Effects of neurokinin receptor antagonists in virus-infected airways

We investigated the effects of a neurokinin-1 (NK(1)) receptor antagonist (SR-140333) and a NK(2) receptor antagonist (SR-48968) on airway responsiveness and on the function of neuronal M(2) muscarinic receptors, which normally inhibit vagal acetylcholine release, in guinea pigs infected with parainfluenza virus. Antagonists were given 1 h before infection and daily thereafter. Four days later, bronchoconstriction induced by either intravenous histamine (which is partly vagally mediated) or electrical stimulation of the vagus nerves was increased by viral infection compared with control. In addition, the ability of the muscarinic agonist pilocarpine to inhibit vagally induced bronchoconstriction was lost in virus-infected animals, demonstrating loss of neuronal M(2) receptor function. Macrophage influx into the lungs was inhibited by pretreatment with both antagonists. However, only the NK(1) receptor antagonist prevented M(2) receptor dysfunction and inhibited hyperresponsiveness (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 NK(1) receptor antagonist, but not by a NK(2) receptor antagonist, whereas both antagonists had similar anti-inflammatory effects.