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PubMed1990

Relationship of different serum levels of theophylline on methacholine sensitivity.

With an increased awareness of the importance of bronchial hyperreactivity on the clinical state of asthma, efforts at establishing effective treatment for asthma have been aimed at trying to reduce the level of bronchial hyperreactivity. This study investigated whether or not theophylline at different serum concentrations had any effect on bronchial hyperreactivity, as measured by methacholine challenges. Twelve adult subjects with mild asthma participated. All subjects were atopic and were nonsmokers. Subjects were studied on three separate occasions according to a double-blind, randomized, crossover study design with one of the following medications: two placebo capsules in the morning and evening, a placebo and 250 mg of sustained-release theophylline in the morning and evening, or two 250 mg sustained-release theophylline capsules each morning and evening. Subjects were administered their medication between 5 and 15 days before performing methacholine challenges in the morning at the presumed trough level, and in the afternoon at the presumed peak serum theophylline level. Despite statistically significant differences in the pulmonary function and theophylline levels between the two active dosages (p less than 0.05 for both), there was no difference in methacholine sensitivity at the time of ingestion of the two dosage forms. There was also no correlation between a particular theophylline level and degree of methacholine sensitivity. It was concluded that, although theophylline has significant bronchodilator capability, it has little, if any, effect on bronchial hyperreactivity, as measured by methacholine challenges. Thus, other forms of long-term therapy should be used in reducing bronchial hyperreactivity.

Adult↗
PubMed1990

Comparative protective effect of the inhaled beta 2-agonist salbutamol (albuterol) on bronchoconstriction provoked by histamine, methacholine, and adenosine 5'-monophosphate in asthma.

We have investigated the ability of salbutamol to protect against bronchoconstriction induced by methacholine, histamine, and adenosine 5'-monophosphate (AMP) in nine subjects with asthma. In a double-blind, placebo-controlled study, salbutamol, 2.5 mg administered by nebulization, increased the geometric mean provocation concentrations of methacholine, histamine, and AMP required to produce a 20% decrease in FEV1 from 0.3 to 2.2, 0.4 to 3.8, and 4.0 to 106.7 mg/ml after placebo and active treatment, respectively (p less than 0.01). Thus, this dose of beta 2-adrenoceptor agonist displaced the concentration-response curves for methacholine, histamine, and AMP to the right in a parallel fashion by 8.8 (0.6 to 29.3)-, 10.3 (1.4 to 33)-, and 26.6 (1.5 to 76.6)-fold, respectively, the difference between the results for AMP and those for histamine and methacholine being statistically significant (p less than 0.01). For six of the nine subjects studied, salbutamol displaced the concentration-response curve for AMP to the right by greater than 50-fold. There was no correlation between bronchodilatation and protection against bronchoconstriction induced by any of the agonists. We conclude that salbutamol protects against bronchoconstriction provoked by methacholine and histamine by functional antagonism, whereas with AMP, an additional activity is demonstrable, possibly involving inhibition of mast cell-mediator release.

Adenosine Monophosphate↗
PubMed1990

Assessment of airway hyperresponsiveness in chronic stable asthma.

Airway reactivity and disease severity were investigated in 24 subjects with stable chronic bronchial asthma. Disease severity was determined by assigning a disease severity score (DSS) representing six clinical and therapeutic parameters. Airway hyperresponsiveness was assessed in two ways: airway reactivity score (ARS) based on the number of positive responses to a question concerning exposure to 22 nonspecific inhaled irritants and methacholine challenge testing and determining the cumulative dose causing a 20% reduction in FEV2 (CMD20). A significant correlation between DDS and CMD20 (r = 0.57; p less than 0.003) and DSS and ARS (r = 0.67; p less than 0.0003) attested to the important influence of airway hyperresponsiveness on disease severity. Significant correlations for ARS with CMD20 (r = -0.60; p less than 0.002) suggested the consistency with which the ARS estimated methacholine hyperresponsiveness. We found no statistically significant correlations between DSS, ARS, or CMD20 and the age of subject, duration of asthma, or other host characteristics. There was not a significant correlation between the degree of airway obstruction and DSS or ARS noted. The results of this investigation demonstrate the value of the use of clinical information for assessing airway hyperresponsiveness and disease severity in patients with chronic stable asthma. Both ARS and DSS are useful clinical tools for estimating methacholine reactivity.

