Histamine reactivity during the refractory period after exercise induced asthma.

Abstract

An episode of exercise induced asthma will usually be followed by a period during which further exercise will not induce asthma. Postulated mechanisms include persistence of catecholamines released during exercise, development of tolerance to released mediators, and mediator depletion. To investigate the underlying mechanism further eight asthmatic men underwent three experimental protocols as follows: two treadmill runs of eight minutes; two incremental challenges with histamine inhalation; and a treadmill run of eight minutes followed by an incremental challenge with histamine inhalation. In each case the two challenges began 40 minutes apart. Patients performed the paired exercise trial first. Refractoriness to bronchoconstriction was shown in the repeated exercise studies but did not occur with repeated histamine challenge. The geometric mean histamine concentrations required to produce a 20% fall in forced expiratory volume in one second (FEV,) were 1*53 mg/ml and 093 mg/ml for the first and second challenges respectively (NS) and 1-4 mg/ml (NS) for the histamine challenge after exercise. It is concluded that refractoriness to exercise induced asthma is not explained by the development of smooth muscle tolerance to repeated histamine exposure or by the persistence of catecholamines released during exercise. The data are consistent with the theory of mediator depletion as the cause of refractoriness.

Influence of exercise-induced bronchoconstriction on refractoriness

“…Our study was not designed to contribute to current hypotheses on mediator depletion [3,19], increased release of catecholamines [4,8,33], release of inhibitory prostaglandins [11,23,29], reduced responsiveness of bronchial smooth muscles [ 15,16], or an alteration of the responsivity of the bronchial microcirculation [13] to explain exercise-induced refractoriness.…”

Effects of diurnal variation and prolonged refractoriness on repeated measurements of airways responsiveness to methacholine.

“…As this difference could not have been due to diurnal variation it raised the possibility of prolonged refractoriness to methacholine. Of the 24 subjects 19 had undergone their methacholine tests on consecutive days and five on non-consecutive days. A separate analysis of the results for the group whose tests were performed on consecutive days showed that there was again a significant difference in airways responsiveness between tests, and that removing those subjects not tested on consecutive days had made this difference more Geometric mean PD20 at 08:00 hours Ratio of PD20 at 08:00 hours on day 2 to PD20 at 08:00 hours on day 1 against the geomeric mean PD20 at 08:00 hours for 19 subjects tested on consecutive days (investigation 1).…”

“…Mean ratio (95% confidence interval) and p values for differences between PD20 results for tests performed at each measurement point for19 subjects studied on consecutive days (investigation 1)…”

Protective effect of bronchial challenge with hypertonic saline on nocturnal asthma

“…The pathophysiology of the refractory period has been investigated for approximately 30 years and has not been fully elucidated. Several mechanisms have been evaluated, with no evidence of mast cell mediator depletion (21), catecholamine production (25) or a direct action on smooth muscle (26).…”