The effects of indomethacin on refractoriness following exercise both with and without a bronchoconstrictor response

Abstract

T Th he e e ef ff fe ec ct ts s o of f i in nd do om me et th ha ac ci in n o on n r re ef fr ra ac ct to or ri in ne es ss s f fo ol ll lo ow wi in ng g e ex xe er rc ci is se e b bo ot th h w wi it th h a an nd d w wi it th ho ou ut t a a b br ro on nc ch ho oc co on ns st tr ri ic ct to or r r re es sp po on ns se e ABSTRACT: Repeated exercise tests demonstrate refractoriness to the development of exercise-induced asthma (EIA). It is unclear whether it is the initial exercise per se or the resulting bronchoconstriction that causes the attenuated response to the second exercise challenge. This study was designed to determine whether the reported blocking of the refractory period by indomethacin requires a significant bronchoconstriction following the primary exercise challenge.Thirteen asthmatic teenagers (aged 12-16 yrs) were tested on four visits. Each visit included two 7 min treadmill exercise challenges at 80% maximum heart rate, separated by a 30 min rest. Conditions for the second exercise challenge (Ch2) were always thermoneutral (20-22°C and 25-35% relative humidity (RH); whilst challenge one (Ch1) was completed twice in thermoneutral and twice in warm-humid breathing conditions (33-35°C and 90-95% RH). A pretreatment for 3 days in a double-blind design with either placebo or indomethacin was completed. Forced expiratory volume in one second (FEV 1 ) was measured before and repeatedly following each challenge. The % fall in FEV 1 following Ch1 of the placebo thermoneutral trial was taken as reference. "Percent protection" at each visit was expressed as the decrease in EIA following Ch2, compared to reference.Warm-humid breathing reduced the EIA post Ch1 by 75%, whilst providing similar protection to thermoneutral conditions. Indomethacin had no significant effect on EIA after Ch1, but reduced "percent protection" for both warm-humid (from 67 to 16%) and thermoneutral (from 70 to 26%) conditions.The data indicate that inhibitory prostaglandins play a major role in EIA refractoriness and suggest that the release of these prostaglandins is initiated by some exercise factor, independent of the development of bronchoconstriction.

Pre-Exercise Hyperpnea Attenuates Exercise-Induced Bronchoconstriction Without Affecting Performance

“…In fact, pre-treatment with COX-inhibitors (e.g. indomethacine) significantly abolished refractoriness to repeated physical exercise, independent of intensity or the condition of inspired air [17,33]. No such inhibitor-induced suppression was observed in a study with repeated hyperpnea challenges [34], suggesting that exercise per se and not the level of ventilation might trigger release of protective PGs.…”

“…Interestingly, one study showed that exercising with warm and humid air did not induce substantial EIB but this exercise was still effective in preventing EIB in the following exercise challenge [17]. From a practical point of view, however, warm-up exercise using warm and humid air is a technically challenging approach.…”

Urinary excretion of lipid mediators in response to repeated eucapnic voluntary hyperpnea in asthmatic subjects

“…The observation that pretreatment with inhalation of PGE 2 has been shown to inhibit the response to exercise challenge (25), as well as the inhibiting effect of nonsteroidal antiinflammatory drug pretreatment on the development of refractoriness (24,26,36), has led to the speculation that PGE 2 is the key mediator of refractoriness. However, there are no previous reports on increased excretion of PGE 2 following exercise challenge in asthmatic subjects, rather a decrease in the levels of PGE 2 has been seen in induced sputum (13).…”

“…This finding suggested a decreased responsiveness to the released mediators at the level of the airway smooth muscle as one possible mechanism in refractoriness (21,22). Because nonsteroidal anti-inflammatory drugs almost completely abolish refractoriness (26), it has been proposed that PGE 2 may be of importance for the development of refractoriness (24,26,36). How-ever, there is to date no direct evidence for release of PGE 2 in vivo during the refractory period.…”

Controversies and challenges of exercise-induced bronchoconstriction and their implications for children

“…48 This may be related to the endogenous production of prostaglandin-2, which actively relaxes airway smooth muscle. 49 Data from studies of vitamin C supplements have demonstrated that patients with asthma have decreased levels of ascorbic acid in their leukocytes. In a study of 20 asthmatic patients with EIB (mean age 13.8 years), each received 2 g of ascorbic acid 1 hour before exercise.…”