Adult↗
PubMedDate not supplied

Does beta-adrenoceptor activation stimulate Ca2+ mobilization and inositol trisphosphate formation in parotid acinar cells?

The effects of the beta-adrenoceptor agonist, isoprenaline, on Ca2+ mobilization and inositol phosphate formation in parotid acinar cells were examined. Isoprenaline (2 microM) failed to increase cytosolic [Ca2+] in acinar cells, as measured by Fura-2 fluorescence, even in the presence of a phosphodiesterase inhibitor. Likewise, neither the 8-bromo nor the dibutyryl derivatives of cAMP (both at 2 mM concentration) increased [Ca2+]i. However, in confirmation of results previously published, a higher concentration of isoprenaline (200 microM) increased cytosolic [Ca2+]i of rat parotid acinar cells, from 104 +/- 4 nM to 151 +/- 18 nM. The increase in [Ca2+]i in response to isoprenaline, while transient in the absence of extracellular Ca2+, was sustained in Ca2(+)-containing medium. This isoprenaline-stimulated Ca2+ signal was more potently antagonized by phentolamine than by propranolol, suggesting that the higher concentration of isoprenaline activated alpha-adrenoceptors. Furthermore, the Ca2+ signal generated in response to the alpha-adrenoceptor agonist, phenylephrine, also was blocked by the same concentrations of propranolol necessary to block the effects of isoprenaline, suggesting that propranolol may block alpha-adrenoceptors under certain experimental conditions. The high concentration of (-)isoprenaline (200 microM) also increased inositol (1,4,5) trisphosphate and inositol (1,3,4) trisphosphate formation 45% within 30 s. Analogous to the increase in intracellular Ca2+, the formation of inositol phosphates stimulated by isoprenaline was more potently antagonized by the alpha-adrenoceptor antagonist, phentolamine, than by the beta-adrenoceptor antagonist, propranolol, again suggesting that isoprenaline interacts with alpha-adrenoceptors on parotid cells. Thus, the effects of isoprenaline on [Ca2+]i do not appear to be mediated by cAMP.(ABSTRACT TRUNCATED AT 250 WORDS)

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1990

Calcium efflux across the plasma membrane of rat parotid acinar cells is unaffected by receptor activation or by the microsomal calcium ATPase inhibitor, thapsigargin.

The rate of Ca2+ extrusion across the plasma membrane of rat parotid acinar cells was determined by measuring the decay of the intracellular calcium concentration, [Ca2+]i, following the addition of EGTA to agonist stimulated cells. In the presence of extracellular Ca2+, the muscarinic cholinergic receptor agonist, methacholine, rapidly increased [Ca2+]i (peaking within 5 s), which then decreased to a higher steady state level. This elevated steady state level was dependent on extracellular Ca2+ concentration. Likewise, thapsigargin, a non-phorbol ester tumor promoter that does not increase inositol phosphates, gradually increased [Ca2+]i, peaking within 1 min and then declining to a new elevated plateau level which was also dependent on extracellular Ca2+. [Ca2+]i, elevated by methacholine or thapsigargin, was rapidly decreased by the addition of EGTA by a process the kinetics of which depended on the value of [Ca2+]i before the addition of EGTA. That is, [Ca2+]i increased as a function of the extracellular Ca2+ concentration and also the apparent half-time for Ca2+ extrusion following the addition of EGTA to cells was increased as the [Ca2+]i increased. This presumably reflects the saturable nature of the Ca2+ extrusion mechanism. The steady state [Ca2+]i in cells stimulated with methacholine or thapsigargin in nominally Ca2+ free medium was similar to the steady state [Ca2+]i in unstimulated cells in normal, Ca2(+)-containing medium. Under these similar [Ca2+]i conditions, stimulated and unstimulated cells showed a similar time course of decay upon addition of EGTA. In addition, neither methacholine nor phorbol myristate acetate decreased the sustained elevation of [Ca2+]i induced by ionomycin.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1980

Continuous automated assay of alpha-amylase release from superfused rat salivary gland.

