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PubMed1987

Homologous desensitization of substance-P-induced inositol polyphosphate formation in rat parotid acinar cells.

Maximal concentrations of substance P and methacholine induced a rapid increase in [3H]inositol trisphosphate ([3H]IP3) formation. After about 1 min, the [3H]IP3 in the substance-P-treated cells ceased to increase further, whereas in the methacholine-treated cells [3H]IP3 continued to increase. Addition of methacholine to the substance-P-treated cells caused a rapid increase in [3H]IP3, whereas a second addition of a 10-fold excess of substance P had no effect. Pretreatment of cells with substance P, followed by removal of the substance P by washing, resulted in a decreased response to a second application of substance P. A similar protocol involving pretreatment with methacholine had no effect on subsequent responsiveness to substance P. Analysis of [3H]substance P binding to substance-P-treated cells indicated that the number of receptors for substance P was decreased, but the affinity of the receptors for substance P was unaffected. After substance P pretreatment, a prolonged incubation (2 h) restored responsiveness of the cells to substance P, measured as [3H]IP3 formation, and restored the number of binding sites to control values. These findings indicate that, in the rat parotid gland, substance P induces a homologous desensitization of its receptor, which involves a slowly reversible down-regulation or sequestration of substance-P-binding sites.

Animals↗
PubMed1989

Capacitative calcium entry in parotid acinar cells.

The intracellular Ca2+ indicator, fura-2, was used to monitor changes in cytosolic [Ca2+] in parotid acinar cells. When parotid cells were incubated in a medium containing low [Ca2+], and [Ca2+] was restored to the physiological range, there was a small increase in cytosolic [Ca2+]. If, however, the cells were first activated by a muscarinic agonist, and receptor activation was terminated before the addition of Ca2+ by the addition of a pharmacological excess of the muscarinic-receptor antagonist atropine, the initial increase in cytosolic [Ca2+] was faster and transiently larger than in the control cells which had not been previously stimulated. This suggested that a stimulation of Ca2+ entry occurred owing to the prior emptying of the agonist-regulated intracellular Ca2+ pool. This extra Ca2+ influx seen in pool-depleted cells persisted even when the interval between the addition of atropine and Ca2+ was increased from 1 to 20 min. Also, when the pool was allowed to refill by adding atropine in the presence of extracellular Ca2+, and Ca2+ was then sequentially removed and restored, the rise in cytosolic [Ca2+] after the addition of extracellular Ca2+ was not rapid, and resembled the increase seen in unstimulated cells. These results indicate that, when the agonist-sensitive Ca2+ pool is emptied by an agonist, Ca2+ influx across the plasma membrane is increased. This influx of Ca2+ occurs independently of the concentrations of inositol phosphates and probably of any second messengers linked directly to receptor activation. It appears rather to be a consequence of the empty state of the Ca2+ pool. Further, we suggest that, whenever the agonist-sensitive Ca2+ pool is emptied by agonist activation, the plasma-membrane permeability to Ca2+ will be increased, and this may account, at least in part, for the phenomenon of receptor-activated Ca2+ entry.

Animals↗
PubMed1977

Bronchial provocation in the study of sensations associated with disordered breathing.

1. Lung volumes, airway resistance and flow/volume curves were measured in ten asthmatic subjects at times when tightness in the chest was just sensed (threshold symptom). 2. These measurements when the threshold symptom was induced by methacholine inhalation were compared with those when a similar symptom occurred spontaneously, in the same subjects. 3. Values during the methacholine-induced thresholds were very similar to those observed when threshold symptoms developed spontaneously. 4. Controlled bronchial provocation mimics spontaneous asthma sufficiently well to allow this technique to be used in the study of sensations associated with breathing. This has some advantages over the already established models utilizing external hindrances to breathing.

Adult↗
PubMed1984

Methacholine dose-response curves in normal and asthmatic man: effect of starting conductance and pharmacological antagonism.

