Double-stranded RNA causes airway hyperreactivity and neuronal M₂ muscarinic receptor dysfunction

Viral infection causes dysfunction of inhibitory M₂ muscarinic receptors (M₂Rs) on parasympathetic nerves, leading to airway hyperreactivity. The mechanisms of M₂R dysfunction are incompletely understood. Double-stranded RNA (dsRNA), a product of viral replication, promotes the expression of interferons. Interferon-γ decreases M₂R gene expression in cultured airway parasympathetic neurons. In this study, guinea pigs were treated with dsRNA (1 mg/kg ip) on 2 consecutive days. Twenty-four hours later, anesthetized guinea pigs had dysfunctional M₂Rs and were hyperresponsive to electrical stimulation of the vagus nerves, in the absence of inflammation. DsRNA did not affect either cholinesterase or the function of postjunctional M₃ muscarinic receptors on smooth muscle. M₂Rs on the nerves supplying the heart were also dysfunctional, but M₂Rs on the heart muscle itself functioned normally. Thus dsRNA causes increased bronchoconstriction and bradycardia via increased release of ACh from the vagus nerves because of loss of M₂R function on parasympathetic nerves in the lungs and heart. Production of dsRNA may be a mechanism by which viruses cause dysfunction of neuronal M₂Rs and airway hyperreactivity.