A method of continuous automated amylase assay is described. This relies on the absorption of iodine by starch to produce a blue color that can be quantified colorimetrically. Digestion of the starch by amylase released from parotid tissue slices reduces the intensity of the color formed, allowing quantification of the amylase released. The assay in sensitive to 0.05 U/amylase/ml and linear up to 13 U/ml. Typical tissue responses to acetyl-beta-methylcholine and isoprenaline are presented.

Amylases↗
PubMed1987

Comparison of isometric and isotonic responses of human small airway smooth muscle in vitro.

The difference between isometric and isotonic responses of human small airway smooth muscle to a number of pharmacological agonists was studied. The isotonically measured sensitivity to methacholine was 1.4 times less than the isometrically measured value (p less than 0.05), and similar small discrepancies were found for histamine, leukotriene, prostaglandin F2 alpha, isoproterenol, and theophylline. Maximal isometric force and isotonic shortening after methacholine were linearly related (p less than 0.01). The between-methods difference is relatively small. Because the difference was of similar magnitude and in the same direction in all tissues studied, it is of little practical importance for conventional pharmacological experiments.

Bronchi↗
PubMed1982

Effects of ketotifen, a benzocycloheptathiophene, on metacholine- and acetylcholine-induced contractions of canine respiratory smooth muscle.

The relaxant effects of ketotifen on isolated respiratory smooth muscle contracted by methacholine or acetylcholine were examined. Although potent dose-dependent relaxation was observed, it appears that more than 100 times the concentration is required to relax muscle contracted with cholinergic agonists than has been reported for muscle contracted by histamine. This observation offers a possible explanation for the findings of several investigators that dosages of ketotifen administered to patients protect against histamine-induced, but not methacholine- or acetylcholine-induced, bronchospasm.

Acetylcholine↗
PubMedDate not supplied

Airway cholinergic responsiveness in rabbits in relation to antigen sensitization and challenge.

The development of bronchial hyperresponsiveness to cholinergic agents in relation to antigen sensitization and repeated antigen challenge was investigated in a rabbit model. Rabbits immunized to produce preferentially specific IgE antibodies had a modest enhancement of their bronchoconstrictive response (measured as an increase in pulmonary resistance) to aerosolized methacholine compared to sham-immunized and unimmunized controls. A further enhancement was observed subsequent to a series of seven antigen challenges given transtracheally, such that the geometric mean dose of methacholine required to increase pulmonary resistance by 100% (PD100 RL) was 89 cumulative breath units (CBU) compared to 372 CBU for sham-immunized controls and 871 CBU for unimmunized controls (p less than 0.05 for ANOVA). Although methacholine also decreased dynamic compliance, the changes were not different among the three groups. Isolated intrapulmonary bronchi from the three groups did not differ in log concentration of methacholine yielding a half-maximal contraction (log EC50). The range of EC50 values was 15-fold compared to a 90-fold range of PD100 RL. In vivo cholinergic responsiveness of the pupillary muscle did not correlate with bronchial responsiveness. Thus, pulmonary antigen challenge of IgE-producing rabbits produced a marked increase in bronchial responsiveness which did not correlate with in-vitro bronchial responsiveness or with in vivo pupillary responsiveness.

Animals↗
PubMed1986

Effects of periods of conditioning stimulation and of neuropeptides on vagal action at the heart.

The strength of action of the parasympathetic innervation of the heart was tested, in anaesthetized dogs, by regular delivery of bursts of supramaximal electrical pulses at low frequency to the cut, cardiac end of the vagus nerve. Periods of 'conditioning' stimulation of the same nerve at relatively high frequencies (15-30 Hz, for 15-300 s) were found to cause a slowly developing potentiation (up to 280% increase in the vagally induced prolongation of pulse interval) of the cardiac action of the low-frequency stimulation. This potentiation lasted for periods of up to 30 min after the conditioning period. Similar potentiation could be elicited for the action of one vagus nerve by conditioning the vagus on the other side. Potentiation of vagal action was not associated with an enhancement of the response of the heart to injected methacholine. Several neuropeptides, reported to be present in cardiac autonomic nerves, were tested for ability to mimic this effect when administered by intravenous injection. Vasoactive intestinal polypeptide, neurotensin, somatostatin and substance P all failed to do so at the doses tested. Vasopressin did induce an enhancement of cardiac vagal efficacy, but effective pharmacological blockade of its action did not block the potentiation caused by conditioning stimulation. In the absence of any evidence of neuromodulation of vagal action by these neuropeptides, it was presumed that the effect could be attributed to a classical homosynaptic post-tetanic potentiation mechanism involving intracellular accumulation of calcium ions in prejunctional nerve terminals.

