Role of histamine release in hypertonic saline induced bronchoconstriction.

In a study designed to determine the protective effect of the specific histamine H1 antagonist terfenadine on hypertonic saline induced bronchoconstriction, 10 asthmatic subjects underwent hypertonic saline challenge (3.6%) after premedication with placebo or terfenadine (120 mg) 12 and two hours before the challenge. Hypertonic saline was administered in a dose dependent manner and the response determined as the dose of hypertonic saline that induced a 20% fall in FEV1 (PD20 FEV1). FEV1 was on average 11% greater with terfenadine than with placebo given before the challenge with hypertonic saline. PD20 FEV1 was attenuated by a mean of 2.5 fold after terfenadine (geometric mean PD20 FEV1 was 22 litres after placebo and 56 l after terfenadine). There was substantial intersubject variation in the inhibitory effect of terfenadine on hypertonic saline induced bronchoconstriction: the ratio of the PD20 hypertonic saline after terfenadine to that after placebo ranged from 0.9 to 10.0. Terfenadine inhibited histamine induced bronchoconstriction in the eight subjects in whom it was tested, by 13 to 160 fold compared with placebo in four subjects and by greater than 2 to greater than 9 fold in the four who showed no response to the highest dose of histamine given (16 mg/ml). These results suggest that histamine release has a role in hypertonic saline induced bronchoconstriction in some individuals; other mediators or mechanisms may have a more prominent role in others.

Airway responses to hypertonic saline, exercise and histamine challenges in bronchial asthma.

The airway responses to histamine, exercise and ultrasonically nebulized hypertonic saline have been compared in ten asthmatic patients. The responses to hypertonic saline were not significantly different when the same volume of aerosol was given in a single dose or in 10 l aliquots, suggesting that the challenge is cumulative. The variability of the response to hypertonic saline challenge was not significantly different from that of exercise challenge. Response to hypertonic saline correlated significantly with exercise (r = 0.68, p less than 0.05) and with histamine response (r = 0.74, p less than 0.02), but the correlation between exercise and histamine was not statistically significant (r = 0.15, p greater than 0.1). These findings suggest that exercise-induced asthma has a closer relationship to bronchial responsiveness to hypertonic saline aerosol than it does to non-specific reactivity demonstrated by histamine challenge.

A comparison of mediator and catecholamine release between exercise- and hypertonic saline-induced asthma.

Serum neutrophil chemotactic activity (NCA) and plasma histamine concentrations were measured in 9 asthmatic subjects with exercise-induced asthma after inhalation challenge with ultrasonically nebulized 3.6% hypertonic saline, which was administered either in a dose-dependent manner (HSDR) or as a continuous single dose (HSC), and after cycle ergometer exercise. The mean decreases in FEV1 elicited by HSDR, HSC, and exercise were 26, 27, and 25%, respectively, and were not significantly different. There was an approximate 300% maximal increase in NCA detected after both HSC and exercise challenges. Gel filtration chromatography on columns of Ultragel ACA 34 indicated that the NCA released after HSC provocation and exercise were 600 to 700 kDa. There was an approximate 100% maximal increase in NCA after HSDR challenge, and this was significantly less (p = 0.016) than that after HSC and exercise. Exercise but not hypertonic challenge was associated with a basophilia and a significant increase in plasma histamine. There was a significant increase in plasma norepinephrine concentrations after exercise but not after HSC challenge in 7 asthmatics. Epinephrine concentrations did not change after exercise or HSC inhalation. NCA was measured in 5 subjects subjected to 2 HSC challenges that were separated by 60 min. There was an increase in NCA detected after both provocations. The increase after the second challenge was significantly greater (p = 0.27 x 10(-4)) than that observed after the initial provocation, despite a substantially reduced bronchoconstrictor response after the second challenge.

Pathogenetic mechanisms of exercise-induced asthma and the refractory period.

Exercise is a powerful stimulus to the development of asthma. In most asthmatic subjects the airways obstruction recovers spontaneously within 60 minutes, but in some subjects there is more prolonged airflow obstruction which requires bronchodilator treatment. Approximately 40-50% of subjects with EIA will show a refractory period of two to four hours after an initial exercise task, during which time an identical exercise task will evoke significantly less (less than 50%) bronchoconstriction. In some patients, particularly children, EIA will be followed three to nine hours later by a further episode of bronchospasm, termed the late asthmatic response. There remains considerable debate about the pathogenesis of EIA the refractory period and the late asthmatic response.

