Inhibition of Hypertonic Saline-induced Bronchoconstriction by Terfenadine and Flurbiprofen: Evidence for the Predominant Role of Histamine

Abstract

We investigated the possible inhibitory effects of terfenadine, a histamine H1-receptor antagonist, and flurbiprofen, a cyclooxygenase inhibitor, on the bronchoconstrictor effect of inhaled 3.6% hypertonic saline in a randomized, double-blind study. Nine mildly asthmatic subjects with a history of exercise-induced asthma took part. This was conducted, first as a dose-response study and, second, as a time-course study. In the dose-response study, the provocative dose of saline-laden air causing a 25% fall in FEV1 was calculated (PD25). Terfenadine (180 mg) and the combination of terfenadine (180 mg) plus flurbiprofen (100 mg) both protected significantly against hypertonic saline challenge, achieving increases in PD25 values by factors of 7.24 and 6.30, respectively. Flurbiprofen (100 mg) also displaced the dose-response to the right, increasing the PD25 by a factor of 1.92, but this protection was significantly less than that afforded by terfenadine. In the time-course studies, a single inhalation of hypertonic saline previously shown to cause at least a 25% fall in FEV1 was administered, and FEV1, was followed for 30 min. Preadministration of terfenadine reduced the mean area under the curve of percentage fall in FEV1-time response by 68.5%, with similar results obtained with the combination of terfenadine and flurbiprofen. We conclude that the bronchoconstriction in asthma provoked by inhaled hypertonic saline is mediated predominantly through the hyperosmolar release of histamine from airway mast cells, with a minor contribution being made by prostanoids.

Dry air- and hypertonic aerosol-induced bronchoconstriction and cellular responses in the canine lung periphery

“…In contrast, aerosolized indomethacin was reported to inhibit ultrasonically nebulized distilled water (UNDW)-induced airway obstruction in asthmatic subjects [40]. Our results are consistent with those of FINNERTY and co-workers [35], who concluded that prostaglandins played a minor role in the development of HIB in subjects with asthma. The fact that indomethacin does protect against UNDW but does not attenuate responses to hypertonic aerosols suggests that these two stimuli operate via different pathways.…”

“…Although mediator release has been implicated in AIB [12,19,21,33] and HIB [34][35][36], the role of biochemical mediators in the initiation of these responses remains controversial. The protection provided by antihistamines [19,34,35], mast cell "stabilizers" [36], cyclooxygenase inhibitors [11,19], and leukotriene receptor antagonists [21,37,38] suggest at least a partial role for these mediators in the development of AIB and HIB.…”

“…The protection provided by antihistamines [19,34,35], mast cell "stabilizers" [36], cyclooxygenase inhibitors [11,19], and leukotriene receptor antagonists [21,37,38] suggest at least a partial role for these mediators in the development of AIB and HIB. In this study, although leukotrienes were not elevated in BAL after challenge with either dry air or 14.4% NaCl, MK-0591, a leukotriene biosynthesis inhibitor, significantly attenuated AIB in dogs [20].…”

Montelukast attenuates the airway response to hypertonic saline in moderate-to-severe COPD

“…Besides the inability of a b 2 -agonist to afford complete protection, little is known about the protective measures against the effects of hypertonic saline in COPD. In contrast, studies in patients with asthma have revealed significant protection by different types of drugs, such as antihistamines and nedocromil, suggesting mast cell activation and neural pathways as potential mechanisms [7][8][9].…”

Models and mechanisms of exercise-induced asthma

“…Most but not all studies of asthmatic subjects implicate a role for histamine in AIB (table 1). Terfenadine inhibits AIB [102] and HAIB [146] similarly. Studies of allergic rabbits also implicate a role for histamine in AIB (table 1).…”