The effect of inhaled heparin on bronchial reactivity to sodium metabisulphite and methacholine in patients with asthma

Abstract

Inhaled heparin inhibits the early response to allergen and exerciseinduced asthma, probably by inhibiting mast cell mediator release. Recent animal studies suggest that heparin might also inhibit cholinergic neurotransmission in asthma by restoring inhibitory M 2 receptor function. We have tested the hypothesis that heparin inhibits neurally-mediated bronchoconstriction in asthma by examining the effect of inhaled heparin on bronchial reactivity to sodium metabisulphite. We also examined the effect of inhaled heparin on methacholine-induced bronchoconstriction to exclude a direct effect on airway smooth muscle.Eleven patients with mild asthma inhaled nebulized heparin (1,000 U·kg -1 ) or placebo (normal saline) in a randomized, double-blind fashion, 10 min before a challenge with sodium metabisulphite. Nine patients were also challenged with methacholine after the same dose of heparin or placebo.Inhaled heparin did not significantly change forced expiratory volume in one second (FEV1), nor did it alter the provocative dose of sodium metabisulphite or methacholine required to cause a 20% fall in FEV1 (PD20). Geometric mean sodium metabisulphite PD20 was 2.54 and 2.15 µmol after placebo and heparin, respectively (mean difference -0.24 doubling doses; 95% confidence interval (95% CI) -0.64-0.17). Geometric mean methacholine PD20 was 1.00 and 1.51 µmol after placebo and heparin, respectively (mean difference 0.6 doubling doses; 95% CI -0.25-1.5).Thus, heparin inhaled at doses sufficient to inhibit allergen and exercise-induced bronchoconstriction has no effect on the response to sodium metabisulphite and methacholine challenge in asthma. This argues against an inhibitory effect on neural pathways or airway smooth muscle. Eur Respir J., 1996, 9, 217- Inhaled heparin has been shown to inhibit both the early response to allergen and exercise-induced bronchoconstriction in subjects with asthma [1, 2]. The mechanism of action is unclear, although studies on isolated human mast cells in vitro suggest that heparin inhibits mast cell mediator release [3,4]. The inhibitory effect of heparin in the airway might extend to neural pathways, since animal studies show that heparin reverses allergen-induced inhibitory M 2 receptor dysfunction [5].The function of the M 2 inhibitory receptor function is impaired in asthma and this may be partly responsible for bronchial hyperreactivity to irritant stimuli, such as sulphur dioxide and sodium metabisulphite [6]. We have tested the hypothesis that heparin restores M 2 autoreceptor function and, thus, inhibits cholinergic neurotransmission in asthma by examining the effect of inhaled heparin on sodium metabisulphite-induced bronchoconstriction. We also examined the effect of inhaled heparin on methacholine-induced bronchoconstriction to exclude a direct effect on airway smooth muscle. Methods SubjectsEleven subjects (8 males and 3 females) with mild stable asthma but no other important illnesses were recruited from the City Hospital asthma register. Subjects were nonsmokers, w...

Heparin, Derived from the Mast Cells of Human Lungs Is Responsible for the Generation of Kinins in Allergic Reactions due to the Activation of the Contact System

“…It was found that mainly heparin of low MW modifies the antigen–induced airway response and that heparin of ultra low MW is the most effective fraction in the prevention of allergic bronchoconstriction and airway hyperresponsiveness [33, 34, 35]. An influence on immunologically active cells, such as mast cells, basophils, eosinophils, endothelial cells, cell migration, as well as IL–4, IL–5 and TNF–α has also been described.…”

Asthma and coagulation

“…100 Of note, however, trials of inhaled heparin on the bronchoconstrictive response to methacholine have yielded mixed results. 101,102 Bleeding complications have not been reported after inhalation of heparin. At present, inhaled heparin is not used in clinical practice as adjunctive therapy for asthma attacks.…”

Effect of inhaled heparin on lung function and coagulation in healthy volunteers

“…The effects of inhaled heparin on bronchial asthma have been the subject of several studies [1][2][3][4][5][6][7] because heparin possesses anti-inflammatory properties. Results from these studies have been inconsistent, possibly because of the administration of different and unquantified doses of heparin to the lower respiratory tract (LRT).…”

“…In addition, the output from jet nebulizers is often overestimated due to evaporative water loss during nebulization [9], leading to smaller amounts of drug deposited in the LRT than expected. Furthermore, different groups of patients have been studied and the effects of heparin have been assessed using different methods of provocation, such as exercise, allergens, histamine, methacholine, adenosine, adenosine monophosphate (AMP) and metabisulphite [1][2][3][4][5][6][7], making comparisons difficult.…”