Circulating concentrations of histamine, neutrophil chemotactic activity, and catecholamines during the refractory period in exercise-induced asthma.

Circulating mediators and catecholamine concentrations have been measured in eight subjects with asthma who were subjected to two bouts of cycle ergometer exercise separated by 1 hour. The maximum falls in FEV1 were 21.9 +/- 2.3% (mean +/- SEM; n = 8) and 5.5 +/- 1.3% (mean +/- SEM; n = 8) after the first and second exercises, respectively. Serum neutrophil chemotactic activity (NCA) and plasma histamine and catecholamine levels in venous blood were measured with a microchemotaxis and two radioenzymatic techniques, respectively. There was a significant increase in NCA and plasma histamine concentrations after both exercise challenges, and there was no significant difference in the release of these mediators between the two exercise tests. Gel filtration chromatography demonstrated that the NCA detected after the first and second exercise tests had molecular sizes of approximately 600,000 daltons. There was no significant time-dependent increase in plasma norepinephrine and epinephrine concentrations after either exercise task, even though the patients were refractory to exercise-induced asthma after the second exercise. These results suggest that the refractory period in exercise-induced asthma is not caused by mediator depletion, as indicated by NCA and histamine measurements, or by protection of the airways through catecholamine release.

A comparison of the refractory periods induced by hypertonic airway challenge and exercise in bronchial asthma.

We have compared the changes in FEV1 of 10 asthmatic patients who were subjected in random order to paired challenges with different combinations of exercise and aerosolized hypertonic 3.6% saline. The challenges were separated by 60 min when the FEV1 values had returned to within 10% of baseline values. Four patients were refractory to exercise-induced asthma (EIA) after an initial exercise task, and these patients also demonstrated a refractory period to hypertonic-saline-induced bronchoconstriction after an initial hypertonic challenge. Furthermore, hypertonic challenge produced refractoriness to EIA in the patients, and exercise rendered them refractory to hypertonic-saline-induced asthma. Six subjects were not refractory to EIA after an initial exercise task, and they were also not rendered refractory by an initial hypertonic challenge to asthma induced by hypertonic saline or by exercise. Histamine-induced bronchoconstriction in the 4 refractory subjects did not induce a refractory period to EIA, indicating that the refractory periods developing after hypertonic saline challenge and exercise were not due to the bronchoconstriction alone. Inhalation of isotonic saline in the same volumes as those used for hypertonic challenges did not induce a refractory period, indicating that the refractory period caused by the inhalation of hypertonic saline was not due to the volumes of fluid inhaled. Thus, exercise and aerosolized hypertonic saline induced refractoriness interchangeably, suggesting that airway hypertonicity and exercise produced a refractory period through a very similar, if not identical, final common pathway.

Changes in pulmonary clearance of technetium labelled DTPA during haemodialysis.

An index of pulmonary epithelial permeability has been studied in 12 patients with chronic renal failure during haemodialysis. It was assessed by the half time clearance from lung to blood (t 1/2 LB) of a nebulised solution containing technetium labelled diethylene triamine pentacetic acid (99mTc DTPA). Six patients were cigarette smokers and six were non-smokers. The non-smokers had greater predialysis permeability (mean 37.7, range 24-54 min) than non-smokers without renal disease (mean 60.2, range 38-99 min; p less than 0.025). The t 1/2 LB was measured before dialysis and during the first half hour and the last half hour of dialysis in all 12 patients and also during other periods of dialysis in 10 of them. Dialysis lasted for five hours in 11 patients and four hours in one patient. There was no significant change in the t 1/2 LB of 99mTc DTPA during early dialysis; but as dialysis progressed there was a statistically significant increase in t 1/2 LB, suggesting a reduction of pulmonary epithelial permeability. These results show no increase in an index of pulmonary epithelial permeability in association with the pulmonary sequestration of neutrophils that occurs in early haemodialysis. They also suggest that in chronic renal failure the epithelial permeability is increased and that this can be modified by haemodialysis.