nebulized water. To determine whether hyperosmolar aerosols also increase sensitivity to methacholine, we studied 13 subjects with asthma on 3 days. On day 1, the PD20 to methacholine was determined. On day 2, a challenge with nebulized 4.5% saline was followed by a challenge with methacholine 40 to 60 minutes later. On day 3, a challenge with nebulized water was followed by a methacholine challenge. Sensitivity to methacholine was significantly increased after water (p less than 0.02) but not after 4.5% saline. Furthermore, there was no relationship between the PD20 to water and to 4.5% saline. When the Spearman's correlation coefficient was used to compare sensitivity to the challenges, there was a significant relationship between the PD20 to 4.5% saline and methacholine (p less than 0.01) but not between the PD20 to water and methacholine. These results suggest that the mechanism of asthma induced by hyperosmolar and hypo-osmolar solutions is different.

Adolescent↗
PubMed1990

Factors related to the nocturnal worsening of asthma.

The nocturnal worsening of asthma is a very common problem, yet little is known about the relationships between the nocturnal worsening and daytime lung function, methacholine bronchial responsiveness, the degree of the circadian variability in bronchial responsivity, and the nocturnal sleep pattern. This study demonstrates in 20 asthmatic patients that the overnight fall in the peak expiratory flow rates (PEFR) is related to the severity of daytime airflow limitation (r = 0.73, p less than 0.001) and daytime bronchial responsiveness (r = 0.48, p less than 0.05). In individuals with larger overnight decrements in PEFR, bronchial responsivity at 0400 h is so great that normal saline inhalation alone can produce a greater than 20% fall in the FEV1. Sleep quality and sleep staging are not correlated to the change in the PEFR. Thus, the overnight decrement in asthmatic lung function is related to the daytime severity of asthma as determined by daytime measurements of airflow limitation and bronchial responsiveness as well as the circadian variation in bronchial responsivity.

Adult↗
PubMed1988

Peripheral type benzodiazepine receptor and airway smooth muscle relaxation.

It has been postulated that a benzodiazepine receptor with a micromolar affinity may be associated with Ca++ channels in peripheral organs. We examined the actions of Ro5-4684 (parachlorodiazepam) and midazolam on guinea pig tracheal smooth muscle contraction. Binding studies using [3H]Ro5-4684 indicate the presence of a "peripheral" type binding site with a Kd of approximately 4 nM and maximum binding of 1 pmol/mg of protein. Midazolam did not displace radioligand. In tension studies no activity was seen for Ro5-4684 or midazolam at concentrations below 1 microM. Higher concentrations relaxed the airway smooth muscle under basal tone, the effect was augmented significantly by epithelium removal. Similar results were obtained in tissues precontracted with methacholine or KCl. Midazolam (1 or 100 microM) significantly (P less than .05) attenuated the response to Ca++ in K+-depolarized tracheal strips, the effect was greater at low Ca++ concentrations. The compounds appear to function as Ca++ antagonists in airway smooth muscle but ar not typical as shown by their ability to reduce basal tone in airway smooth muscle.

Animals↗
PubMed1989

Airway responsiveness to methacholine after inhalation of nebulized hypertonic saline in bronchial asthma.

To assess whether the changes in airway methacholine (Meth) responsiveness induced by an initial hypertonic challenge determine the response to a subsequent hypertonic provocation, 11 subjects with asthma had bronchial challenges with 3.6% hypertonic saline (HS) and Meth in a dose-dependent manner and in random order. Challenges consisted of (1) an HS challenge (HS1) followed 1 hour later by a second HS challenge (HS2), (2) a Meth challenge alone (Meth1), and (3) an HS challenge followed 1 hour later by a Meth challenge (Meth2). The dose of HS that produced a 35% fall in SGaw (PD35) in HS1 was 69 L (geometric mean), and the PD35 in HS2 was 107 L (p = 0.02). Refractory index (PD35 HS2/PD35 HS1) ranged from 0.7 to 5.0. After HS challenge, airway responsiveness to Meth increased, and the Meth PD35 fell from 0.26 mumol to 0.11 mumol (geometric mean, p = 0.004). There was an inverse linear correlation between the refractory index and increases in Meth sensitivity (PD35 Meth1/PD35 Meth2) (r = -0.66; p = 0.027). After an initial HS challenge, the ratio of PD35 HS to PD35 Meth increased in all subjects, indicating that all subjects had become less responsive to HS compared to Meth, irrespective of their refractory index. We suggest that an initial HS challenge induces protective mechanisms toward a subsequent HS challenge in all individuals. The degree of increase in Meth responsiveness elicited by the initial provocation is a major factor in determining the airway response to a subsequent HS challenge.

