Inhaled transmembrane ion transport modulators and non-steroidal anti-inflammatory drugs in asthma.

Several stimuli which aVect the osmolarity of airway surface liquid may induce bronchoconstriction in asthmatic subjects, indicating that in these patients the control of the bronchial calibre is aVected by the physicochemical characteristics of the airways lining fluid. In the last few years this hypothesis has been confirmed using a number of drugs which are known to aVect cellular ion transport. Loop diuretics inhibit the bronchial obstructive response to ultrasonically nebulised distilled water (UNW) in a dose dependent fashion. It is still unclear, however, whether this protective activity is attributable to the main pharmacological activity of frusemide—the inhibition of the Cl/ Na/K co-transport—since loop diuretics far more potent than frusemide on this mechanism, such as piretanide, torasemide or bumetanide, are markedly less eVective than frusemide in preventing UNW induced bronchoconstriction when given by inhalation in equipotent diuretic doses (fig 1). In addition to UNW, frusemide was also found to be eVective in reducing the bronchoconstriction induced by a variety of “indirect” stimuli including exercise, allergens, hyperosmotic aerosols, metabisulphite, and aspirin. 5 The natriuretic activity of frusemide is known to be partially inhibited by cyclooxygenase (COX) inhibitors, and a single study found a complete abrogation of the protective eVect of frusemide against exercise induced asthma after oral treatment with indomethacin. However, when we investigated whether aspirin like drugs would aVect the bronchoprotective activity of this drug, we found that inhalation of lysine-aspirin had a potentiating—rather than an inhibitory—eVect on the protective activity of inhaled frusemide against UNW induced bronchoconstriction. Inhaled sodium salicylate had no eVect, suggesting that this activity could be due to COX inhibition. In further experiments we confirmed that inhaled COX inhibitors failed to abrogate the protective activity of frusemide against other stimuli such as allergen or exercise. 5 Similarly, inhalation of lysineaspirin failed to inhibit the protective eVect of torasemide or of bumetanide against UNW induced bronchoconstriction. Furthermore, oral treatment with COX inhibitors failed to inhibit the protective activity of frusemide against bronchoconstriction induced by exercise, metabisulphite, UNW, 5 and hypertonic saline. These observations, together with the lack of evidence that frusemide is able to induce production of prostaglandin E (PGE) by human epithelial cells, strongly argue against a role for prostaglandins in the protective activity of frusemide against bronchoconstriction. Nevertheless, aspirin like drugs are clearly able to aVect airway responses, as shown by their ability to precipitate asthma attacks in sensitive patients or to attenuate the response to a variety of stimuli. Some of these activities, such as the protective activity against the early asthmatic response to allergen challenge, appear to be unrelated to their anti-COX potency. On the other hand, their ability to induce bronchoconstriction in aspirin sensitive patients is related mostly to their anti-COX-1 activity, since aspirin like drugs with prevalent anti-COX-2 activity such as carprofen, nimesulide, and meloxicam are relatively well tolerated by aspirin sensitive patients. Chromones, which have been known for a long time for their protective activity against bronchoconstriction induced by a variety of stimuli, have recently been shown to inhibit chloride channels in vitro. This observation, together with the strong similarity in the spectrum of bronchoconstrictor stimuli against which frusemide and chromones exert their protective eVect, suggest that these drugs may act through a similar mechanism related to ion transport regulation. Inhalation of lysineaspirin also failed to inhibit the protective activity of disodium cromoglycate, although it was not found to have a potentiating eVect as observed with frusemide. Figure 1 Protective eVect against UNW induced bronchoconstriction of increasing doses of inhaled frusemide, administered from a pressurised metered canister (5 mg/puV) and piretanide administered through a jet nebuliser. Data are expressed as the percentage protection attained in the same patient using an optimal dose of 40 mg frusemide through a jet nebuliser. Values are mean (SE) of 8–12 asthmatic patients. Frusemide Piretanide