The bronchial response of 11 normal and ten stable asthmatic subjects to increasing concentrations of methacholine aerosol was assessed by serial measurements of specific airways conductance (sGaw) in a body plethysmograph. Cumulative log dose-response curves were constructed. The threshold provocative dose of methacholine needed to cause a 35% fall in starting sGaw ( PD35 ) and the steepest slope of the response were measured from each curve. On separate days subjects were premedicated with 0.9% NaCl solution (control) in duplicate, chlorpheniramine, salbutamol and atropine, the last-named at two different doses, one twice the other. Asthmatic subjects had a lower mean PD35 and a lower mean slope than normal subjects. Pretreatment with salbutamol resulted in a greater increase in sGaw than after atropine but caused a smaller increase in PD35 in both groups. There was a dose-dependent increase in PD35 after the two doses of atropine, but no significant difference in bronchodilatation between doses. Mean steepest slope approximately doubled in these three sets of challenges. Chlorpheniramine caused a small degree of bronchodilatation and there was a non-significant increase in mean PD35 and in mean steepest slope in both normal and asthmatic groups. There was a positive linear correlation between starting sGaw and steepest slope in each group of premedicated challenges, such that when sGaw was high, either spontaneously or due to bronchodilatation, the slope was steeper. We conclude that increases in PD35 to methacholine after antagonist drugs are predominantly the result of pharmacological antagonism.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1985

The human eccrine sweat gland adenylate cyclase system: response to agonists.

Cyclic AMP accumulation has been measured in whole human sweat glands. The mean rate in glands from 19 subjects was 0.519 +/- 0.316 pmol of cyclic AMP formed 5 min-1 micrograms-1 of DNA, which is comparable with that reported for other tissues. Cyclic AMP accumulation in the sweat gland is stimulated fourfold by prostaglandin (PG) E1 and fivefold by PGE2 (0.1 mmol/l), in accord with stimulation in renal tubules and medullary membranes. Bradykinin (10 micrograms/ml) increases the rate threefold and this is substantially prevented by indomethacin (1.5 X 10(-5) mol/l), as also is a fivefold stimulation by cyclic GMP (10(-5) mol/l). Mecholyl (10(-2) mol/l) and isoprenaline (6 X 10(-6) mol/l) increase the rate five- and four-fold respectively, and these agonist effects are largely abolished by atropine and propranolol. The stimulation and inhibition pattern suggests a direct action of PGE, enhancement of prostaglandin synthetase by cyclic GMP and stimulation of guanylate cyclase by mecholyl and bradykinin. Isoprenaline presumably stimulates adenylate cyclase directly. This complex chain of events, from cholinergic stimulation to an enhancement of adenylate cyclase, demonstrated in vitro, constitutes a potential for flexible and fine control of sweat gland function.

Adenylyl Cyclases↗
PubMed1986

The combined effects of two pairs of mediators, adenosine with methacholine and prostaglandin D2 with histamine, on airway calibre in asthma.

Mediators released from mast cells and secondary effector cells in the airways contribute to bronchoconstriction of allergic asthma. This study investigates methods for defining the effect of two inflammatory mediators on airway calibre in asthma. In an initial study on three asthmatic subjects, subconstrictor (subthreshold) concentrations of two mast cell derived mediators, histamine and prostaglandin (PG) D2, produced similar displacement to the left of a histamine concentration-specific airways conductance (sGaw) response curve. With both agonists enhancement of histamine-induced bronchoconstriction was greater at low histamine concentrations. Since potentiation of histamine-induced bronchoconstriction was independent of the class of subconstrictor agent given, it is likely to represent a physiological rather than a pharmacological interaction. During provoked asthma different constrictor mediators are likely to be released simultaneously into the airways. A method was therefore devised to investigate the combined effect of equiconstrictor concentrations of two mediators on airway calibre. Two pairs of inhaled bronchoconstrictor agonists were chosen for study: adenosine with methacholine and PGD2 with histamine. For each agonist, concentration-sGaw response curves were constructed, from which were derived the provocation concentrations of agonist causing a 25% fall in sGaw from baseline (PC25) and required to further this to 50% (PC50-25). On separate days, eight subjects received paired inhalations of methacholine-adenosine, methacholine-methacholine and adenosine-adenosine. The concentration used for the first inhalation was the PC25 value and for the second inhalation the PC50-25 value. Before, immediately after the first inhalation, and at regular intervals after the second inhalation, sGaw was followed for 30 min.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine↗
PubMed1987

Bronchial hyper-responsiveness after human cardiopulmonary transplantation.

1. Bronchial responsiveness to inhaled methacholine was studied in ten heart-lung transplant (HLT) recipients a mean 10.6 months (range 1.5-28 months) post-HLT and in ten normal subjects. 2. The mean provocation dose of methacholine producing a 20% fall in FEV1 (PD20 FEV1) was significantly lower in the HLT recipients (1.70 +/- 3.96 mg vs 11.55 +/- 3.79 mg; P less than 0.001), as was the mean provocation dose of methacholine producing a 50% fall in specific airway conductance (PD50 sGAW) (0.08 +/- 0.08 mg vs 5.13 +/- 5.47 mg; P less than 0.005). 3. These results establish the presence of significant bronchial hyper-responsiveness to inhaled cholinergic agonists in the transplanted lung.