Administration, Inhalation↗
PubMed1989

Gustatory rhinitis: a syndrome of food-induced rhinorrhea.

The consumption of certain foods causes watery rhinorrhea (gustatory rhinitis) in many individuals. To examine the underlying mechanisms responsible for this common phenomenon, 12 subjects ingested control foods and positive foods (foods that cause rhinorrhea). Nasal lavages performed 10 minutes after each food challenge were analyzed for albumin and total protein. Positive food challenge, but not control food challenge, induced rhinorrhea in all subjects. Positive food challenge increased albumin (7.8 +/- 1.9 to 24.5 +/- 7.6 mg/L; p less than 0.025) and total protein (79 +/- 9 to 258 +/- 41 mg/L; p less than 0.001) without altering the ratio of albumin to total protein (albumin percent). Nasal pretreatment with atropine clinically blocked the positive food-induced rhinorrhea and significantly inhibited secretion of both albumin and total protein, again without affecting the albumin percent. Thus, gustatory rhinitis is produced by spicy foods that stimulate atropine-inhibitable muscarinic receptors (probably on submucosal glands), and the syndrome can be treated prophylactically by use of topical atropine.

Administration, Topical↗
PubMed1977

Role of the parasympathetic system in antigen-induced bronchospasm.

Human subjects, sensitive to ragweed, inhaled aerosols of increasing concentrations of ragweed pollen extract in the presence and absence of pretreatment with inhaled atropine. The cumulative dose of antigen required for a 35% decrease in airways conductance was termed PD35. Atropine, 1.2 or 5 mg, increased airways conductance before antigenic challenge but did not alter signigicantly the PD35 for ragweed extract, although these doses of atropine inhibited airways responses to inhaled methacholine chloride and citric acid. We conclude that the cholinergic nervous system plays a modulating role in bronchomotor tone and responses to irritants, but that parasympathetic reflexes are not invariably a major component of human bronchial responses to inhaled allergen.

Airway Resistance↗
PubMed1976

Pharmacological assessment of 3-tert-butylsydnone.

The pharmacological effects of the mesoionic derivative, 3-tert-butylsydnone, were investigated. Administration to rats caused clonic convulsions. The CD50 of 3-tert-butylsydnone was 0.471 +/- 0.033 mmole/kg. Trimethadione, but not phenytoin sodium or proadifen hydrochloride, protected the rat from the effects of 3-tert-butylsydnone. After administration of this compound, pentobarbital sodium sleeping time was reduced in the rat, but blood pressure and ECG were unchanged in the dog. Pretreatment of the mouse with 3-tert-butylsydnone did not influence the LD50 of epinephrine hydrochloride. The action of methacholine chloride in the rat was not blocked, and the pupil of the rabbit eye was unaffected. Tests for analgesic and oxytocic activity were negative. Chronic administration of a small dose to the rat for 70 days had no effect on blood glucose, blood urea nitrogen, hemoglobin, or microhematocrit values.

Anesthesia↗
PubMed1978

Tracheobronchial secretions collected from intact dogs. II. Effects of cholinomimetic stimulation.

The effect of cholinomimetic stimulation on the quantity and composition of tracheobronchial secretions (TBS) collected from intact dogs was studied. After the administration of methacholine chloride, the collection rate of TBS increased over threefold within 10 min and returned to the control level by 50 min. Even though there was an increase in the total amount of protein collected, the protein concentration of the secretions decreased initially by 40%, returning to normal by 30 min. This was the result of an apparent dilution of the secretions by nonproteinaceous components. In addition, at 10 min, there was an increase in the protein associated with mucins. These responses were blocked by the preadministration of atropine. When TBS was separated into supernatant and pellet phases by centrifugation, we found that, following methacholine, there was a 35% increase in the ratio of albumin to IgG in the supernatant phase. These results suggest that the increased secretion due to methacholine may result, in part, by a selective filtration of fluid from the interstitial and/or vascular compartment(s) with proteins appearing in the secretory mixture based partially on their size.

Animals↗
PubMed1975

Enzyme secretion in the absense of zymogen granules.