Animals↗
PubMed1983

Distribution of three hexose derivatives across the pancreatic epithelium: paracellular shunts or cellular passage?

It has been proposed that the pancreatic epithelium is permeable to three presumably passively distributed non-electrolytes, namely sucrose, inulin and mannitol, via paracellular shunts, and that the increased flux of sucrose and inulin seen during augmented digestive enzyme secretion is due to an increase in the permeability of these shunts. The present study considers this hypothesis by comparing the permeability of the epithelium to three different hexose derivatives, mannitol, inositol and 3-O-methyl-glucose, in both the unstimulated state and after the augmentation of protein secretion with a cholinergic drug. The epithelium was found to be more permeable to mannitol than to either inositol or 3-O-methyl-glucose. In the unstimulated state, the concentration of mannitol in ductal fluid at the steady state was approx. 54% of its concentration in the interstitium, as compared to 12% for inositol and 8% for 3-O-methyl-glucose. Cholinergic stimulation substantially increased the concentration of inositol and 3-O-methyl-glucose in secretion, but did not increase that of mannitol. The increase in the concentration of inositol occurred in the absence of an increase in its rate of transepithelial movement. Taken together, the results suggest that: (1) there is a substantial passage of mannitol through the cells of the epithelial layer, and (2) the increased concentration of inositol and 3-O-methyl-glucose in ductal fluid that occurs with stimulation is due to an increase in their efflux from secretory cells.

3-O-Methylglucose↗
PubMed1984

Cyclic GMP-dependent protein kinase activation in canine tracheal smooth muscle by methacholine and sodium nitroprusside.

Methacholine (3 microM) and sodium nitroprusside (300 microM) increased cGMP-dependent protein kinase activity ratios (activity without cGMP divided by activity with 2 microM cGMP) in canine tracheal smooth muscle from a control value of 0.47 to 0.55 and 0.71, respectively. This correlates with 3-fold and 6-fold increases in cGMP concentrations in response to methacholine and sodium nitroprusside, respectively. Addition of charcoal to the homogenizing buffer prior to homogenization had no significant effect on the cGMP-dependent protein kinase response to either agent, suggesting that activation of the enzyme was not occurring as a result of cGMP release during homogenization. In order to limit cGMP dissociation from cGMP-dependent protein kinase during the assay procedure, it was necessary to perform assays at a reduced temperature (0 degree C) and with an abbreviated incubation time (2.5 min). When assayed at 30 degrees C, activated cGMP-dependent protein kinase rapidly lost activity. This inactivation occurred whether the enzyme had been activated exogenously, by exposing a supernatant fraction of canine trachealis to 0.1 microM cGMP, or endogenously, by treating intact canine trachealis with methacholine or sodium nitroprusside. By assaying instead at 0 degree C, the inactivation of cGMP-dependent protein kinase was minimized. Therefore, the activity ratio obtained by this new modified assay provided an estimate of the endogenous activation state of cGMP-dependent protein kinase. The data indicate that cGMP responses in canine trachealis to both methacholine and sodium nitroprusside are functionally linked to activation of cGMP-dependent protein kinase and are consistent with the hypothesis that cGMP, via cGMP-dependent protein kinase activation, regulates smooth muscle contractility.

Animals↗
PubMed1985

Effect of activation of muscarinic receptors on intracellular free calcium and secretion in bovine adrenal chromaffin cells.