Administration, Inhalation↗
PubMed1988

Effect of inhaled methacholine on gas mixing efficiency.

1. Pulmonary function tests, including alveolar mixing efficiency by the single-breath and multi-breath methods, and ventilation scans were performed on 16 volunteer subjects. The tests were repeated after the inhalation of a methacholine aerosol in sufficient dosage to increase airways resistance. 2. After inhalation of methacholine there was a significant fall in mean series dead space of 31 ml (P less than 0.05), and mean multi-breath alveolar mixing efficiency fell from 68% to 36% (P less than 0.001), a fall occurring in all subjects. Mean single-breath alveolar mixing efficiency measured on the first breath of the nitrogen washout fell from 76% to 70%, but this change did not reach statistical significance (0.1 greater than P greater than 0.05). 3. In eight of the subjects, technically adequate lung scans and pulmonary function tests were obtained both before and not more than 30 min after methacholine inhalation. In seven there were obvious visible defects on the ventilation scans, and in five of these the computer-calculated underventilation score became abnormal. 4. Thus inhalation of methacholine causes maldistribution of ventilation, a fall in alveolar mixing efficiency and a fall in series dead space, presumably brought about by bronchoconstriction. The parallel component of this maldistribution of ventilation, as judged by 81mKr ventilation scanning, does not of itself seem to be sufficient to explain the fall in alveolar mixing efficiency, and therefore a degree of diffusion limitation is probably involved as well.

Administration, Inhalation↗
PubMed1988

Effect of single respiratory manoeuvres on specific airway conductance in heart-lung transplant recipients.

1. The time course and magnitude of the effect of single slow and rapid respiratory manoeuvres on specific airway conductance (sGaw) was assessed in seven normal control subjects and in seven heart-lung transplant (HLT) recipients before and after experimentally induced bronchoconstriction. 2. Neither full inspiration, full exhalation nor vital capacity manoeuvres significantly altered sGaw in normal controls or HLT recipients under baseline conditions despite the presence of hyper-responsiveness to methacholine (MC) in the latter group. 3. After induced bronchoconstriction, single slow and rapid inspirations to total lung capacity transiently abolished or attenuated the bronchoconstriction in normal controls. This effect was absent in the HLT recipients. 4. In HLT recipients, the combination of hyper-responsiveness to MC, the absence of bronchoconstriction with respiratory manoeuvres and the absence of significant bronchodilatation after deep inspiration suggest lack of normal pulmonary innervation.

Adult↗
PubMed1995

Effect of ozone exposure on maximal airway narrowing in non-asthmatic and asthmatic subjects.

1. Ozone is a major constituent of air pollution in the summer. Epidemiological studies have demonstrated that there is an increase in hospital admissions for respiratory diseases 1 day after peak levels of ambient ozone. This may be due to an increase in the responsiveness of the airways to bronchoconstrictor stimuli. 2. In the present study we therefore studied the effect of a controlled exposure to ozone on the maximal degree of airway narrowing to a non-specific bronchoconstrictor, methacholine, 12 h after exposure. Both non-asthmatic and mild-asthmatic volunteers were exposed to ozone. 3. The study had a single blind design. Experimental exposures were to filtered air, 0.40 ppm ozone and filtered air respectively, at 1-week intervals. The duration of each exposure was 2 h with alternating periods of 15 min rest and exercise. At 12 h after exposure, methacholine inhalation challenge tests and sputum induction were performed. 4. Twelve hours after exposure to ozone there was a significant increase in the maximal degree of airway narrowing to methacholine (P < 0.02) compared with exposure to air, in non-asthmatic as well as asthmatic subjects. These physiological changes were accompanied by a significant rise in the percentage of neutrophils in induced sputum (P < 0.02). All changes had returned to baseline values 1 week after exposure to ozone. 5. Exposure to ozone causes a transient increase in the maximal degree of airway narrowing to methacholine in both non-asthmatic and asthmatic subjects. These laboratory results, obtained using relatively high ozone exposure in carefully selected subjects, might provide an explanation for the temporal relationship between ambient ozone levels and hospital admissions for asthma.

Adult↗