Effects of neurokinin receptor antagonists in virus-infected airways

We investigated the effects of a neurokinin-1 (NK1) receptor antagonist (SR -140333) and a NK2 receptor antagonist (SR-48968) on airway responsiveness and on the function of neuronal M-2 muscarinic receptors, which normally in hibit vagal acetylcholine release, in guinea pigs infected with parainfluen za virus. Antagonists were given 1 h before infection and daily thereafter. Four days later, bronchoconstriction induced by either intravenous histami ne (which is partly vagally mediated) or electrical stimulation of the vagu s nerves was increased by viral infection compared with control. In additio n, the ability of the muscarinic agonist pilocarpine to inhibit vagally ind uced bronchoconstriction was lost in virus-infected animals, demonstrating loss of neuronal M-2 receptor function. Macrophage influx into the lungs wa s inhibited by pretreatment with both antagonists. However, only the NK1 re ceptor antagonist prevented M-2 receptor dysfunction and inhibited hyperres ponsiveness (measured as an increase in either vagally induced or histamine -induced bronchoconstriction). Thus virus-induced M-2 receptor dysfunction and hyperresponsiveness are prevented by a NK1 receptor antagonist, but not by a NK2 receptor antagonist, whereas both antagonists had similar anti-in flammatory effects.