Pure pancreatic juice was collected from the cannulated common bile duct of anesthetized rats after an overnight fast. Digestive enzyme secretion was followed in these animals during and after the progressive degranulation of acinar cells produced by sequentially applied cholinergic stimuli. The kinetics of degranulation, a progressive decrease in the number of zymogen granules in acinar cells, was estimated from the relative cell volume occupied by electron-opaque granules at various times using a random pointcount stereological technique to examine tissue sections. Three hourly injections of methacholine chloride were sufficient to produce the almost complete disappearance of electron-opaque granules from secretory cells. Greatly augmented enzyme secretion was still observed in their absence, 7-25 times greater than control values: 10-fold for protein output overall, 7-fold for trypsinogen, and 25-fold for chymotrypsinogen. Secretion in the absence of zymogen granules is discussed relativeto exocytosis and three-compartment (intracellular storage, cytoplasm, and duct lumen)secretory models.

Animals↗
PubMed1977

Uropharmacology: v. choline esters and other parasympathomimetic drugs.

Various parasympathomimetic drugs are discussed, including the choline esters, bethanechol, carbachol, methacholine chloride, and furtrethonium. Other cholinomimetic agents include muscarine, muscarone, arecholine, and pilocarpine. Anticholinesterase agents inhibit or inactivate acetylcholinesterase enzyme and thus result in a prolonged stimulation of cholinergic receptors by endogenous ACh. Bethanechol is the most widely used parasympathomimetic drug in the United States. Its action is mainly muscarinic with activity largely confined to the urinary bladder and to a lesser degree the gastrointestinal tract. It can be administered only subcutaneously or orally, and adequate dosage is necessary for a successful response.

Animals↗
PubMed1992

In vivo evaluation of airway and pulmonary tissue response to inhaled methacholine in the rat.

The current study was designed to assess the methacholine dose-response behaviour of the airways and pulmonary parenchyma with the aid of alveolar capsules. The experiments were performed in eight adult female Wistar rats (155-250 g). The animals were anaesthetized with sodium pentobarbital (30 mg kg-1 i.p.) and mechanically ventilated. Measurements of tracheal (ptr) and alveolar (pA) pressures and the pressure change across the airway (p(aw)) were performed prior to and after exposing rats to aerosols generated from sequentially increasing concentrations of methacholine chloride solution (2, 4, 8, 16, 32, 64 and 128 mg ml-1) through the breathing circuit. Baseline p(aw) and pA mean (+/- SD) values (6.44 +/- 2.06 and 8.25 +/- 3.44 cmH2O, respectively) were not statistically different (P = 0.220). The increases in ptr and pA were significant during the dose-response study (P = 0.001), whereas p(aw) was not increased. The increase in pA was significantly higher than that of p(aw) (P less than 0.001). The relationship between the mean (+/- SE) values of ptr and pA could be well described by a straight line (r = 0.990, P less than 0.001). There were also significant correlations based on regression equations between ptr and p(aw) (r = 0.947, P less than 0.001) and pA and p(aw) (r = 0.913, P = 0.004). These findings suggest that the pulmonary tissue of rats is a major component responsible for the increase in lung impedance observed after methacholine challenge. In addition, airway and pulmonary parenchyma pressure changes were correlated, suggesting that both lung regions have a similar sensitivity to the agonist. Our results indicate that the response of peripheral tissues should be considered during bronchial challenge protocols in rats.

Administration, Inhalation↗
PubMed1989

Autonomic denervation hypersensitivity in the primary glaucomas.

Autonomic denervation hypersensitivity of the iris was assessed in 44 patients with primary closed-angle glaucoma, 20 patients with primary open-angle glaucoma, and 40 age- and sex-matched control subjects. Significantly increased pupillary constriction in response to 2.5% methacholine chloride, indicating parasympathetic denervation hypersensitivity, was present in both closed-angle (p less than 0.02) and open-angle glaucoma patients (p less than 0.001), compared with the control group. Significantly increased pupillary dilatation in response to 0.5 per cent phenylephrine hydrochloride, indicating sympathetic denervation hypersensitivity of the iris, was also present in both closed-angle glaucoma (p less than 0.01) and open-angle glaucoma patients (p less than 0.05). The association between autonomic neuropathy and the primary glaucomas is discussed, with particular reference to the potential effects of autonomic dysfunction on aqueous dynamics.

Aged↗