Stimulation of the nicotinic receptor of bovine chromaffin cells results in a rise in intracellular free calcium [( Ca2+]i) and subsequent release of catecholamine. This response is totally dependent on the presence of external Ca2+. Monitoring [Ca2+]i using quin-2 demonstrated a rise in [Ca2+]i in response to muscarinic agonists which was approximately 4-times less than that obtained in response to nicotinic stimulation. This atropine-sensitive [Ca2+]i rise occurred after a 10-s lag and was found to be independent of the external Ca2+, implying the existence of an intracellular Ca2+ source. Despite producing this [Ca2+]i rise low concentrations of the muscarinic agonist, methacholine (under 1 X 10(-3) M), failed to trigger secretion itself and did not effect the secretory response elicited by nicotine. Challenging the cells with higher methacholine concentrations (over 1 X 10(-3) M) resulted in the same [Ca2+]i rise, no secretion, but an inhibition of secretion due to nicotine. This latter response, however, was found to be atropine-insensitive and therefore non-muscarinic. The [Ca2+]i rise and secretion due to depolarization by 55 mM K+ were largely unaffected by prior addition 1 X 10(-2) M methacholine, inferring that high concentrations of methacholine inhibit nicotine-induced secretion by interacting with the nicotinic receptor. These results provide evidence consistent with the existence of an intracellular Ca2+ store mobilized by muscarinic receptor activation in bovine chromaffin cells and show that, despite causing a rise in [Ca2+]i, bovine chromaffin cell muscarinic stimulation does not effect secretion itself or secretion induced by either nicotine or high K+.

Aminoquinolines↗
PubMed1986

Prostacyclin synthesis by the corpora cavernosa of the human penis: evidence for muscarinic control and pathological implications.

The present study demonstrates that human corpus cavernosum tissue has the capacity to produce prostacyclin (PGI2), a vasodilator and potent inhibitor of platelet aggregation. The release of PGI2 was stimulated by cholinergic (muscarinic) but not adrenergic agents. Since penile erection in man is dependent upon parasympathetic stimulation, the vasodilatory action of PGI2 may contribute to the initiation and maintenance of erection.

Atropine↗
PubMed1987

The effect of lead on cholinergic contractile function in the rat forestomach.

Previous studies have demonstrated that subchronic exposure to lead in rats slows gastric emptying. Therefore, the isometric contractile response of the forestomach from lead-treated rats was examined in vitro. Male Wistar rats were fed 4% lead acetate in their diet (NIH-07); controls were pair-fed. After 7 weeks, blood lead levels reached 180-389 micrograms/dl. The forestomach was dissected and suspended in buffer which for lead-treated rats contained 1.2 X 10(-5) M lead acetate. Subchronic lead exposure had no effect on the maximum tonic contraction induced by KCl, methacholine or serotonin. However, lead-treated tissue showed enhanced sensitivity to methacholine with a reduction in EC50 to 59.7% of control. This effect was not observed in control tissue exposed to lead (1.2 X 10(-5) M) only in vitro. Higher in vitro concentrations of lead (16 X 10(-5) M) produced an increase in methacholine EC50. Physostigmine-induced increase in tension was also significantly greater in tissue from lead-treated rats. Electric field stimulation, which produced a contraction attributable to postganglionic acetylcholine release, was unaltered in lead-treated tissue. These results indicate that lead intoxication did not impair the contractile apparatus of the forestomach smooth muscle. The lack of net effect on activation of intramural cholinergic neurons, despite the enhanced sensitivity to a cholinergic agonist, may indicate reduction in acetylcholine release in lead-treated tissue.

Administration, Oral↗
PubMed1982

The three-ion test for the identity of the ionophores mediating the hyperpolarizing response to cholinomimetics in neurones of Helix aspersa.

1. The hyperpolarizing response investigated is mediated by Cl- ions. Additional anions NO-3 and BrO-3 were introduced into the perfusate to produce a system with 3 permeant anions. 2. Under such circumstances the reversal potential (Er) becomes a means of discriminating between the molecular mechanisms invoked by different agonists that produce an increase in anionic conductance. 3. A statistically significant difference of 0.49 mV was detected between the Er for acetylcholine and those for acetyl-beta-methyl choline and tetramethylammonium (acetylcholine more negative). 4. This difference was not significantly affected by changing to a different 3-ion solution. 5. It is argued from theoretical grounds that a change in this difference is to be expected when molecular mechanisms differ; alternative explanations for the difference are suggested.

Acetylcholine↗