SODIUM METABISULFITE AND CITRIC-ACID INDUCE BRONCHOCONSTRICTION VIA ASULFITE-SENSITIVE PATHWAY IN THE ISOLATED GUINEA-PIG LUNG

Inhalation of sodium metabisulfite (MBS; 80 mM; pH 2.9 +/- 0.1) or cit ric acid (CA; 0.4 M; pH 2.0 +/- 0.1) aerosols induced a reduction in c ompliance and conductance in the isolated perfused and ventilated guin ea pig lung without affecting perfusion flow. The effect was dependent on the pH of the nebulized solution since inhalation of 80 mM MBS aer osols at pH 7.4 did not induce any effect on bronchial tone. Concomita ntly to the bronchoconstriction induced by MBS or CA an increased leve l of calcitonin gene-related peptide (CGRP-LI) in the effluent perfusa te was observed, indicating activation of sensory nerves, Sodium sulfi te, a dissolution product of MBS, has previously been shown by our stu dies to reduce bronchoconstriction induced by inhalation of sulfur dio xide, in the isolated perfused and ventilated guinea pig lung. In the present study perfusion of the lung with sodium sulfite (3 mM) before and during exposure to aerosols with either MBS or CA attenuated the b ronchoconstriction induced by the acidic solutions. The release of CGR P-LI induced by MBS or CA was not affected by sodium sulfite. Sulfite treatment did not modify perfused guinea pig lung reactivity towards a cetylcholine (4 nmol), bradykinin (100 pmol), histamine (10 nmol), ser otonin (500 pmol) and substance P fragment 5-11, a substance P analogu e resistant to degrading enzyme (500 pmol). However, an inhibitory eff ect by sodium sulfite was observed on bronchoconstriction induced by t he NK-2 agonist neurokinin A fragment 4-10 (NKA 4-10, 25 pmol). These results indicate that MBS- or CA-induced bronchoconstriction was depen dent on the low pH of the aerosol solution and coincided with activati on of sensory nerves. Sulfite modulation of the bronchoconstricting ac tion of inhaled MBS and CA is suggested to be related to a sulfite-sen sitive step in the signal transduction of the neuropeptide NKA.